A Randomized, Double-blind, Placebo-controlled, Multicenter Phase IIa Clinical Study to Evaluate Safety and to Explore Efficacy of N-Rephasin® SAL200, in Patients With Persistent Staphylococcus Aureus Bacteremia
Phase: PHASE2
Conditions: Staphylococcus Aureus Bacteremia, Anti-Bacterial Agents
Sponsor: Intron Biotechnology, Inc.

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Protocol 
 
Study Title: 
筯族磲壊橒勦櫖 汞穢 滆暓昷 勦笎溣 筞沖櫖昢 N-Rephasin⡶ SAL200汞 橎洊
昷 磏儆 愕 氦箮昷汊 痖族穞匶 氊穢 怺沗氊愶洛, 決渗 圎儆廂, 稒岂柢懺-堆
浶, 埪匶分 洊匶 2旇 沊旇柢竞 
 
A randomized, double-blind, placebo-controlled, multicenter phase IIa clinical 
study to evaluate safety and to explore efficacy of N-Rephasin⡶ SAL200 in 
patients with persistent Staphylococcus aureus bacteremia 
 
 
 
 
Protocol No. ITB-101 
Version No. 2.1 
Version Date 05/09/2019 
 
 
 
 
 
iNtRON Biotechnology, Inc. 
 
 
Confidentiality Information 
The information contained in this protocol is owned by iNtRON Biotechnology, Inc., and therefore, it is provided to 
the investigator and the Institutional Review Board (IRB) confidentially.  
This document should not be disclosed to others without the written agreement of iNtRON Biotechnology, Inc., and 
the exception is when it is necessary to obtain consent from the subject. 
 

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Signature 
 
 
 
Sponsor of the Clinical Study Protocol [ITB-101 / ver 2.1] 
 
iNtRON Biotechnology, Inc. 
Seong Jun Yoon, Chief Executive Officer 
 
 
 
Signature:  
 
Date:  
 
 
 
 
As I have read and understood all the information in this protocol, I hereby sign at the bottom. 
In addition, I agree with the information specified in this protocol and agree to conduct the clinical study as specified 
in the protocol. I hereby confirm that I will conduct this clinical study in accordance with all relevant regulations 
applicable to the Korea Good Clinical Practice (KGCP) and ICH Good Clinical Practice (GCP). I will fulfill my major 
responsibilities as an investigator in accordance with the Declaration of Helsinki and the Institutional Review Board 
(IRB) regulations, and fulfill my responsibilities towards the sponsor and contract representative. 
 
 
 
Investigator of the Clinical Study Protocol [ITB-101 / ver 2.1] 
 
Name of the study site:  
 
Principal investigator:  
 
 
 
 
Signature: 
 
Date:  
 
 
 
 

Protocol No. ITB-101 
  
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೐ Definitions of Terms and Abbreviations 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
CPK 
Creatine Phosphokinase 
CRF 
Case Report Form 
ECG 
Electrocardiogram 
(K)GCP 
(Korea) Good Clinical Practice 
HED 
Human Equivalent Dose 
IBW 
Ideal Body Weight 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IRB 
Institutional Review Board 
LDH 
Lactate Dehydrogenase 
LLOQ 
Lower Limit of Quantification 
MRSD 
Maximum Recommended Starting Dose 
NAS 
Network-Attached Storage 
NCE 
New Chemical Entity 
NOAEL 
No-Observed-Adverse-Effect Level 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time 
RBC 
Red Blood Cell 
SBP 
Systolic Blood Pressure 
tmax 
Time to reach the maximum concentration (Cmax) after a single dose 
WBC 
White Blood Cell 
MSSA 
Methicillin-sensitive Staphylococcus aureus 
MRSA 
Methicillin-resistant Staphylococcus aureus  

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೐ Protocol Synopsis  
 
Study title 
筯族磲壊橒勦櫖 汞穢 滆暓昷 勦笎溣 筞沖櫖昢 N-Rephasin⡶ SAL200汞 橎洊昷 
磏儆 愕 氦箮昷汊 痖族穞匶 氊穢 怺沗氊愶洛, 決渗 圎儆廂, 稒岂柢懺-堆浶, 
埪匶分 洊匶 2旇 沊旇柢竞 
 
A randomized, double-blind, placebo-controlled, multicenter phase IIa clinical study to 
evaluate safety and to explore efficacy of N-Rephasin⡶ SAL200 in patients with persistent 
Staphylococcus aureus bacteremia 
Sponsor 
iNtRON Biotechnology, Inc. 
Study drug 
N-Rephasin⡶ SAL200 
Study sites 
2 sites in total 
• 
Seoul National University Bundang Hospital (Professor Hong Bin Kim, Division of 
Infectious Diseases) 
• 
Seoul National University Hospital (Professor Wan Beom Park, Division of Infectious 
Diseases) 
Clinical study 
objective 
To evaluate the safety and explore the efficacy after a single intravenous administration of 
N-Rephasin⡶ SAL200 (3 mg/kg) in addition to a conventional standard treatment for 
persistent Staphylococcus aureus bacteremia in S. aureus bacteremia patients whose S. 
aureus bacteremia lasts for 48 hours or longer despite antibiotic treatment to which S. 
aureus is susceptible. 
Phase and 
design 
Phase IIa, randomized, double-blind, placebo-controlled, multicenter clinical study 
Target patients 
Patients whose S. aureus bacteremia lasts even after 48 hours from the time when 
treatment using a susceptible antibiotic was started despite antibiotic treatment to which 
S. aureus is susceptible 
Number of 
subjects 
50 subjects in total: 25 subjects in each group (including a dropout rate of approximately 
20%) 
 
Arms 
Sample size 
Drug regimen 
Control group 
n=25 
Conventional standard of care + placebo 
Study group 
n=25 
Conventional standard of care + N-Rephasin⡶ 
SAL200 

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Clinical study 
duration 
36 months from the date of the approval for the clinical study plan by the IRB 
Method of 
administration 
of the 
investigational 
product 
Investigational product 
Active ingredient 
Method of administration 
Study drug 
N-Rephasin⡶ SAL200 
SAL200 
(SAL-1 18 mg/mL) 
A single intravenous injection of the 
study drug in addition to a standard 
treatment 
Placebo 
Remaining formulation 
buffer excluding the 
active ingredient of 
the study drug 
A single intravenous injection of the 
placebo in addition to a standard 
treatment 
 
Subject 
eligibility 
X Inclusion criteria 
 
1) Those with MSSA/MRSA bacteremia who are confirmed to have more than a pair of 
Gram-positive bacteria in a blood culture performed at 48–96 hours after the start of 
antibiotic treatment to which S. aureus is susceptible 
2) Males and females aged ≥ 19 years 
3) Those who understand the information in the subject information sheet and received 
the informed consent form 
 
X Exclusion criteria 
 
1) In the cases that an appropriate antibiotic has not been administered within 48 hours 
after the occurrence of bacteremia (the report time point of Department of Laboratory 
Medicine) 
2) In the cases that the Gram-positive strain, identified in a blood culture performed at 
48–96 hours after the start of antibiotic treatment to which S. aureus is susceptible, is 
not the same strain of S. aureus which was cultured when the definite diagnosis of S. 
aureus bacteremia was made 
3) Those who have passed 48 hours after confirmation of persistent S. aureus bacteremia 
through a blood culture performed at 48–96 hours after the start of antibiotic 
treatment to which S. aureus is susceptible 
4) Those who have symptoms of septic shock at the time of acquisition of the informed 
consent form 
³ In the cases that systolic blood pressure is < 90 mmHg or blood pressure is lower 
than usual by ≥ 40 mmHg despite appropriate fluid treatment is given 
³ In the cases that a hypertensor is required to be used to maintain systolic blood 
pressure at ≥ 90 mmHg 
5) Those who are infected with mixed bacterial species 

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6) Those who are hypersensitive to N-Rephasin⡶ SAL200 or have a clinically significant 
hypersensitivity to it or who have a past history thereof 
7) Pregnant or breastfeeding women and women of child-bearing potential (those who 
have a possibility to become pregnant and do not agree to take appropriate 
contraceptive measures during the study period) 
8) Those who participated in other clinical studies within 30 days prior to enrollment as 
subjects 
9) Patients with any conditions that may interfere with study participation or accurate 
evaluation according to the investigator’s judgment 
10) Those who may die within 72 hours due to other serious complications (e.g., cerebral 
infarction) according to the investigator’s judgment 
Study method 
Clinical study process 
 
 
1) Patients whose S. aureus bacteremia lasts for 48 hours or longer even after the 
standard treatment for S. aureus bacteremia  
2) Randomization according to the study site 
3) The control group will receive a single intravenous injection of the placebo in addition 
to the standard treatment for persistent S. aureus bacteremia. 
4) The study group will receive a single intravenous injection of N-Rephasin⡶ SAL200 at 
3 mg/kg in addition to the standard treatment for persistent S. aureus bacteremia. 
5) A blood culture is performed 18 hours (± 6 hours) after administration of N-Rephasin⡶ 
SAL200.  
6) Blood cultures will continue to be performed every 24 hours (± 6 hours) or 48 hours (± 6 
hours) after the time point of the previous blood culture performed until the results of 
the blood culture at 2 consecutive days (e.g., Day 2 and Day 3, or Day 8 and Day 10) are 
confirmed as negative conversions (treatment completion) 
7) Side effects will be observed at the time point of the first blood culture after 
Confirmation of 
persistent 
bacteremia 
N-Rephasinט SAL200 or placebo 
administration 
Susceptible 
antibiotic 
treatment 
initiation 
2nd blood 
culture 
G(+) 
confirmation 
Obtaining an 
informed 
consent form 
Blood culture/determine negative conversion in the 
first blood culture 
Blood culture/determine 2 consecutive negative conversions 
Final confirmation of treatment 
success/failure 
1st blood 
culture 
1st blood culture 
MSSA/MRSA 
confirmation 
Standard of care 
initiation 
Last treatment 
visit 
Follow-up 
Administration of a standard treatment for MSSA/MRSA until confirmation of 
2 consecutive negative conversions 
General examination schedule prior
to obtaining consent 

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administration of N-Rephasin⡶ SAL200 or the placebo and at the time point at intervals 
of 24 hours or 48 hours thereafter 

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Clinical 
evaluation 
X Primary endpoints 
x Safety endpoints 
- Checking on adverse events 
- Laboratory tests 
- Anaphylaxis test, inflammatory cytokine test 
- Physical examination/vital signs 
 
X Secondary endpoints 
x Efficacy Endpoint ①  
- Proportion of patients whose first blood culture performed after administration of 
the investigational product is negative 
x Efficacy Endpoint ②  
-  Proportion of patients who die due to S. aureus bacteremia by Day 14 
x Efficacy Endpoint ③  
-  Proportion of treatment failure of S. aureus bacteremia by Day 14 (if 2 
consecutive negative conversions were not observed in blood cultures performed 
until Day 14)  

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Statistical 
analysis 
X Primary endpoints 
x Safety analysis is performed in the safety set. A distribution table of the number of 
patients who experienced at least one side effect (incidence) and distribution tables 
of the relationship of the investigational product to the reported adverse events 
(distribution tables for severity and the relationship to the drug) will be presented 
for each group (study group, control group) to confirm the safety.  
The results of the laboratory tests, anaphylaxis test, inflammatory cytokine test, and 
vital signs at baseline and the last visit will be summarized as mean values and 
standard deviations, and the changes before and after the treatment within each 
group will be confirmed.  
Categorical data will be divided into normal and abnormal data and summarized as 
frequency and percentage, and the differences before and after treatment within 
each group will be confirmed.  
 
X Secondary endpoints 
x Proportion of patients whose first blood culture performed after administration of 
the investigational product is negative 
- The descriptive statistics for the proportion of patients who are negative in the 
first blood culture after administration of the treatment (the rate of negative 
conversion) will be presented by each treatment group. Whether the rate of 
negative conversion in the study group is superior to that in the control group 
will be evaluated in a descriptive statistical manner.  
 
x Proportion of patients who die due to S. aureus bacteremia at Day 14 after the 
onset of bacteremia (according to the first confirmatory decision of bacteremia) 
-  The descriptive statistics for the rate of mortality due to S. aureus bacteremia 
by Day14 will be presented and evaluated by treatment group.  
 
x Proportion of treatment failure of S. aureus bacteremia by Day 14 (if 2 consecutive 
negative conversions were not observed in blood cultures performed until Day 14) 
-  The descriptive statistics for the treatment failure rate of S. aureus bacteremia 
by Day14 will be presented and evaluated. 
Interim analysis 
• Analysis time point: When 28 or more and 32 or less subjects have terminated 
participation in the clinical study 
• Purpose: Safety assessment (all adverse events occurred during the clinical study period) 
is the main purpose, and efficacy assessment (to present the proportion of each of the 
secondary endpoints and to compare between the treatment group) will be performed as 
well for an exploratory purpose. 
 

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೐ Clinical Study Schedule Table 
 
 
Observation item 
Screening10 
Treatment 
Follow-up11  
D-1 
D112 
D2 
D3~D13 
D14 
4W ± 5d 
Written consent 
√ 
  
  
 
 
  
Checking on the 
inclusion/exclusion criteria 
√ 
  
  
 
 
  
Randomization1 
  
√ 
  
 
 
  
History of illness 
√ 
 
 
 
 
 
Data on demographic statistics 
√ 
 
 
 
 
 
Vital Signs2 
√ 
√2 
√ 
√ 
√ 
( √ ) 
Physical examination3 
√ 
  
√ 
√3 
√ 
( √ ) 
Laboratory 
tests4, 13 
Hematology 
√ 
 
√ 
√4 
√ 
( √ ) 
Blood chemistry 
√ 
 
√ 
√4 
√ 
( √ ) 
Urinalysis 
√ 
 
√ 
√4 
√ 
( √ ) 
Anaphylaxis test5, 13 
 
√ 
√ 
√5 
 
 
Inflammatory cytokine test5, 13 
 
√ 
√ 
√5 
 
 
Pregnancy test6 
√ 
  
 
 
 
( √ ) 
Skin reaction test 
√ 
 
 
 
 
 
Administration of the 
investigational product7 
 
√ 
 
 
 
 
Administration of drugs required 
for concomitant treatments8 
 
√ 
√ 
√ 
√ 
 
Blood culture/evaluation (blood 
collection)9 
  
  
√ 
√9 
√ 
 
Checking on medication 
history/concomitant medications 
√ 
√ 
√ 
√ 
√ 
√ 
Checking on concomitant 
treatments 
 
√ 
√ 
√ 
√ 
√ 
Adverse events 
 
√ 
√ 
√ 
√ 
√ 
1. Subjects who have passed screening will be assigned a subject number via randomization. 
2. Vital signs will be measured once daily during the remaining treatment period except for Day 1 (including screening), 
and they will be measured 12 times at the following time points at Day 1: 
³ 
Before administration of the investigational product (1 time) 
³ 
15 and 30 minutes after initiation of the investigational product administration (2 times) 
³ 
Immediately after the end of the investigational product administration, 30 minutes, 1, 2, 3, 4, 8, 16, and 24 hours 
after the administration (9 times) 
3. Physical examination will be performed at screening and Day 2, and it will be performed at an interval of “once in 2 
days” after Day 2 (Days 4, 6, 8, 10, 12, and 14). It will be performed only until when the results of the blood 
culture/evaluation at 2 consecutive days are confirmed (treatment completion) as negative conversions. 
4. Laboratory tests will be performed at screening and Day 2, and will be performed at Day 7 (± 48 hours) and Day 14 (± 48 
hours) after Day 2. 

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Hematology  
:  
WBC, RBC, Hemoglobin, Platelets 
Blood biochemistry  
:  
Total protein, Albumin, Total bilirubin, AST, ALT, ALP, Total cholesterol, 
Serum creatinine 
Urinalysis  
:  
Protein, Glucose, Blood, Ketones 
5. The anaphylaxis test and inflammatory cytokine test will be performed at Day 1 (before the investigational product 
administration and immediately after the end of the investigational product administration), Day 2, and Day 7 (± 48 
hours). 
Anaphylaxis test  
:  
C3a, C4a, Mast Cell Tryptase  
Inflammatory cytokine test 
:  
IL-1b, IL-2, IL-6, TNF-α 
6. A pregnancy test will be performed as a urine test or a serum hCG test only for women of childbearing potential. 
7. The enrolled subjects will receive administration of the investigational product at Day 1. 
8. Administration of drugs required for concomitant treatment will be among the drugs in “11.7.1 Drugs required for 
concomitant treatments” as determined by the investigator. 
9. Collection of blood samples for blood cultures at Day 2 will be carried out to fulfill 18 hours (± 6 hours) from the 
administration of the investigational product, collection of blood samples for blood cultures at Days 3–8 will be carried 
out to fulfill 24 hours (± 6 hours) from collection of blood samples for blood cultures for the previous time point (once 
daily), and collection of blood samples for blood cultures at Days 8–14 will be carried out to fulfill 48 hours (± 6 hours) 
from collection of blood samples for previous blood cultures (once in 2 days). Collection of blood samples for blood 
cultures will be performed throughout the clinical study period until negative conversions (treatment completion) are 
confirmed at 2 consecutive days. 
10. In the case that a subject has records of the relevant laboratory tests 7 days before screening, patient records may be 
used without performing additional laboratory tests at screening. 
11. The tests for the relevant date will be performed when the subject visits for a follow-up at W4 ± 5 days, and 
concomitant medications, concomitant treatment, and adverse events will be checked via telephone monitoring. In the 
case of the subjects who can visit the hospital as outpatients, vital signs, physical examination, and laboratory tests will 
be performed, and concomitant medications, concomitant treatments, and adverse events will be checked as well.  
12. Subjects who are suitable for the subject eligibility can have procedures for Day −1 and Day 1 simultaneously. 
13. In the case that negative conversions (treatment completion) are confirmed at 2 consecutive days before Day 7, 
laboratory tests, anaphylaxis test and inflammatory cytokine test will be performed additionally. 

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೐ Clinical Study Process 
 
  
Pre-enrollment 
All Subjects: Written consent, screening subjects by the inclusion and 
exclusion criteria, and selection of subjects eligible for the clinical study 
based on the medical history data 
 
Ὅ 
Enrollment 
Randomization 
 
Ὅ 
Study Group 
Study drug treatment group 
(n=25) 
Control drug treatment group 
(n=25) 
 
Ὅ 
Treatment Period 
(D1~D14) 
Clinical and adverse event observation 
(analysis of the efficacy and safety assessment items, discontinuation of 
the study drug administration) 
 
Ὅ 
Follow-up Duration 
(4 week) 
Clinical and adverse event observation 
(safety assessments and confirmation of occurrence of adverse events) 
 
Ὅ 
Clinical Study Report 
Evaluation and analysis of the final result of the clinical study/completion 
of the clinical study report 

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Table of Contents 
 
 
Cover page 
೐ Definitions of Terms and Abbreviations ................................................................................................................. 3 
೐ Protocol Synopsis ................................................................................................................................................... 4 
೐ Clinical Study Schedule Table ................................................................................................................................10 
೐ Clinical Study Process ............................................................................................................................................12 
1. Name and phase of the clinical study.....................................................................................................................17 
2. Name and address of the study site .......................................................................................................................17 
3. Principal investigator of the clinical study ..............................................................................................................17 
4. Independent Data Monitoring Committee (IDMC) .................................................................................................17 
5. Name and address of the sponsor .........................................................................................................................18 
5.1 Name and address of the sponsor ....................................................................................................................18 
5.2 Name and address of the contract research organization .................................................................................18 
6. Objective and background of the clinical study ......................................................................................................18 
6.1 Background of the clinical study .......................................................................................................................18 
6.2 Rationale and objective of the clinical study .....................................................................................................20 
6.2.1 Result of the nonclinical studies on the study drug (N-Rephasin⡶ SAL200) ................................................21 
6.2.2 Result of the Phase 1 clinical study on the study drug (N-Rephasin⡶ SAL200) ...........................................22 
6.3 Clinical design ...................................................................................................................................................22 
6.4 Objective of the clinical study ...........................................................................................................................22 
6.5 Data related to the nonclinical studies .............................................................................................................23 
6.5.1 Data related to the efficacy study ...............................................................................................................23 
6.5.2 Data related to the safety pharmacology study ..........................................................................................24 
6.5.3 Data related to the pharmacokinetic study ................................................................................................25 
6.5.4 Data related to the toxicity studies ............................................................................................................28 
6.6 Data related to the clinical study ......................................................................................................................49 
6.6.1 Data related to the Phase 1 clinical study ...................................................................................................49 
7. Code name of the investigational product, etc. or generic name of the active ingredient, ingredients and their qua
ntities, formulation, etc. ............................................................................................................................................54 
7.1 Investigational product .....................................................................................................................................54 
7.1.1 Study drug ..................................................................................................................................................54 
7.1.2 Placebo .......................................................................................................................................................54 
7.2 Storage method and shelf life ...........................................................................................................................54 
7.3 Packaging and labeling of the investigational product ......................................................................................55 
7.3.1 Packaging ...................................................................................................................................................55 
7.3.2 Labeling ......................................................................................................................................................55 
7.3.3 Management and records of the investigational product ...........................................................................55 
8. Target disease ........................................................................................................................................................56 
9. Criteria for the inclusion and exclusion of subjects, target number of subjects and its rationale ...........................56 

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9.1 Inclusion criteria ...............................................................................................................................................56 
9.2 Exclusion criteria ..............................................................................................................................................56 
9.3 Target number of subjects and its rationale .....................................................................................................58 
10. Duration of the clinical study ...............................................................................................................................58 
11. Methods of the clinical study ...............................................................................................................................59 
11.1 Design of the clinical study .............................................................................................................................59 
11.2 Process of the clinical study ............................................................................................................................59 
11.3 Randomization of subjects ..............................................................................................................................60 
11.4 Dosage and method of administration ...........................................................................................................60 
11.5 Administration period ....................................................................................................................................62 
11.6 Blinding and unblinding ..................................................................................................................................62 
11.7 Concomitant medication administration criteria ............................................................................................62 
11.7.1 Drugs required for concomitant treatments .............................................................................................62 
11.7.2 Medications and treatments allowed to be administered and performed concomitantly ........................63 
11.7.3 Medications and treatments prohibited from being administered and performed concomitantly ...........63 
11.8 Discontinuation of the administration ............................................................................................................63 
12. Observation items, clinical test items, and observation test methods .................................................................64 
12.1 Observation items ..........................................................................................................................................64 
12.1.1 Demographic information ........................................................................................................................64 
12.1.2 Medical history and medication history ...................................................................................................64 
12.1.3 Vital signs .................................................................................................................................................65 
12.1.4 Physical examination ................................................................................................................................65 
12.1.5 Laboratory tests and pregnancy test ........................................................................................................65 
12.1.6 Anaphylaxis test and inflammatory cytokine test .....................................................................................65 
12.1.7 Skin test ....................................................................................................................................................65 
12.1.8 Blood culture/evaluation (blood collection) .............................................................................................66 
12.2 Clinical study schedule ....................................................................................................................................67 
12.3 Visit schedule .................................................................................................................................................69 
12.3.1 Screening (Day −1) ....................................................................................................................................69 
12.3.2 Administration of the investigational product (Day 1) ..............................................................................69 
12.3.3 
Follow-up observation period (Day 2 to Day 14) ...................................................................................70 
12.3.4 Follow-up (W4 ± 5 days) ...........................................................................................................................74 
12.4 Unscheduled visit and hospitalization ............................................................................................................75 
13. Expected side effects and precautions for use .....................................................................................................75 
14. Discontinuation and dropout, and progress and early termination of the clinical study ......................................76 
14.1 Discontinuation and dropout criteria for individual subjects ..........................................................................76 
14.2 Entry from Step 1 to Step 2 .............................................................................................................................77 
14.3 Early termination of the clinical study ............................................................................................................78 
14.4 Replacement of subjects who drop out ..........................................................................................................78 
15. Effectiveness evaluation criteria, and methods of evaluation and interpretation ................................................78 
15.1 Primary endpoints ..........................................................................................................................................78 
15.2 Secondary endpoints ......................................................................................................................................78 
15.3 Statistical analysis methods ............................................................................................................................79 

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15.3.1 Demographic baseline data ......................................................................................................................79 
15.3.2 Primary endpoint analysis method ...........................................................................................................79 
15.3.3 Secondary endpoint analysis methods .....................................................................................................79 
15.4 Statistical analysis sets ...................................................................................................................................80 
15.4.1 Safety set ..................................................................................................................................................80 
15.4.2 FAS (Full Analysis Set) ...............................................................................................................................80 
15.4.3 PP (Per Protocol) ......................................................................................................................................80 
15.5 Issues related to the statistical analysis and method to handle missing data..................................................80 
15.6 Interim analysis ..............................................................................................................................................81 
16. Evaluation criteria for safety including side effects, method of evaluation, and reporting method .....................81 
16.1 Safety evaluation method ..............................................................................................................................81 
16.2 Safety evaluation criteria ................................................................................................................................81 
16.2.1 Definition of an adverse event (AE) ..........................................................................................................81 
16.2.2 Definition of an adverse drug reaction .....................................................................................................82 
16.2.3 Serious adverse event/adverse drug reaction...........................................................................................82 
16.2.4 Unexpected adverse drug reaction ...........................................................................................................83 
16.2.5 Severity of adverse events ........................................................................................................................83 
16.2.6 Causality relationship of adverse events ..................................................................................................83 
16.2.7 Exacerbation of underlying diseases or health condition that is already present ......................................84 
16.3 Observation period .........................................................................................................................................85 
16.4 Safety evaluation set ......................................................................................................................................85 
16.5 Method, frequency, and time to detect adverse events and serious adverse events ......................................85 
16.6 Documentation of adverse events and serious adverse events.......................................................................85 
16.7 Rules for reporting of serious adverse events .................................................................................................86 
16.7.1 Expedited reporting of serious adverse events .........................................................................................86 
16.7.2 Obligations related to serious adverse events ..........................................................................................87 
16.8 Follow-up on adverse events ..........................................................................................................................88 
16.9 Emergency ......................................................................................................................................................88 
17. Informed consent form ........................................................................................................................................88 
18. Subject indemnification policy .............................................................................................................................90 
19. Examination and treatment criteria for subjects after the clinical study ..............................................................90 
20. Measures for protection of the subject safety .....................................................................................................90 
20.1 Study site ........................................................................................................................................................91 
20.2 Principal investigator ......................................................................................................................................91 
20.3 Sub-investigators ............................................................................................................................................91 
20.4 Sponsor ..........................................................................................................................................................91 
21. Other matters required to conduct the clinical study safely and scientifically .....................................................91 
21.1 Approval of the Institutional Review Board (IRB) ...........................................................................................91 
21.2 Approval of the protocol and the protocol amendment .................................................................................92 
21.3 Compliance with the protocol and amendments to the protocol ....................................................................92 
21.4 Protection of subjects .....................................................................................................................................93 
21.5 Monitoring .....................................................................................................................................................93 
21.6 Case report forms ...........................................................................................................................................94 

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21.7 Preservation of records ..................................................................................................................................95 
21.8 Maintaining data and subject records .............................................................................................................96 
21.8.1 Maintaining confidentiality of data ..........................................................................................................96 
21.8.2 Maintaining subject records .....................................................................................................................96 
21.9 Termination of the clinical study ....................................................................................................................96 
21.10 Reporting of early termination or discontinuation of the clinical study ........................................................96 
21.11 Deviation from the protocol .........................................................................................................................97 
21.12 Essential documents .....................................................................................................................................97 
22. Use of the study result .........................................................................................................................................98 
23. Responsibilities ....................................................................................................................................................98 
24. Literature references ......................................................................................................................................... 100 
[Attachment 1] Subject Information Sheet and Informed Consent Form 
[Attachment 2] Indemnification Policy for Victims  

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1. Name and phase of the clinical study 
A randomized, double-blind, placebo-controlled, multicenter phase IIa clinical study to evaluate safety and to 
explore efficacy of N-Rephasin⡶ SAL200 in patients with persistent Staphylococcus aureus bacteremia 
 
 
 
2. Name and address of the study site 
Name of the study site 
Address 
Seoul National University 
Bundang Hospital 
82, Gumi-ro 173beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, 
Republic of Korea 
Seoul National University 
Hospital 
101, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea 
 
 
 
3. Principal investigator of the clinical study 
Name 
Affiliation and title 
Hong Bin Kim 
Professor, Division of Infectious Diseases, Seoul National University Bundang 
Hospital 
Wan Beom Park 
Professor, Division of Infectious Diseases, Seoul National University Hospital 
 
 
 
4. Independent Data Monitoring Committee (IDMC) 
Name 
Affiliation and title 
Dong Gun Lee 
Professor, Department of Infectious Disease, Seoul St. Mary’s Hospital of the 
Catholic University of Korea 
Chung Jong Kim 
Professor, Department of Infectious Diseases, Ewha Womans University Seoul 
Hospital 
Yong Seong Joo 
Professor, Department of Statistics, Dongguk University 
 
 
The IDMC will be established and operated to ensure the safety of the subjects and to implement 
recommendations for the progress, termination, and change of the clinical study. The IDMC will convene meetings 
at predefined time points and other requests to evaluate the safety data.  
The IDMC will have a role to implement interim evaluation of the clinical study, and may evaluate the safety of 
the investigational product and monitor the overall conduct of the study as necessary. The IDMC will complete the 
IDMC charter and will confirm the committee member selection and the meeting schedule prior to opening a 
meeting for the predefined interim evaluation. The IDMC charter includes methods to secure supplementation of 
information, to guarantee appropriate communications, etc.  
In addition, in the case that a serious adverse event such as death occurs, the IDMC may have access to the 
information of the group to which the relevant subject is assigned and evaluate the adverse event, if deemed 
necessary by the sponsor. 

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5. Name and address of the sponsor 
5.1 Name and address of the sponsor 
Company name 
iNtRON Biotechnology, Inc. 
Chief executive officer 
Seong Jun Yoon 
Address 
137, Sagimakgol-ro, Jungwon-gu, Seongnam-si, Gyeonggi-do, 13202, Republic 
of Korea 
Telephone number 
+82-31-739-5352 
Fax number 
+82-31-736-7246 
 
 
5.2 Name and address of the contract research organization  
Company name 
Symyoo Inc. 
Address 
2nd floor, 6, Hannam-daero 42-gil, Yongsan-gu, Seoul, 04417, Republic of Korea 
Telephone number 
+82-70-4335-5468 
Fax number 
+82-2-749-2050 
+82-2-6442-4753 (eFax) 
 
 
6. Objective and background of the clinical study 
6.1 Background of the clinical study  
Bacteremia is a bacterial infectious disease caused by an infection with active bacteria in circulating blood [4]. 
Bacteremia may not have clinical significance since it can also occur as a temporary harmless bacteremia as a result 
of dental treatment or other minor medical procedure, but in the case of serious bacteremia, it can progress to a 
more serious local or systemic infection if proper treatment is not given. Even though most bacteremia resolves, 
serious sequelae are common. Such bacteremia may cause pneumonia, pyogenic arthritis, osteomyelitis, meningitis, 
and cerebral edema, leading to death. 
Staphylococcus aureus, which acts as a primary cause of bacteremia, is a bacterium that is most commonly 
isolated from clinical specimens among gram-positive micrococci, and it is known as a pathogenic organism that 
causes purulent disease, sepsis, encephalomeningitis, and food poisoning clinically, spreads from the nasal cavity or 
skin to other person, causes nosocomial infections such as surgical site infections and pneumonia [1][2]. In addition, 
it is being reported that the chances of getting an infection with a disease by direct contact between the physician 
and the patient through blood, saliva, or medical devices are quite high in dental care. Recently, nosocomial 
infections with Staphylococcus aureus has been steadily increasing, and infections with Staphylococcus aureus make 
treatment of patients more difficult, extend the duration of hospital stay, increase medical costs, and moreover, 
they can be fatal. Therefore, pathogenic infections with Staphylococcus aureus can be important problems [3][4][5]. 
Several antibacterial agents have been designed to treat infectious diseases caused by Staphylococcus aureus, but 
the frequent use of antibiotics has started to isolate bacteria strains resistant to methicillin as well as several other 

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antibacterial agents [6]. 
Methicillin-resistant Staphylococcus aureus (MRSA) was first isolated in the United States in 1968, and 20 to 25% 
of Staphylococcus aureus isolated from hospitalized patients hospitalized in early 1990s were identified as MRSA. 
The rate has been increasing continuously, and according to the National Nosocomial Infection Surveillance System 
(NNIS) in the United States, 50% or more of Staphylococcus aureus isolated from patients in intensive care units in 
1999 and 59.5% or more in 2003 were identified as MRSA [7]. The frequency of MRSA isolation is increasing every 
year and is increasing globally in Europe and the United States as well as Singapore, Japan, Australia, the Republic of 
Korea, etc. recently, and the rate of increase is especially high in the Republic of Korea. The MRSA rate investigated 
in 12 universities and general hospitals in the nation in 2004 was 67%, and it was 86% in patients in intensive care 
units, which was very high [8]. According to preceding overseas studies, antibiotic resistance has been shown to 
cause prolonged hospitalization, expensive treatment replacement, increase in surgery frequency, increase in ICU 
admission, and so on [9].  
 
Persistent bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible 
Staphylococcus aureus (MSSA) occurs in between 6% and 38% of all Staphylococcus aureus bacteremia cases, and 
its clearance median time is between 7 to 9 days. Persistent bacteremia is defined as a condition that bacteremia 
persists for 3 to maximum of 7 days or more, despite appropriate active antibiotic treatment, and it is defined 
somewhat differently depending on the investigators. Its risk factors include sources of the infection (e.g., 
endocarditis or spinal osteomyelitis), pathogenic phenotypes (vancomycin heteroresistance), antibiotic treatment, 
maintenance or presence of prosthetic materials and its capability to remove infection clusters (e.g., surgical 
drainage). MRSA (clearance median time: 8–9 days) persists longer than MSSA (clearance median time: 3 days). 
Such a difference in the persistence between MRSA and MSSA appears to be due to pathogen-specific factors [38]. 
 
Accordingly, the development of a new antibiotic substance is urgent that can lead the public health and the 
pharmaceutical technology and even treat bacteria resistant to conventional antibiotics.  
 
Based on the preceding basic study data mentioned above, iNtRON Biotechnology, Inc. found a part of the gene 
that is directly related to lytic activity from the genome of a bacteriophage, produced and isolated the enzyme 
protein belonging to endolysin from this using molecular biology technology and biotechnology, and named this as 
SAL-1. After formulating this, N-Rephasin⡶ SAL200 has been developed.  
 
Currently, antibiotics such as vancomycin or daptomycin are being used to treat MRSA bacteremia [1], but MRSA 
is often resistant to other antibiotics as well [2], and Staphylococcus aureus resistant to vancomycin or daptomycin 
has already appeared [3][4]. In consideration of these, a new antibacterial substance is needed that has a new 
mechanism, is safer, and has no concerns of developing resistance as well as potent antibacterial activity.  
 
The study drug that has been developed according to such a demand and being used in this clinical study 
(N-Rephasin⡶ SAL200) is an intravenous injection that was developed as a treatment for methicillin-resistant 
Staphylococcus aureus (MRSA) bacteremia and that contains the endolysin SAL-1, a lytic protein derived from the 
bacteriophage SAP-1 which is a microorganism having a specific antibacterial activity against Staphylococcus aureus, 
as an active ingredient. Unlike conventional antibiotics, SAL-1, the active ingredient of the study drug, has an 
antibacterial effect that destroys a specific structure of the peptidoglycan layer in the cell wall of 

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methicillin-resistant and methicillin-non-resistant Staphylococcus aureus, and therefore, it is effective in treatment 
of infectious diseases caused by Staphylococcus aureus and in treatment of infectious diseases caused by 
methicillin-resistant Staphylococcus aureus. 
6.2 Rationale and objective of the clinical study 
The study drug used in this clinical study (N-Rephasin⡶ SAL200) is an intravenous injection that was developed as 
a treatment for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and that contains the endolysin 
SAL-1, a lytic protein derived from the bacteriophage SAP-1 which is a microorganism having a specific antibacterial 
activity against Staphylococcus aureus, as an active ingredient. Unlike conventional antibiotics, SAL-1, the active 
ingredient of the study drug, has an antibacterial effect that destroys a specific structure of the peptidoglycan layer 
in the cell wall of methicillin-resistant and methicillin-non-resistant Staphylococcus aureus, and therefore, it is 
effective in treatment of infectious diseases caused by Staphylococcus aureus and in treatment of infectious 
diseases caused by methicillin-resistant Staphylococcus aureus. 
Currently, antibiotics such as vancomycin or daptomycin are being used to treat MRSA bacteremia [1], but MRSA 
is often resistant to other antibiotics as well [2], and Staphylococcus aureus resistant to vancomycin or daptomycin 
has already appeared [3][4]. In consideration of these, a new antibacterial substance is needed that has a new 
mechanism, is safer, and has no concerns of developing resistance as well as potent antibacterial activity.  
Among bacteriophages that are microorganisms with antibacterial activity by specifically infecting only bacteria, 
only the bacteriophage that specifically affects Staphylococcus aureus (named as SAP-1) was isolated, and the 
genome sequence was obtained from the isolated bacteriophage. Using genetic engineering and biotechnology, an 
endolysin (named as SAL-1), which is an enzyme protein that is directly involved in the lysis of Staphylococcus 
aureus, was produced/purified, and this has been used as an active ingredient to formulate the study drug 
N-Rephasin⡶ SAL200. Bacteriophages induce lysis of host bacteria in order to release offsprings proliferated in 
bacteria after infecting specific bacteria. In this process, two proteins called holin and endolysin are involved. Holins 
form micropores on the cell membrane, and endolysins are released through these micropores, which hydrolyze 
the bond in the peptidoglycan layer of the cell wall, causing the lysis of the host bacteria as a result [5]. In the 
natural world, endolysins are produced from the genetic information of bacteriophages and act inside of the 
bacteria; however, lysis of the bacteria can be induced even if endolysins are produced using a genetic 
recombination technology and treated outside of the cell [6]. Therefore, considering that the conventional 
antibiotic substances has a mechanism that inhibits cell wall synthesis, inhibits protein synthesis, destroys cell 
membranes, or inhibits DNA synthesis, this study drug has a novel mechanism of action that has never been applied 
so far, and therefore, it acts even against bacteria that have acquired resistance to conventional antibiotics 
regardless of their resistance [6].  
The genus Staphylococcus includes many bacterial species, including Staphylococcus aureus and Staphylococcus 
epidermidis. Through the nonclinical efficacy studies on N-Rephasin⡶ SAL200, it has been confirmed that the below 
22 bacterial species in the genus Staphylococcus among the bacterial species belonging to the genus Staphylococcus 
are susceptible to N-Rephasin⡶ SAL200.  

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As described above, it was confirmed that N-Rephasin⡶ SAL200 has antibacterial activity against various species 
that belong to the genus Staphylococcus, but the Phase IIa clinical study is intended to be conducted on 
Staphylococcus aureus among the bacteria that belong to the genus Staphylococcus against which N-Rephasin⡶ 
SAL200 displays antimicrobial activity.  
 
Through preceding nonclinical efficacy studies, it has been confirmed that N-Rephasin⡶ SAL200 has antibacterial 
activity against various Staphylococcus aureus strains, and N-Rephasin⡶ SAL200 also has antibacterial activity 
against MSSA, MRSA, and bacteria resistant to other antibiotics (linezolid, vancomycin, daptomycin, oxacillin, etc.). 
These facts show that N-Rephasin⡶ SAL200 is effective in treating bacteremia caused by Staphylococcus aureus. 
 
6.2.1 Result of the nonclinical studies on the study drug (N-Rephasin⡶ SAL200) 
The peptidoglycan layer, which is the target site of the bacteriophage and its derived lytic protein endolysin, 
does not exist in animal or plant cells, and therefore, according to its mechanism, it does not affect cells in a target 
of treatment for infectious diseases, such as human cells, and only acts on bacteria specifically. As a result of the 
study on the cytotoxicity of SAL-1 against actual animal cells, it was found that there was no effect on the animal 
cells [Table 1]. 
 
[Table 1] Data related to the nonclinical efficacy studies on N-Rephasin⡶ SAL200 
No. 
Title 
Study site 
1 
Evaluation of the efficacy of lysin formulations against Staphylococcus 
aureus 
Kyungpook National University 
School of Medicine 
Department of Microbiology 
2 
Efficacy study on N-Rephasin⡶ SAL200 using mice (efficacy study on 
N-Rephasin⡶ SAL200 against MRSA in mice) 
Orient Genia Inc. 
3 
Basic antibacterial activity of N-Rephasin⡶ SAL200 
iNtRON Biotechnology, Inc. 
Biotechnology Laboratory 
4 
Investigation of the activity of N-Rephasin⡶ SAL200 against S. aureus in 
various conditions 
iNtRON Biotechnology, Inc. 
Biotechnology Laboratory 

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5 
Efficacy study on N-Rephasin⡶ SAL200 in serum (MIC/MBC) 
iNtRON Biotechnology, Inc. 
Biotechnology Laboratory 
6 
Search for antibacterial activity 
Culture Collection of 
Antimicrobial Resistance 
Microbes 
7 
Biofilm removal activity of N-Rephasin⡶ SAL200 
iNtRON Biotechnology, Inc. 
Biotechnology Laboratory 
8 
Study in animals treated with N-Rephasin⡶ SAL200 after inducing 
infection with Staphylococcus aureus 
iNtRON Biotechnology, Inc. 
Biotechnology Laboratory 
9 
Efficacy study on N-Rephasin⡶ SAL200 against Staphylococcus aureus 
which has developed resistance to conventional antibiotics 
BioScience LABORATORIES, 
INC. in the United States 
10 
Study on antibacterial activity of N-Rephasin⡶ SAL200 against 
Staphylococcus genus 
iNtRON Biotechnology, Inc. 
Biotechnology Laboratory 
 
The results of the nonclinical studies on the study drug (N-Rephasin⡶ SAL200) shows promise that the study 
drug will have great efficacy for treatment of MRSA bacteremia in human subjects. 
 
6.2.2 Result of the Phase 1 clinical study on the study drug (N-Rephasin⡶ SAL200) 
The following results were found through the Phase 1 clinical study conducted to evaluate the safety and 
explore the characteristics of pharmacokinetics and pharmacodynamics after the continuous intravenous infusion 
of the study drug (N-Rephasin⡶ SAL200) for 1 hour in healthy male adult volunteers. The continuous intravenous 
infusion of N-Rephasin⡶ SAL200 for 1 hour has excellent tolerability within the dose range of 0.1–3 mg/kg, and it 
showed pharmacokinetic nonlinearity within the dose range of 0.1–10 mg/kg. In the ex vivo pharmacodynamic 
evaluation, methicillin-resistant Staphylococcus aureus was inhibited as the dose increased within the dose range 
of 0.1–10 mg/kg. 
 
 
6.3 Clinical design  
Randomized, double-blind, placebo-controlled, multicenter, Phase IIa clinical study 
 
 
6.4 Objective of the clinical study 
To conduct a Phase IIa clinical study to evaluate the safety and explore the efficacy after a single intravenous 
administration of N-Rephasin⡶ SAL200 (3 mg/kg) in addition to a conventional standard treatment for persistent S. 
aureus bacteremia in S. aureus bacteremia patients whose S. aureus bacteremia lasts for 48 hours or longer 
despite antibiotic treatment to which Staphylococcus aureus is susceptible. 

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6.5 Data related to the nonclinical studies 
The data of the nonclinical studies on the study drug (N-Rephasin⡶ SAL200) are the data related to the efficacy 
study [Table 2.1], the data related to the safety pharmacology study [Table 2.2], the data related to the 
pharmacokinetic study (1) [Table 2.3], the data related to the pharmacokinetic study (2) [Table 2.4], and the data 
related to the toxicity studies [Tables 2.5–2.13] as shown below.  
 
6.5.1 Data related to the efficacy study 
 
[Table 2.1] Data related to the nonclinical efficacy studies on N-Rephasin⡶ SAL200 
No. 
Title 
Study site 
1 
Evaluation 
of 
the 
efficacy 
of 
lysin 
formulations 
against 
Staphylococcus aureus 
Kyungpook National University 
School of Medicine 
Department of Microbiology 
2 
Efficacy study on N-Rephasin⡶ SAL200 using mice (efficacy study 
on N-Rephasin⡶ SAL200 against MRSA in mice) 
Orient Genia Inc. 
3 
Basic antibacterial activity of N-Rephasin⡶ SAL200 
iNtRON Biotechnology, Inc. 
Biotechnology Laboratory 
4 
Investigation of the activity of N-Rephasin⡶ SAL200 against S. 
aureus in various conditions 
iNtRON Biotechnology, Inc. 
Biotechnology Laboratory 
5 
Efficacy study on N-Rephasin⡶ SAL200 in serum (MIC/MBC) 
iNtRON Biotechnology, Inc. 
Biotechnology Laboratory 
6 
Search for antibacterial activity 
Culture Collection of 
Antimicrobial Resistance 
Microbes 
7 
Biofilm removal activity of N-Rephasin⡶ SAL200 
iNtRON Biotechnology, Inc. 
Biotechnology Laboratory 
8 
Study in animals treated with N-Rephasin⡶ SAL200 after inducing 
infection with Staphylococcus aureus 
iNtRON Biotechnology, Inc. 
Biotechnology Laboratory 
9 
Efficacy study on N-Rephasin⡶ SAL200 against Staphylococcus 
aureus which has developed resistance to conventional antibiotics 
BioScience LABORATORIES, INC. 
in the United States 
10 
Study on antibacterial activity of N-Rephasin⡶ SAL200 against 
Staphylococcus genus 
iNtRON Biotechnology, Inc. 
Biotechnology Laboratory 

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6.5.2 Data related to the safety pharmacology study 
 
[Table 2.2] Summary of the data on the safety pharmacology study on N-Rephasin⡶ SAL200 
Test 
item 
Detailed 
item 
Animal 
species, 
strain, 
gender, and 
number of 
animals per 
group 
Route 
of 
applic
ation 
Dose 
adminis
tered 
Test result 
Comp
liance 
with 
GLP 
Study # 
Central 
nervous 
system 
Modified 
Irwin (1964) 
method 
Temperature 
32 each of 
male and 
female SPF 
Crl:CD SD 
rats 
IV  
bolus 
0, 
0.5,  
12.5, 
25 
(mg/kg) 
As a result of measuring at 0.5, 1, 2, 6, 
and 24 hours, no changes in general 
behavior 
and 
temperature 
were 
observed in both male and female 
animals. Therefore, it was determined 
that there is no effect on the central 
nervous system. 
O 
G11044 
Respirat
ory 
system 
Tidal 
volume, 
minute 
respiratory 
volume, and 
respiration 
rate 
32 male SPF 
Crl:CD SD 
rats 
IV  
bolus 
0, 
0.5, 
12.5, 
25 
(mg/kg) 
As a result of measuring the tidal 
volume before the administration and 
at 0.5, 1, 2, 6, and 24 hours after the 
administration, no differences were 
observed at all time points for 
measurement when compared to the 
vehicle control group. There were 
significant increases in the respiratory 
rate at 24 hours in the 0.5 mg/kg 
treatment 
group, 
and 
significant 
increases in the minute respiratory 
volume were observed at 0 hours in 
the 0.5 mg/kg treatment group. Such 
increases were not determined to be 
an effect by the test substance. 
O 
G11045 
Cardiov
ascular 
system 
Blood 
pressure, 
heart rate, 
electrocardi
ogram, and 
general 
symptoms 
4 male 
beagle dogs 
IV  
bolus 
0, 
0.5, 
12.5, 
25 
(mg/kg) 
It 
was 
determined 
that 
the 
cardiovascular system was not affected 
by the dose up to 25 mg/kg when 
administered intravenously twice at an 
interval of a week in beagle dogs. 
When administered 3 times or more 
repeatedly at an interval of a week, 
changes 
were 
observed 
in 
the 
cardiovascular 
system 
that 
were 
determined to be due to immune 
responses. 
O 
G11046 
Whole-cell 
patch-clamp 
CHO cells 
expressing 
hERG 
 
0, 
50, 
200, 
350, 
500 
(mg/mL) 
IC50 > 500 μg/mL  
O 
G11047 

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6.5.3 Data related to the pharmacokinetic study 
 
[Table 2.3] Summary of the data on the pharmacokinetic study (1) 
Study title 
Single-intravenous-dose pharmacokinetic study on N-Rephasin⡶ SAL200 using rats 
Data 
suitability 
□ Data submitted upon approval (approved country) 
□ Specialized academic journal (SCI) 
; Domestic and overseas institutions 
□ GLP 
Study 
objective 
Conducted to confirm pharmacokinetics after intravenous administration of the test 
substance N-Rephasin⡶ SAL200 in rats. 
Study drug 
Target drug 
N-Rephasin⡶ SAL200 
Control 
drug 
Formulation buffer-1 
Details of the 
study 
Test system 
SPF [Crl:CD (SD)] rats 
Study 
method 
1) Composition of the study groups, volume of the solution administered, 
and dose 
Group 
Gender 
Number of 
animals 
(animals) 
Animal 
number 
Volume of 
the solution 
administered 
(mL/kg) 
Dose 
(mg/kg) 
V.C. 
M 
4(3+1) 
1-4 
1.26 
0 
F 
4(3+1) 
45-48 
T1 
M 
10(9+1) 
5-14 
0.02 
0.4 
F 
10(9+1) 
49-58 
T2 
M 
10(9+1) 
15-24 
0.08 
1.6 
F 
10(9+1) 
59-68 
T3 
M 
10(9+1) 
25-34 
0.31 
6.25 
F 
10(9+1) 
69-78 
T4 
M 
10(9+1) 
35-44 
1.26 
25 
F 
10(9+1) 
79-88 
 
2) Observation and test items 
- Observation of general symptoms and dead animals: During the 
acclimation, administration and observation periods, the animals were 
observed once daily for occurrence of general symptoms and death. In the 
case that there were any abnormalities, the severity of symptoms was 
summarized using Parh/Tox System (v. 4.2.2) according to the types of 
symptoms, date of onset, and frequency. 
- Weight measurement: It was performed once each at the time of group 
separation (acquisition) and on the day of the test substance 
administration. 

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Results 
(tabulated 
data, etc.) 
Dose 
(mg/kg) 
Gender 
Kel 
(1/h) 
t1/2 
(h) 
Cmax 
(μg/mL) 
C0  
(μg/mL) 
AUClast 
(μg·h/mL) 
AUCinf 
(μg·h/mL) 
CL 
(mL/h/kg) 
MRTlast  
(h) 
1.6 
Male 
8.138 
0.09 
0.85 
1.25 
0.21 
0.22 
7337.1 
0.13 
 
Female 
3.797 
0.18 
0.25 
0.29 
0.09 
0.10 
15566.5 
0.19 
6.25 
Male 
0.390 
1.78 
14.47 
68.88 
4.85 
5.87 
1064.1 
0.26 
 
Female 
4.197 
0.17 
15.24 
49.09 
4.15 
4.18 
1496.6 
0.13 
25 
Male 
0.645 
1.07 
87.41 
175.57 
30.10 
30.80 
811.7 
0.45 
 Female 
0.397 
1.75 
19.52 
20.89 
15.02 
17.06 
1465.2 
0.93 
 
Conclusion 
and 
review 
comments 
When the test substance N-Rephasin⡶ SAL200 was administered intravenously to rats at a 
single dose of 0.4–25 mg/kg, the systemic exposure (AUCinf) showed a dose-dependent 
increase. In addition, a pattern of bi-exponential decay was observed in the 25 mg/kg 
treatment group in which the completion of a concentration profile over time is easy. There 
was no apparent difference between male and female animals, but the systemic exposure 
was somewhat higher in male animals.  

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[Table 2.4] Summary of the data on the pharmacokinetic study (2) 
Study title 
Single-intravenous-dose pharmacokinetic study on N-Rephasin⡶ SAL200 using beagle dogs 
Data 
suitability 
□ Data submitted upon approval (approved country) 
□ Specialized academic journal (SCI) 
; Domestic and overseas institutions 
□ GLP 
Study 
objective 
Conducted to confirm pharmacokinetics after intravenous administration of the test 
substance N-Rephasin⡶ SAL200 in beagle dogs. 
Study drug 
Target 
drug 
N-Rephasin⡶ SAL200 
Control 
drug 
Formulation buffer-1 
Details of 
the study 
Test 
system 
Canis familiaris (beagle dog) 
Study 
method 
1) Composition of the study groups, volume of the solution administered, and 
dose 
Group 
Gender 
Number of 
animals 
(animals) 
Animal 
number 
Volume of 
the solution 
administered 
(mL/kg) 
Dose 
(mg/kg) 
V.C. 
M 
1 
1 
1.26 
0 
F 
1 
6 
T1 
M 
1 
2 
0.02 
0.4 
F 
1 
7 
T2 
M 
1 
3 
0.08 
1.6 
F 
1 
8 
T3 
M 
1 
4 
0.31 
6.25 
F 
1 
9 
T4 
M 
1 
5 
1.26 
25 
F 
1 
10 
2) Observation and test items 
- Observation of general symptoms and dead animals: During the acclimation, 
administration and observation periods, the animals were observed once daily 
for occurrence of general symptoms and death. In the case that there were any 
abnormalities, the severity of symptoms was summarized using Parh/Tox System 
(v. 4.2.2) according to the types of symptoms, date of onset, and frequency. 
- Weight measurement: It was performed once each at the time of group 
separation (acquisition) and on the day of the test substance administration. 
Results 
(tabulated 
data, etc.) 
Dose 
(mg/kg) 
Gender 
Kel 
(1/h) 
t1/2 
(h) 
Cmax 
(μg/mL) 
C0  
(μg/mL) 
AUClast 
(μg·h/mL) 
AUCinf 
(μg·h/mL) 
CL 
(mL/h/kg) 
MRTlast  
(h) 
6.25 
Male 
0.132 
5.25 
0.75 
1.99 
0.36 
2.16 
2894.4 
0.37 
 Female 
1.151 
0.60 
1.12 
3.44 
0.45 
0.61 
10234.1 
0.31 
25 
Male 
0.505 
1.37 
18.57 
134.15 
10.71 
11.61 
2152.7 
0.73 
 Female 
0.639 
1.08 
17.93 
27.15 
9.71 
10.25 
2440.1 
0.79 
 

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Conclusion 
and review 
comments 
When a single dose of the test substance N-Rephasin⡶ SAL200 was administered 
intravenously to beagle dogs, the systemic exposure (AUClast) of N-Rephasin⡶ SAL200 showed 
a dose-dependent increase, and there was no apparent difference between the male and 
female animals. Additionally, the elimination half-life of the test substance in the 25 mg/kg 
treatment group was 1.1–1.4 hours, and therefore, it is thought to be eliminated from the 
body within a relatively short time. 
 
 
6.5.4 Data related to the toxicity studies 
The data on the toxicity studies on the study drug (N-Rephasin⡶ SAL200) are the summary of the data on the 
single-dose toxicity study in rats [Table 2.5], the summary of the data on the 2-week DRF toxicity study in rats [Table 
2.6], the summary of the data on the 4-week repeat-dose toxicity study in rats [Table 2.7], the summary of the data 
on the 2-week DRF toxicity study in beagle dogs [Table 2.8], the summary of the data on the 2-week repeat-dose 
toxicity study in beagle dogs [Table 2.9], the summary of the data on other toxicity studies (1) [Table 2.10], the 
summary of the data on other toxicity studies (2) [Table 2.11], the summary of the data on the DES toxicity study in 
monkeys [Table 2.12], and the summary of the data on the 5-day repeat-dose toxicity study in monkeys [Table 2.13] 
as shown below. 
 
[Table 2.5] Summary of the data on the single-dose toxicity study in rats 
Study title 
Single-intravenous-dose toxicity study on N-Rephasin⡶ SAL200 using rats 
Compliance 
with GLP 
; Yes □ No 
□ Performed before 01/01/2003 □ Documents submitted upon approval 
; Domestic and overseas specialized institutions 
Test substance 
(substance 
name) 
N-Rephasin⡶ SAL200 
Study No. 
G11039 
Test animals 
Species 
□ Mice ; Rats □ Beagle dogs □ Monkeys □ Others (rabbits, guinea pigs) 
Strain 
Crl:CD(SD) 
Route of 
administration 
□ Oral □ Subcutaneous ; Intravenous □ Intraperitoneal □ Intramuscular 
□ Others (percutaneous, inhalation) 
Administration 
period 
(observation 
period) 
Single dose (observation for 15 days) 
Dosage form 
; Solution □ Suspension □ colloid 
Dose (mL/kg) 
5 each of male and female animals per group, 5.4(vehicle control), 1.35, 2.7, and 5.4 mL/kg 
for each test group 
Details of the 
test 
Test group 
T1 
T2 
T3 
Vehicle control 
Concentration 
administered 
(mL/kg) 
1.35 
(25.11 mg/kg) 
2.7 
(50.22 mg/kg) 
5.4 
(100.44 mg/kg) 
5.4 
(0 mg/kg) 
Test animals 
(M/F) 
M 
F 
M 
F 
M 
F 
M 
F 
Number of 
5 
5 
5 
5 
5 
5 
5 
5 

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animals per group 
Reviewer’s 
comments 
(test results) 
(1) Dead animals 
No dead animals were observed in male and female animals in all study groups during the 
study period. 
(2) General symptoms 
No adverse events related to the test substance administration were observed in male and 
female animals in all study groups during the study period. 
(3) Weight changes 
No weight changes related to the test substance administration were observed in male and 
female animals in all study groups during the study period. 
(4) Necropsy findings 
No macroscopic abnormal findings related to the test substance administration were 
observed in all the male and female animals. 
As a result of the study, no mortality, general symptoms, weight changes, and macroscopic 
necropsy findings related to the test substance administration were observed in male and 
female animals in all study groups. 
In conclusion, the median lethal dose by a single intravenous administration of this test 
substance in rats was determined to exceed 100 mg/kg. 
 
[Table 2.6] Summary of the data on the 2-week DRF toxicity study in rats 
 
Study title 
2-week repeat-intravenous-dose toxicity study and toxic dose range-finding study on 
N-Rephasin⡶ SAL200 using rats 
Compliance 
with GLP 
; Yes □ No 
□ Performed before 01/01/2003 □ Documents submitted upon approval 
; Domestic and overseas specialized institutions 
Test substance 
(substance 
name) 
N-Rephasin⡶ SAL200 
Study No. 
G11040 
Test animals 
Species 
□ Mice ; Rats □ Beagle dogs □ Monkeys □ Others (rabbits, guinea pigs) 
Strain 
Crl:CD(SD) 
Route of 
administration 
□ Oral □ Subcutaneous ; Intravenous □ Intraperitoneal □ Intramuscular 
□ Others (percutaneous, inhalation) 
Administration 
period 
(observation 
period) 
June 14, 2011–June 27, 2011 (study end date: July 5, 2011) 
Dosage form 
; Solution □ Suspension □ colloid 
Dose (mL/kg) 
In 5 each of male and female animals, 1.26 (vehicle control), 0.32, 0.63, and 1.26 mL/kg for 
each test group 
Details of the 
test 
Test group 
V. Control 
T1 
T2 
T3 
Concentration 
administered 
(mg/kg/day) 
0.00 
6.25 
12.50 
25.00 
Test animals 
(M/F) 
M 
F 
M 
F 
M 
F 
M 
F 
Number of animals 
per group 
5 
5 
5 
5 
5 
5 
5 
5 
Reviewer’s 
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comments 
(test results) 
No deaths of animals occurred during the study period. 
(2) General symptoms 
No abnormal findings were observed for general symptoms due to the test substance. 
(3) Weight changes 
No weight changes caused by the test substance administration were observed. 
(4) Feed consumption 
No changes caused by the test substance administration were observed in all the test 
substance treatment groups. 
(5) Ophthalmic examination 
No abnormal findings caused by the test substance administration were observed. 
(6) Urinalysis 
For the urine volume, male animals showed significant increases or a trend of increase in 
the test substance treatment groups (6.25, 12.5 and 25 mg/kg/day) compared to the vehicle 
control group (approximately 1.2 times, 1.4 times, and 1.7 times, respectively, compared to 
the vehicle control group), but there was no difference in female animals. No changes 
caused by the test substance administration were observed in other tests. 
(7) Hematology 
Neutrophils decreased in male animals in the 6.25 and 25 mg/kg/day treatment groups 
(approximately 0.5 times and 0.6 times, respectively, compared to the vehicle control 
group), and female animals in the 6.25 and 12.5 mg/kg/day treatment groups 
(approximately 0.6 times and 0.7 times, respectively, compared to the vehicle control 
group) showed a trend of decrease, but dose-dependent trends were not observed. It was 
confirmed that eosinophils showed significant dose-dependent decreases in female animals 
in the 6.25, 12.5 and 25 mg/kg/day treatment groups (approximately 0.6 times, 0.5 times, 
and 0.4 times, respectively, compared to the vehicle control group). Monocytes decreased 
significantly in male animals in the 6.25, 12.5 and 25 mg/kg/day treatment groups 
(approximately 0.5 times, 0.6 times, and 0.5 times, respectively, compared to the vehicle 
control group), but dose-dependent trends were not observed. It was observed that 
basophils decreased significantly by approximately 0.7 times compared to the vehicle 
control group only in female animals in the 12.5 mg/kg/day treatment group. Lymphocytes 
increased significantly by approximately 1.1 times compared to the vehicle control group in 
male animals in all treatment groups, but dose-dependent trends were not observed. 
It was determined that the significant changes in the hematology item observed in this 
study were not related to the test substance as the changes were small, dose-dependent 
trends were not observed, or changes in related organs were not observed. 
(8) Blood biochemistry 
Total bilirubin increased significantly in male animals in the 6.25 and 12.5 mg/kg/day 
treatment groups (approximately 1.4 times and 1.4 times, respectively, compared to the 
vehicle 
control 
group), 
but 
dose-dependent 
trends 
were 
not 
observed. 
Gamma-glutamyltransferase increased significantly by approximately 4.3 times compared to 
the vehicle control group in female animals in the 12.5 mg/kg/day treatment group, but it 
was confirmed as an insignificant result since there were major differences among the 
animals. 
It was determined that the significant changes in the blood biochemistry item observed in 
this study were not related to the test substance as dose-dependent trends were not 
observed or changes in related organs were not observed. 
(9) Necropsy findings 
In male animals, 2 cases of enlarged spleen were observed in the 25 mg/kg/day treatment 
group, and 1 case of enlarged thymus was observed in the 6.25 mg/kg/day treatment group. 
In female animals, 1 and 3 cases of enlarged spleen were observed in the 12.5 and 
25 mg/kg/day treatment groups, respectively, and 2, 2 and 4 cases of enlarged thymus were 
observed in the 6.25, 12.5 and 25 mg/kg/day treatment groups, respectively. 
Among the necropsy findings observed in this study, the incidence of increased spleen and 

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thymus size in female animals were found to increase in correlation with the dose of the 
test substance. But, it was difficult to confirm the relationship to the test substance, as they 
were not severe and histological findings were not confirmed. 
(10) Organ weights 
In male animals, the absolute weights of seminal vesicles increased significantly in the 6.25 
and 25 mg/kg/day treatment groups (approximately 1.3 times and 1.3 times, respectively, 
compared to the vehicle control group), the relative weights increased significantly by 
approximately 1.3 times, 1.3 times and 1.3 times in the 6.25, 12.5 and 25 mg/kg/day 
treatment groups, respectively, and the absolute weights of the pituitary gland increased 
1.2 times in the 25 mg/kg/day group. In female animals, the absolute weights and relative 
weights of the spleen increased by 1.4 times, respectively, at 25 mg/kg/day. 
The organ weights that showed significant changes observed in this study had small 
changes, or their changes were not recognized as dose-dependent changes, and the 
histological findings need to be confirmed. 
Consideration 
and conclusion 
The no-observed-adverse-effect level of N-Rephasin⡶ SAL200 induced by 2-week 
repeat-dose in rats was estimated to exceed 25 mg/kg/day. 
 
 
[Table 2.7] Summary of the data on the 4-week repeat-dose toxicity study in rats 
Study title 
4-week repeat-intravenous-dose toxicity and toxicokinetic study on N-Rephasin⡶ SAL200 
using rats (including a 2-week recovery period) 
Compliance 
with GLP 
; Yes □ No 
□ Performed before 01/01/2003 □ Documents submitted upon approval 
; Domestic and overseas specialized institutions 
Test substance 
(substance 
name) 
N-Rephasin⡶ SAL200 
Study No. 
G11041 
Test animals 
Species 
□ Mice ; Rats □ Beagle dogs □ Monkeys □ Others (rabbits, guinea pigs) 
Strain 
Crl:CD(SD) 
Route of 
administration 
□ Oral □ Subcutaneous ; Intravenous □ Intraperitoneal □ Intramuscular 
□ Others (percutaneous, inhalation) 
Administration 
period 
(observation 
period) 
Administration period/study end date: 
1) Main group (♂): November 22, 2011–December 19, 2011/December 20, 2011 
2) Main group (♀): November 22, 2011–December 20, 2011/December 21, 2011 
3) Recovery group: November 22, 2011–December 19, 2011/January 3, 2012 (recovery 
period: 2 weeks) 
Dosage form 
; Solution □ suspension □ colloid 
Dose (mL/kg) 
1.5  

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Details of the 
test 
Toxicity group 
Test group 
G1 
G2 
G3 
G4 
Concentration 
administered 
(mg/kg/day) 
0 
4 
10 
25 
Test animals 
(M/F) 
M 
F 
M 
F 
M 
F 
M 
F 
Number of 
animals per group 
16 
16 
10 
10 
10 
10 
16 
16 
Toxicokinetics group 
Test group 
G1 
G2 
G3 
G4 
Concentration 
administered 
(mg/kg) 
0 
4 
10 
25 
Test animals 
(M/F) 
M 
F 
M 
F 
M 
F 
M 
F 
Number of 
animals per group 
4 
4 
14 
14 
14 
14 
14 
14 
Reviewer’s 
comments 
(test results) 
(1) Mortality: 
No deaths of animals related to the test substance occurred during the study period. 
(2) General symptoms 
No changes in general symptoms related to the test substance were observed during the 
study period. 
(3) Weight changes 
No weight changes related to the test substance administration were observed. 
(4) Feed consumption 
No changes in feed consumption related to the test substance administration were 
observed. 
(5) Ophthalmic examination 
No adverse findings related to the test substance administration were observed. 
(6) Urinalysis 
As a result of the urinalysis in the main group and recovery group, no changes related to the 
test substance administration were observed. 
(7) Hematology 
No changes related to the test substance administration were observed. It was determined 
that some of the changes observed in the hematology performed in the main group and 
recovery group were not related to the test substance administration, as they were not 
dose-dependent, the ranges of changes were small, the values were within the normal 
ranges, or no associated tissue findings were observed. 
(8) Blood biochemistry 
As a result of the blood biochemistry in the main group and recovery group, no changes in 
blood biochemistry item results caused by the test substance administration were observed. 
It was determined that some of the statistically significant changes had no relationship to 
the test substance, as they were not dose-dependent, the ranges of changes were small, the 
values were within the normal ranges, or no associated tissue findings were observed. 
However, some changes in the blood biochemistry item were observed in some animals in 
the main group. Similar items had changes that were observed, although they were not 
dose-dependent. In addition, tissue findings and urinalysis findings that seem to be 
associated with these were observed, although they were not observed in all animals. It was 
determined that the changes observed in each animal were not due to the test substance, 

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as they were not dose-dependent changes and their patterns of occurrence were incidental. 
The items that changed are as shown below. 
Total cholesterol (TCHO), phospholipid (PL) or triglyceride (TG) increased, and albumin (ALB) 
and alkaline phosphatase (ALP) decreased in Animal Nos. 21, 22 and 32 in male animals 
administered at doses of 4 and 10 mg/kg/day and Animal Nos. 69 and 97 in female animals 
administered at doses of 4 and 25 mg/kg/day in the main group. In the urinalysis results, 
urine protein (PRO, 3+) was detected in all the relevant animals. In addition, edematous 
findings were observed in the pancreas, skeletal muscles or hind limbs in some animals 
(Animal Nos. 22, 32 and 34) in necropsy findings, and edema was also confirmed in 
histopathological examination. In Animals Nos. 21, 32, 69 and 97, kidneys’ organ weights 
were increased. In histopathological examination, tubular dilatation, hyaline droplets, and 
casts were commonly observed in the kidneys of Animal Nos. 32, 69, and 97. According to 
the comprehensive results above, decreased albumin in the blood and detection of 
increased urine protein indicate loss of protein through urine, and it was determined that 
this caused edema by changing the osmotic pressure in the body. Although significant 
kidney findings were not observed in all animals, it was determined that detection of 
increased urine protein observed in urinalysis was associated with histological changes 
observed in the kidneys. 
(9) Necropsy findings 
No changes related to the test substance were observed. It was determined that some of 
the necropsy findings observed during visual inspection in the main group and recovery 
group were incidental changes rather than changes caused by the test substance, as no 
dose-dependent changes were observed, and the frequency was low. 
(10) Organ weights 
No changes related to the test substance were observed. It was determined that some of 
the changes observed in the measurement of organ weights in the main group and recovery 
group were not related to the test substance administration, as they were not 
dose-dependent, the ranges of changes were small, the values were within the normal 
ranges, or no associated tissue findings were observed. 
(11) Histopathological examination 
Findings related to the test substance administration were observed in the 
femur/joint/bone marrow. Very mild to mild cases of increased hypertrophic zone in the 
middle physis of a tibia were observed in 9 out of 10 male animals administered at a dose of 
25 mg/kg/day, and a very mild case was observed in 1 out of 10 female animals 
administered at a dose of 25 mg/kg/day. In the recovery group, very mild cases were 
observed in 2 out of 6 male animals and 0 out of 6 female animals administered at a dose of 
25 mg/kg/day, respectively. 
Besides, the findings observed during histopathological examination in the main group and 
recovery group were determined to be spontaneous findings or incidental findings observed 
in animals of similar age of the same species. 
(12) Toxicokinetics 
- Dose dependence: When the test substance N-Rephasin⡶ SAL200 was administered 
intravenously to rats at doses of 10 and 25 mg/kg for 4 weeks, the systemic exposure (to be 
evaluated with AUClast) at Day 1 increased with an increase in the dose administered in both 
male and female animals. 
- Effect by repeated administration: The systemic exposure (AUClast) of N-Rephasin⡶ SAL200 
after the 4-week repeat-dose increased or tended to increase with repeated administration.  
- Differences depending on the gender: The differences between the male and female 
animals in the study substance treatment group tended to be higher in the male animals 
than the female animals, but the differences between the genders were not clear. 
(13) Immunogenicity 
- Before the administration (Day 1) and 2 weeks after initiation of the administration (Day 

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14) 
All animals were determined to be negative or false positive. 
- 4 weeks after initiation of the administration (Day 28) 
In male animals, it was determined that 2 out of 3 cases at the dose of 4 mg/kg/day, 2 out of 
3 cases at the dose of 10 mg/kg/day, and 2 out of 3 cases at the dose of 25 mg/kg/day were 
true positive, and all other cases were all negative or false positive. In female animals, it was 
determined that 1 out of 3 cases at the dose of 0 mg/kg/day, 3 out of 3 cases at the dose of 
4 mg/kg/day, 3 out of 3 cases at the dose of 10 mg/kg/day, and 1 out of 3 cases at the dose 
of 25 mg/kg/day were true positive, and all other cases were all negative or false positive. 
- 6 weeks after initiation of the administration (Day 42) 
In male animals, it was determined that 3 out of 3 cases at the dose of 4 mg/kg/day, 3 out of 
3 cases at the dose of 10 mg/kg/day, and 3 out of 3 cases at the dose of 25 mg/kg/day were 
true positive, and all other cases were all negative. In female animals, it was determined 
that 2 out of 3 cases at the dose of 0 mg/kg/day, 3 out of 3 cases at the dose of 
4 mg/kg/day, 3 out of 3 cases at the dose of 10 mg/kg/day, and 2 out of 3 cases at the dose 
of 25 mg/kg/day were true positive, and all other cases were all negative or false positive. 
Consideration 
and conclusion 
As a result of histopathological examination, changes related to the test substance 
administration were observed in the femur/joint/bone marrow. Increased hypertrophic 
zone, middle physis, tibia was observed in male and female animals administered at a dose 
of 25 mg/kg/day, and it was characterized by the increased hypertrophic zone in the middle 
physis of a tibia. However, it was determined as a non-adverse finding, as there were no 
findings related to cell damage in the relevant area. In the recovery group, very mild cases 
were observed in male and female animals at a dose of 25 mg/kg/day, and the frequency 
and severity decreased compared to the main group. Therefore, it seems that the changes 
were reversible. 
As a result of analyzing toxicokinetics, when N-Rephasin⡶ SAL200 was administered 
intravenously to rats at doses of 4, 10 and 25 mg/kg for 4 weeks repeatedly, the systemic 
exposure (AUClast) of N-Rephasin⡶ SAL200 in the 10 and 25 mg/kg treatment groups 
increased with an increase in the dose administered. The systemic exposure after the 
4-week repeat-dose showed an increase or an increasing trend compared to that at Day 1, 
and no differences were observed between the male and female animals.  
As a result of the antibody analysis, the production of antibodies to N-Rephasin⡶ SAL200 
was observed in most samples of the test substance treatment group from 4 weeks after 
the administration, and a trend of an increase in the antibody titer was observed as groups 
went through the recovery period. 
 
In conclusion, as a result of the 4 weeks of repeated intravenous administration of the test 
substance N-Rephasin⡶ SAL200 in SD rats at doses of 0, 4, 10 and 25 mg/kg/day, no adverse 
effects associated with the test substance were observed in mortality, observation of 
general symptoms, weight measurement, feed consumption, ophthalmic examination, 
urinalysis, hematology, blood biochemistry, necropsy findings, organ weight measurement, 
histopathological examination, toxicokinetic analysis, and immunogenicity analysis during 
the study period. Therefore, the no-observed-adverse-effect level (NOAEL) in this study was 
determined to be 25 mg/kg/day in male and female animals. 
 
 

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[Table 2.8] Summary of the data on the 2-week DRF toxicity study in beagle dogs 
 
Study title 
2-week repeat-intravenous-dose toxic dose range-finding (DRF) study on N-Rephasin⡶ 
SAL200 using beagle dogs 
Compliance 
with GLP 
; Yes □ No 
□ Performed before 01/01/2003 □ Documents submitted upon approval 
; Domestic and overseas specialized institutions 
Test substance 
(substance 
name) 
N-Rephasin⡶ SAL200 
Study No. 
G11042 
Test animals 
Species 
□ Mice □ Rats ; Beagle dogs □ Monkeys □ Others (rabbits, guinea pigs) 
Strain 
Canis familiaris (beagle dog) 
Route of 
administration 
□ Oral □ Subcutaneous ; Intravenous □ Intraperitoneal □ Intramuscular 
□ Others (percutaneous, inhalation) 
Administration 
period 
(observation 
period) 
May 25, 2011–June 7, 2011 (study end date: September 23, 2011) 
Dosage form 
; Solution □ Suspension □ colloid 
Dose (mL/kg) 
In 1 each of male and female animals, 1.4(vehicle control), 0.35, 0.7, and 1.4 mL/kg for each 
test group  
Details of the 
test 
Test group 
V. Control 
T1 
T2 
T3 
Concentration 
administered 
(mg/kg/day) 
0.00 
6.25 
12.50 
25.00 
Test animals 
(M/F) 
M 
F 
M 
F 
M 
F 
M 
F 
Number of animals 
per group 
1 
1 
1 
1 
1 
1 
1 
1 
Reviewer’s 
comments 
(test results) 
(1) Mortality 
No deaths related to the test substance administration occurred throughout the study. 
(2) General symptoms 
As a result of the observation of general symptoms, subdued behavior was observed at Days 
14, 10, and 10–14 in male animals in the 6.25, 12.5 and 25 mg/kg/day treatment groups, 
respectively, and at Days 10–14 in female animals in the 6.25, 12.5 and 25 mg/kg/day 
treatment groups. In female animals, prone position was observed at Days 11–12, and 11 in 
the 6.25 and 12.5 mg/kg/day treatment groups, respectively, and decreased respiration rate 
was observed at Day 14 in the 12.5 and 5 mg/kg/day treatment groups. Also, in female 
animals, vomiting was observed at Day 8 in the 6.25 mg/kg/day treatment group, at Days 10 
and 13 in the 12.5 mg/kg/day treatment group, and at Days 8–11 in the 25 mg/kg/day 
treatment group, and salivation was observed at Day 14 in the 6.25 mg/kg/day treatment 
group and at Days 12–14 in the 12.5 mg/kg/day treatment group. Eye coloration was 
observed at Days 13–14 in female animals in all test substance treatment groups, and skin 
coloration was observed at Day 13 in the 25 mg/kg/day treatment group. 
(3) Weight changes 
As a result of the weight measurement, no changes caused by the test substance 
administration were observed in all the test substance treatment groups. 
(4) Feed consumption 
As a result of the measurement of feed consumption, no changes caused by the test 

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substance administration were observed. 
(5) Ophthalmic examination 
As a result of the ophthalmic examination, no changes caused by the test substance 
administration were observed. 
(6) Urinalysis 
As a result of the urinalysis, no changes caused by the test substance administration were 
observed. 
(7) Hematology 
As a result of the hematology, no adverse effects caused by the test substance 
administration were observed. In male animals, WBCs increased in the 6.25, 12.5 and 
25 mg/kg/day treatment groups (1.66 times, 1.24 times and 1.91 times, respectively, 
compared to the vehicle control group), platelets decreased (0.70 times, 0.58 times and 
0.66 times, respectively, compared to the vehicle control group), and basophils and large 
unstained cells (%) increased (1.53 times, 1.4 times and 1.6 times, respectively, and 2.25 
times, 2 times and 3 times, respectively, compared to the vehicle control group). In female 
animals, platelets, reticulocytes and neutrophils decreased in the 6.25, 12.5 and 
25 mg/kg/day treatment groups (0.67 times, 0.60 times and 0.40 times, respectively; 0.74 
times, 0.63 times and 0.84 times, respectively; 0.56 times, 0.94 times and 0.71 times, 
respectively, compared to the vehicle control group), and monocytes and leukocytes (%) 
increased (1.32 times, 1.47 times and 1.61 times, respectively, and 2 times, 2 times and 3.8 
times, respectively, compared to the vehicle control group). 
As a result of the hematology, it was determined that the changes in the hematology item 
observed were not related to the test substance, as the changes were small in general, or 
dose-dependent trends were not observed. 
(8) Blood biochemistry 
As a result of the blood biochemistry, no adverse effects caused by the test substance 
administration were observed. 
In male animals in the study group, blood urea nitrogen (BUN), total protein (TP), total 
bilirubin (TBIL), and creatine phosphokinase (CK) decreased in the 6.25, 12.5 and 
25 mg/kg/day treatment groups (0.96 times, 0.79 times and 0.84 times, respectively; 0.86 
times, 0.93 times and 0.76 times, respectively; 0.86 times, 0.58 times and 0.48 times, 
respectively; 0.74 times, 0.60 times and 0.46 times, respectively, compared to the vehicle 
control group). In female animals, BUN increased in the 6.25, 12.5 and 25 mg/kg/day 
treatment groups (1.33 times, 1.46 times and 1.11 times, respectively, compared to the 
vehicle control group). 
As a result of the blood biochemistry, it was determined that the changes in the blood 
biochemistry item observed were not related to the test substance, as the changes were 
small, or dose-dependent trends were not observed. 
(9) Necropsy findings 
As a result of the necropsy, no changes caused by the test substance administration were 
observed. 
In all treatment groups, including female animals in the vehicle control group, dark red 
discoloration at the site of administration was observed, but it was determined that this is 
related to the hemorrhage observed in the histopathological examination and is a response 
caused by repeated administration and irritation with a needle. Other findings were the 
changes that occur spontaneously or that are observed incidentally in beagle dogs, and it 
was determined that these changes were not related to the test substance administration. 
(10) Organ weights 
As a result of the measurement of organ weights, no changes caused by the test substance 
administration were observed.  
(11) Histopathological examination 
As 
a 
result 
of 
the 
histopathological 
examination, 
slight 
renal 
tubular 
degeneration/regeneration was observed in a male animal in the 25 mg/kg/day treatment 

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group, but it is difficult to determine the relationship between the histopathological finding 
and the test substance administration, as each group in this study has only 1 animal and no 
finding was observed in the female animal in the same concentration group. 
Other findings observed in the histopathological examination were the changes that occur 
spontaneously or that are observed incidentally in beagle dogs, and it was determined that 
these changes were not related to the test substance administration. 
(12) Measurement of antibodies in blood 
As a result of the analysis of antibodies in serum, antibodies were produced at Day 15 in the 
6.25 and 12.5 mg/kg/day treatment groups, and antibodies were not measured in the 
25 mg/kg/day treatment group. In the 25 mg/kg/day treatment group, it is thought that 
antibodies were not measured due to the effect caused by drug interference and/or the 
removal from the blood by the formation of antigen–antibody complexes. 
 
[Test-Table. Analysis of samples on Day 15] 
Consideration 
and conclusion 
Through the 2-week repeated intravenous administration of N-Rephasin⡶ SAL200 to beagle 
dog, various clinical symptoms presumed to be serum sickness were observed temporarily 
after the administration in all treatment groups administered at 6.25 mg/kg/day or higher, 
but these symptoms disappeared immediately. On the other hand, since the 
histopathological relationship to the test substance administration could not be confirmed, 
the no-observed-adverse-effect level (NOAEL) was determined to be 25 mg/kg/day. 

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[Table 2.9] Summary of the data on the 2-week repeat-dose toxicity study in beagle dogs 
Study title 
2-week repeat-intravenous-dose toxicity and toxicokinetic study on N-Rephasin⡶ SAL200 
using beagle dogs (including a 4-week recovery period) 
Compliance 
with GLP 
; Yes □ No 
□ Performed before 01/01/2003 □ Documents submitted upon approval 
; Domestic and overseas specialized institutions 
Test substance 
(substance 
name) 
N-Rephasin⡶ SAL200 
Study No. 
G11043 
Test animals 
Species 
□ Mice □ Rats ; Beagle dogs □ Monkeys □ Others (rabbits, guinea pigs) 
Strain 
Canis familiaris (beagle dog) 
Route of 
administration 
□ Oral □ Subcutaneous ; Intravenous □ Intraperitoneal □ Intramuscular 
□ Others (percutaneous, inhalation) 
Administratio
n period 
(observation 
period) 
Administration initiation date/necropsy date/study end date 
- Male animals in the main group: November 10, 2011/November 24, 2011/April 27, 2012 
- Female animals in the main group: November 10, 2011/November 25, 2011/April 27, 2012 
- Recovery group: November 10, 2011/December 22, 2011/April 27, 2012 
Dosage form 
; Solution □ Suspension □ colloid 
Dose (mL/kg) 
1.5 
Details of the 
test 
Test group 
G1 
G2 
G3 
G4 
Concentration 
administered 
(mg/kg) 
0 
2.5 
10 
25 
Test animals 
(M/F) 
Main 
group 
Recover
y group 
Main 
group 
Recover
y group 
Main 
group 
Recover
y group 
Main 
group 
Recover
y group 
M 
F 
M 
F 
M 
F 
M 
F 
M 
F 
M 
F 
M 
F 
M 
F 
Number of 
animals per 
group 
3 
3 
2 
2 
3 
3 
- 
- 
3 
3 
- 
- 
3 
3 
2 
2 
Reviewer’s 
comments 
(test results) 
(1) Mortality 
No deaths of animals occurred. 
(2) General symptoms 
In male and female animals in the 2.5 (2 out of 3 animals, 2 out of 3 animals), 10 (3 out of 3 
animals, 3 out of 3 animals) and 25 (5 out of 5 animals, 5 out of 5 animals) mg/kg treatment 
groups, vomiting was observed in each group continuously during the administration from 7 
days after initiation of the administration. 
Prone position was observed in male and female animals in the 2.5 (0 out of 3 animals, 2 out of 
3 animals), 10 (0 out of 3 animals, 3 out of 3 animals) and 25 (3 out of 5 animals, 2 out of 5 
animals) mg/kg treatment groups, and lateral recumbent position was observed in male and 
female animals in the 2.5 (0 out of 3 animals, 1 out of 3 animals), 10 (1 out of 3 animals, 2 out 
of 3 animals) and 25 (1 out of 5 animals, 3 out of 5 animals) mg/kg treatment groups. Subdued 
behavior was observed in male and female animals in the 2.5 (2 out of 3 animals, 3 out of 3 
animals), 10 (1 out of 3 animals, 3 out of 3 animals) and 25 (5 out of 5 animals, 5 out of 5 
animals) mg/kg treatment groups. These findings were observed during the administration 
period from approximately 9 or 10 days after initiation of the administration. 
Irregular respiration was observed in male and female animals in the 2.5 (0 out of 3 animals, 1 
out of 3 animals), 10 (0 out of 3 animals, 2 out of 3 animals) and 25 (2 out of 5 animals, 3 out of 
5 animals) mg/kg treatment groups, and increased respiration rate was observed in the 10 (0 
out of 3 animals, 1 out of 3 animals) and 25 (1 out of 5 animals, 0 out of 5 animals) mg/kg 

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treatment groups. These findings were observed during the administration period from 10 days 
after initiation of the administration. 
The findings above that were observed during the administration period showed a trend of 
recovery during the observation of symptoms in the afternoon on the day of the administration 
after being observed immediately after the administration. 
No findings related to the test substance administration were observed during the recovery 
period. 
Decreased feed consumption, rubbing, and hypersalivation were observed as other findings 
during the administration period, but these findings occurred less frequently, and they were 
observed in the vehicle control group as well. Therefore, it was determined that they were not 
due to the test substance administration. 
(3) Weight changes 
No changes related to the test substance administration were observed in male and female 
animals in all treatment groups. 
(4) Feed consumption 
No changes related to the test substance administration were observed in male and female 
animals in all treatment groups. 
(5) Ophthalmic examination 
No changes related to the test substance administration were observed in male and female 
animals in all treatment groups. 
(6) Urinalysis 
No changes related to the test substance administration were observed in male and female 
animals in all treatment groups. 
(7) Hematology 
Decreased platelet (PLT) levels were observed in male and female animals in the main groups 
of the 2.5, 10 and 25 mg/kg treatment groups. But, the association with the test substance 
could not be determined, as the differences were small among the treatment groups, and no 
associated changes were observed in the histopathological examination. 
It was determined that other changes observed in the main groups and recovery groups were 
not related to the test substance administration, as they were not dose-dependent, the ranges 
of changes were small, and no associated changes were observed in the histopathological 
examination. 
(8) Blood coagulation test 
No changes related to the test substance administration were observed in male and female 
animals in all treatment groups. 
(9) Blood biochemistry 
No changes related to the test substance administration were observed in male and female 
animals in all treatment groups. 
(10) Electrocardiogram 
No changes related to the test substance administration were observed in male and female 
animals in all treatment groups. 
(11) Necropsy findings 
No changes related to the test substance administration were observed in male and female 
animals in all treatment groups. 
Dark red discoloration at the site of administration was observed in all treatment groups, 
including the main groups, recovery groups, and vehicle control group. It was determined that 
this is related to the congestion/hemorrhage observed in the histopathological examination 
and is a response caused by irritation from repeated administration with an injection needle or 
the anesthetization process at the time of necropsy. 
Other findings observed in the visual inspection were the changes that occur spontaneously or 
that are observed incidentally in beagle dogs, and it was determined that these changes were 
not related to the test substance administration. 
 

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(12) Organ weights 
No changes related to the test substance administration were observed in male and female 
animals in all treatment groups. 
The relative weight of kidneys increased (by approximately 1.2 times the control group) in male 
animals in the main group of the 25 mg/kg treatment group. However, it was determined to be 
an incidental change, as no associated changes were observed in the histopathological 
examination. 
(13) Histopathological examination 
No changes related to the test substance administration were observed in male and female 
animals in all treatment groups. 
Mild to severe congestion (hemorrhage), very mild to mild vasculitis/perivasculitis, and very 
mild to moderate edema and inflammatory cell infiltration were observed at the site of 
administration in all treatment groups, including the main groups, recovery groups, and vehicle 
control group. It was determined that these changes were secondary responses caused by 
physical irritation from repeated administration with an injection needle or the process of 
anesthetization of the heart rather than direct effects of the test substance. Other findings 
related to the histopathological examination were the changes that occur spontaneously or 
that are observed incidentally in beagle dogs, and it was determined that these changes were 
not related to the test substance administration. 
(14) Toxicokinetics 
After the intravenous administration of the test substance N-Rephasin⡶ SAL200 to beagle dogs 
at doses of 0, 2.5, 10 and 25 mg/kg/day once daily for 2 weeks, the concentration of 
N-Rephasin⡶ SAL200 in serum was measured. The analysis result of the control group has not 
been tabulated, as all samples in the control group showed that the concentration of 
N-Rephasin⡶ SAL200 was below the limit of quantification (1 μg/mL). Toxicokinetics analysis 
was performed only in the 10 and 25 mg/kg treatment groups in which biological samples are 
relatively easy to quantify. 
After the intravenous administration of the test substance N-Rephasin⡶ SAL200 at doses of 10 
and 25 mg/kg, the systemic exposure (to be evaluated with AUClast) to N-Rephasin⡶ SAL200 
increased 3.2 times in male animals and 4.1 times in female animals with an increase in the 
administered dose by 2.5 times at Day 1. The rate of increase was higher than the increase in 
the administered dose. In addition, the difference in the systemic exposure between the 
gender in the 25 mg/kg treatment group was 1.3 times higher in male animals compared to 
female animals at Day 1 and 1.8 times higher at Day 14, which were somewhat higher, but the 
difference between the gender was not clear. 
The systemic exposure (AUClast) to N-Rephasin⡶ SAL200 after repeated administration for 2 
weeks increased 1.9 times in male animals and 3.3 times in female animals in the 10 mg/kg 
treatment group at Day 14 compared to Day 1. In the 25 mg/kg treatment group in which the 
change in concentration over time was easy to check, it increased 1.9 times in male animals 
and 1.4 times in female animals, showing an increasing trend after repeated administration. 
This is thought to be due to the decrease in the total body clearance and the increase in 
MRTlast. On the other hand, referring to the antibody measurement test result, the systemic 
exposure to N-Rephasin⡶ SAL200 has slightly increased despite the production of antibodies in 
the serum of some animals after repeated administration for 2 weeks. Therefore, it was 
determined that the production of antibodies did not significantly affect the toxicokinetic 
profile itself. 
(15) Antibody analysis 
Before the administration, all animals were determined to be negative or false positive. 
It was determined that male and female animals in the 0 (1 out of 5 animals, 1 out of 5 
animals), 2.5 (2 out of 3 animals, 3 out of 3 animals), 10 (1 out of 3 animals, 3 out of 3 animals) 
and 25 (1 out of 5 animals, 0 out of 5 animals) mg/kg treatment groups were each true positive 

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at 2 weeks after the administration. 
It was determined that male and female animals in the 0 (1 out of 2 animals, 1 out of 2 animals) 
and 25 (1 out of 2 animals, 1 out of 2 animals) mg/kg treatment groups were each true positive 
at 2 weeks of the recovery. 
It was determined that male and female animals in the 0 (1 out of 2 animals, 2 out of 2 animals) 
and 25 (1 out of 2 animals, 1 out of 2 animals) mg/kg treatment groups were each true positive 
at 4 weeks of the recovery. 
Among these antibody measurement results, an increase in antibodies was observed in some 
animals in the vehicle treatment group, but the titer was lower than the N-Rephasin⡶ SAL200 
treatment groups generally, and there were not many cases. Therefore, it was determined that 
there was no effect on the immunogenicity evaluation in this study. 
In addition, according to the results of the serum C3 complement measurement assay 
performed additionally, the concentration of C3 in the N-Rephasin⡶ SAL200 treatment group 
was lower than that in the vehicle control group. 
Consideration 
and 
conclusion 
Vomiting, prone position, lateral recumbent position, subdued behavior, irregular respiration, 
and increased respiration rate that were determined to be caused by the effect of the test 
substance administration were observed in male and female animals in all test substance 
treatment groups from 7 days after initiation of the administration and throughout the 
administration period. This was determined to be temporary symptoms occurred by activation 
of the complement system by the test substance–antibody complexes produced by 
administration of the test substance. Such a possibility was confirmed by the serum C3 
complement measurement assay result. In this assay, the concentration of C3 in the 
N-Rephasin⡶ SAL200 treatment groups was lower than that in the vehicle control group, and it 
was determined that this was due to the activation of complement by the immune complex 
formation. On the other hand, these findings were observed immediately after the 
administration, and they showed a trend of recovery immediately after the onset of symptoms 
and were not observed during the 4-week recovery period after the end of the administration. 
As a result of analyzing toxicokinetics, when N-Rephasin⡶ SAL200 was administered 
intravenously to beagle dogs at doses of 2.5, 10 and 25 mg/kg for 2 weeks repeatedly, the 
systemic exposure (AUClast) of N-Rephasin⡶ SAL200 in the 10 and 25 mg/kg treatment groups, 
which were relatively easy to quantify, increased proportionally with an increase in the dose 
administered. The rate of increase was higher than the increase in the administered dose, and 
no differences were observed between the male and female animals. The systemic exposure of 
N-Rephasin⡶ SAL200 after the 2-week repeat-dose showed a somewhat increasing trend when 
compared to that at Day 1. 
As a result of the antibody analysis, the production of antibodies to N-Rephasin⡶ SAL200 was 
observed in most of the N-Rephasin⡶ SAL200 treatment group from 2 weeks after the 
administration, and it was observed that higher doses administered resulted in lower titer 
values in both male and female animals. Especially in the treatment group in which the highest 
concentration (25 mg/kg) was administered, it was confirmed that several animals showed a 
pattern that there was almost no antibody production until 2 weeks after the administration, 
but it increased as the group went through the recovery period (at 4 weeks and 6 weeks). This 
might be the result of drug interference that interferes with the measurement of the antibody 
due to the remaining of the high concentration of N-Rephasin⡶ SAL200 in blood by producing 
complexes with antibodies, and the drug interference limit in this assay identified in the 
GV11038 study was 150 ng/mL. Therefore, if N-Rephasin⡶ SAL200 is present in serum at a 
concentration higher than 150 ng/mL, there is a possibility that antibody measurement may be 
interrupted. On the other hand, in the result of the toxicokinetic analysis, the concentration of 
N-Rephasin⡶ SAL200 was observed lower than the lower limit of quantification (LLOQ) in all 

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samples prior to the administration, and it was observed that the concentrations became lower 
than the lower limit of quantification in animal samples of all treatment groups within 1 hour 
after the administration. However, the lower limit of quantification of the relevant test method 
is 1 μg/mL, which is higher than the drug interference limit of the antibody measurement assay, 
and therefore, it was determined that the possibility of drug interference in the antibody 
measurement could not be ruled out. Also, it was determined that the antibody in the serum 
could be measured low due to the formation of immune complexes between the produced 
antibodies and excessive N-Rephasin⡶ SAL200, resulting in deposition in the tissues or 
induction of clearance by complement. Such a possibility was confirmed by the serum C3 
complement measurement assay result. 
In this assay result, the concentration of C3 in the N-Rephasin⡶ SAL200 treatment groups was 
lower than that in the vehicle control group, and it was determined that this was resulted due 
to the activation of complement by the immune complex formation. Also, in the case of blood 
samples collected from the high-dose groups, it was determined that no antibody in the blood 
sample was detected, as the relevant dose group had more antigens compared to other dose 
groups, and this resulted in more effective removal of the antigen–antibody complexes by 
activation of the complement. 
From the above results, vomiting, prone position, lateral recumbent position, subdued 
behavior, irregular respiration, and increased respiration rate were observed as general 
symptoms immediately after the administration in male and female animals in the 2.5, 10 and 
25 mg/kg treatment groups as the changes associated with the test substance administration. 
Therefore, the no-observed-adverse-effect level (NOAEL) of the test substance N-Rephasin⡶ 
SAL200 in this study was determined to be < 2.5 mg/kg in both male and female animals. 
 
[Table 2.10] Summary of the data on other toxicity studies (1) 
Study title 
In vivo safety test on N-Rephasin⡶ SAL200 in mice 
Data 
suitability 
□ Data submitted upon approval (approved country) 
□ Specialized academic journal (SCI) 
; Domestic and overseas institutions 
□ GLP 
Study 
objective 
To demonstrate the safety of N-Rephasin⡶ SAL200 in animals even if an excessive dose 
compared to the effective dose is administered intravenously. 
Study drug 
Target drug 
Substance name 
N-Rephasin⡶ SAL200 
Control drug 
Positive 
Not applicable 
Negative 
Vehicle  
[0.01 M L-histidine, pH 6.0, 5% (w/v) sorbitol, 10 mM 
CaCl2, 0.1% (w/v) poloxamer 188] 
Details of the 
study 
Test system 
Mice (BALB/C, 6 weeks old female) 
Study method 
Investigation of general symptoms and weights after single intravenous 
administration by applying various doses (15 mg/kg, 30 mg/kg and 50 mg/kg) 
Evaluation 
indices 
Weights and general symptoms 
Results 
(tabulated 
data, etc.) 
As a result of the observation, no abnormal signs in all respects, such as changes in shine of fur 
and behavior, were observed in the treatment groups compared to the control group. In 
addition, weight changes also showed no significant differences in the control group and 
treatment groups. 
 
<Weight measurement results> 
Target 
Weight (unit: g) 

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Group 
Animal 
0 hr 
24 hr 
48 hr 
72 hr 
96 hr 
Control  
(Group 1) 
1 
20 
19.5 
19 
19 
19 
2 
19 
18 
18 
18 
18 
3 
19 
18.5 
18.5 
18.5 
18.5 
4 
20 
19 
19.5 
19.5 
19.5 
Average 
19.5 
18.8 
18.8 
18.8 
18.8 
15 mg/kg 
treatment 
group 
(Group 2) 
1 
20 
19 
19.5 
19.5 
19 
2 
19 
19 
19 
18.5 
19 
3 
19 
18.5 
18.5 
18 
18.5 
4 
19 
18 
18 
18 
18 
5 
20 
18.5 
19.5 
19.5 
19 
Average 
19.4 
18.6 
18.9 
18.9 
18.7 
30 mg/kg 
treatment 
group 
(Group 3) 
1 
20 
18.5 
18.5 
18.5 
18.5 
2 
20 
19.5 
19.5 
19.5 
19.5 
3 
20 
19.5 
19.5 
19.5 
20 
4 
19.5 
18.5 
19 
19 
18.5 
5 
20 
19 
20 
20 
20 
Average 
19.9 
19 
19.3 
19.3 
19.3 
50 mg/kg 
treatment 
group 
(Group 4) 
1 
19 
19 
19 
19 
19.5 
2 
20 
19 
19.5 
19.5 
20 
3 
19 
18 
18.5 
18.5 
18.5 
4 
20 
18.5 
18.5 
18.5 
18 
5 
20 
19 
18 
18 
17.5 
Average 
19.6 
18.7 
18.7 
18.7 
18.7 
Conclusion 
It has been confirmed that N-Rephasin⡶ SAL200 has no particular toxicity even after 
administration at dose of 50 mg/kg. 
Review 
comments 
It has been determined that N-Rephasin⡶ SAL200 is considerably safe. 
 
[Table 2.11] Summary of the data on other toxicity studies (2) 
Study title 
Measurement of the cytotoxicity of N-Rephasin⡶ SAL200 against animal cells 
Data 
suitability 
□ Data submitted upon approval (approved country) 
□ Specialized academic journal (SCI) 
; Domestic and overseas institutions 
□ GLP 
Study 
objective 
To demonstrate that N-Rephasin⡶ SAL200 is not cytotoxic, as it does not act on animal cells. 
Study drug 
Target drug 
Substance name 
N-Rephasin⡶ SAL200 
Control drug 
Positive 
Not applicable 
Negative 
1× PBS 
Details of the 
study 
Test system 
Animal cells (Hela cells and Raw cells) 
Study method 
Performing an MTT assay, which is the cell viability assay and proliferation 
assay 
Evaluation 
indices 
Cytotoxicity (the quality of being toxic to cells) of N-Rephasin⡶ SAL200 to animal cells 

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Results 
(tabulated 
data, etc.) 
When 1 × 104 animal cells were seeded in the well and proliferated for 72 hours, it was 
confirmed that the presence of N-Rephasin⡶ SAL200 in the contents of the medium has no 
significant level of effect on cell growth. 
 
 
◾ C2: Negative control 
◾ L0.4, L4, L40: N-Rephasin⡶ SAL200 added 
Conclusion 
It was confirmed that N-Rephasin⡶ SAL200 has no cytotoxicity to animal cells. 
Review 
comments 
It has been determined that N-Rephasin⡶ SAL200 has no cytotoxicity to animal cells. 

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[Table 2.12] Summary of the data on the DES toxicity study in monkeys 
Study title 
Single dose-escalation, intravenous-dose toxicity study on N-Rephasin⡶ SAL200 using 
cynomolgus monkeys 
Compliance 
with GLP 
□ Yes ; No 
□ Performed before 01/01/2003 □ Documents submitted upon approval 
; Domestic and overseas specialized institutions 
Test substance 
(substance 
name) 
N-Rephasin⡶ SAL200 
Study No. 
N13036 
Test animals 
Species 
□ Mice □ Rats □ Beagle dogs ; Monkeys □ Others (rabbits, guinea pigs) 
Test animals 
Strain 
Cynomolgus Monkey (Macaca fascicularis) 
Route of 
administration 
□ Oral □ Subcutaneous ; Intravenous □ Intraperitoneal □ Intramuscular 
□ Others (percutaneous, inhalation) 
Administration 
period 
(observation 
period) 
August 28, 2013–September 2, 2013 (study end date: October 8, 2013) 
Dosage form 
; Solution □ Suspension □ colloid 
Dose 
(mL/kg) 
Administration in 1 each of male and female animals while increasing the doses over a total of 6 
times (1, 5, 10, 20, 40 and 80 mg/kg) once daily 
Details of the 
test 
Test group 
G1 
Concentration 
administered 
(mg/kg/day) 
1 
5 
10 
20 
40 
80 
1 
5 
10 
20 
40 
80 
Day of 
administration 
(Day) 
1 
2 
3 
4 
5 
6 
1 
2 
3 
4 
5 
6 
Test animals 
(M/F) 
M 
F 
Number of 
animals 
1 
1 
Reviewer’s 
comments 
(test results) 
(1) Mortality  
No deaths of animals occurred during the study period. 
(2) General symptoms  
No symptoms related to the test substance administration were observed. Vaginal discharge 
was observed in the female animal, but it was determined to be a temporary change that was 
not related to the test substance administration.  
(3) Weight changes 
No weight changes related to the test substance administration were observed. 
(4) Feed consumption  
No changes in feed consumption related to the test substance administration were observed. 
(5) Hematology  
No changes in the hematological indices related to the test substance administration were 
observed. The values that showed changes compared to the period before the administration 
were minor and within the normal range, and therefore it was determined that they had no 
relationship to the test substance administration or toxicological significance.  
(6) Blood biochemistry  
Increases in blood urea nitrogen (BUN, ×2.88 of baseline data) and creatinine (CREA, ×1.56 of 
baseline data) were observed in the male animal. Besides, the values that showed changes 

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compared to the period before the administration were minor and within the normal range, 
and therefore it was determined that they had no relationship to the test substance 
administration or toxicological significance. 
(7) Necropsy findings  
No findings caused by the test substance administration were observed. 
(8) Pharmacokinetic analysis  
After the intravenous administration of the test substance N-Rephasin⡶ SAL200 at doses of 
10 mg/kg (Day 3) and 80 mg/kg (Day 6), the systemic exposure (to be evaluated with AUClast) to 
N-Rephasin⡶ SAL200 increased at a ratio of 1:9 in male animals and 1.8 in female animals with 
a proportional increase in the administered dose by at a ratio of 1.8 at Day 1. At the time of the 
first blood collection, the highest blood concentration was observed, and it decreased by 
multi-exponential decay. In addition, in terms of the systemic exposure, the differences 
between the male and female animals showed 1.3 and 1.1 times in female animals compared to 
those of the male animals, showing no gender differences in the male and female animals. 
Moreover, the elimination half-life (t1/2) of the drug was 2.0–2.2 hours at 10 mg/kg and 2.7–5.0 
hours at 80 mg/kg. The elimination half-life tended to increase with an increase in the dose 
administered, and the volume of distribution was approximately 0.28–0.52 L/kg. Therefore, it 
was expected that the tissue distribution of the test substance was not so large.  
Consideration 
and conclusion 
In this study, to investigate the toxicity of a single dose of the test substance N-Rephasin⡶ 
SAL200, single dose was administered intravenously once daily in 1 each of male and female 
cynomolgus monkeys with single dose-escalating over a total of 6 times (1, 5, 10, 20, 40 and 
80 mg/kg). The mortality rate, general symptoms, weight changes, feed consumption, 
hematology, blood biochemistry, and pharmacokinetic analysis were performed during the 
study period, and the animals were necropsied at 8 days after the first administration and 
visually inspected for findings.  
No deaths of animals occurred during the study period, and no changes in general symptoms, 
body weights, feed consumption, hematology values, and necropsy findings related to the test 
substance administration were observed. 
As a result of the blood biochemistry, increases in blood urea nitrogen (BUN) and creatinine 
(CREA) levels were observed in the male animal, but no other hematology or necropsy findings 
were accompanied, and the changes were observed only in the male animal, not in both male 
and female animals. Therefore, it was difficult to determine that they were the toxicity caused 
by the test substance. 
As a result of the pharmacokinetic analysis, when administered at doses of 10 and 80 mg/kg, 
the systemic exposure (to be evaluated with AUClast) to the test substance N-Rephasin⡶ SAL200 
increased in proportional to the dose administered with an increase in the dose administered in 
male and female animals. No differences were observed between the male and female animals, 
the elimination half-life (t1/2) of the drug was 2.0–2.2 hours at 10 mg/kg and 2.7–5.0 hours at 
80 mg/kg. It tended to increase with an increase in the dose administered, and the volume of 
distribution was approximately 0.28–0.52 L/kg. Therefore, it was expected that the tissue 
distribution was not so large.  
 
From the results above, as a result of the single intravenous administration with an increase in 
the dose of the test substance N-Rephasin⡶ SAL200, it was determined that the maximum 
tolerance dose (MTD) will exceed 80 mg/kg/day. 

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[Table 2.13] Summary of the data on the 5-day repeat-dose toxicity study in monkeys 
Study title 
N-Rephasin⡶ SAL200: 5-day repeat-intravenous-dose toxicity study using cynomolgus monkeys 
Compliance 
with GLP 
; Yes □ No 
□ Performed before 01/01/2003 □ Documents submitted upon approval 
; Domestic and overseas specialized institutions 
Test substance 
(substance 
name) 
N-Rephasin⡶ SAL200 
Study No. 
G13138 
Test animals 
Species 
□ Mice □ Rats □ Beagle dogs ; Monkeys □ Others (rabbits, guinea pigs) 
Strain 
Cynomolgus Monkey (Macaca fascicularis) 
Route of 
administration 
□ Oral □ Subcutaneous ; Intravenous □ Intraperitoneal □ Intramuscular 
□ Others (percutaneous, inhalation) 
Administration 
period 
(observation 
period) 
Male animals: February 6, 2014–February 11, 2014 (study end date: April 2, 2014) 
Female animals: February 7, 2014–February 12, 2014 (study end date: April 2, 2014) 
Dosage form 
; Solution □ Suspension □ colloid 
Dose (mL/kg) 
Administration in 3 each of male and female animals in each group twice daily for 5 days at 
doses of 0 (vehicle control group), 10, 20 and 40 mg/kg/day 
Details of the 
test 
Study 
group 
Gender 
Number of 
animals 
(animals) 
Animal 
number 
Volume of the solution 
administered (mL/kg/day) 
Dose 
(mg/kg/day) 
1st 
2nd 
G1 
Male 
Female 
3 
3 
1 - 3 
13 - 15 
0.98 
0.98 
0 
G2 
Male 
Female 
3 
3 
4 - 6 
16 - 18 
0.245 
0.245 
10 
G3 
Male 
Female 
3 
3 
7 - 9 
19 - 21 
0.49 
0.49 
20 
G4 
Male 
Female 
3 
3 
10 - 12 
22 - 24 
0.98 
0.98 
40 
Reviewer’s 
comments 
(test results) 
(1) Mortality 
No deaths of animals occurred during the study period. 
(2) Observation of general symptoms 
No general symptoms related to the test substance were observed. Besides, other general 
symptoms observed, including loss of fur, scratch wounds, vaginal discharge, soft feces, 
swelling, scars, skin coloration, and loss of tail, occurred less frequently and only occurred in 
specific animals. Therefore, they were determined to be spontaneous or incidental changes. 
(3) Weight 
No significant weight changes related to the test substance were observed. 
(4) Feed consumption 
No changes in feed consumption related to the test substance were observed. 
(5) Ophthalmological examination 
No adverse findings related to the test substance were observed. 
(6) Temperature measurement 
No temperature changes related to the test substance were observed. Other observed changes 
occurred less frequently and only occurred in specific animals. Therefore, they were 

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determined to be spontaneous or incidental changes. 
(7) Electrocardiogram 
No changes related to the test substance were observed. 
(8) Hematology 
No changes related to the test substance were observed. It was determined that the changes 
observed in the hematology were not related to the test substance administration, as they 
were not dose-dependent, the ranges of changes were small, or the values were within the 
normal ranges. 
(9) Blood biochemistry 
No changes related to the test substance were observed. 
(10) Urinalysis 
No changes related to the test substance were observed. 
(11) Macroscopic observation  
No changes related to the test substance were observed. Other observed changes were 
determined to be the changes caused by intravenous administration (site of administration) or 
the spontaneous or incidental changes. 
(12) Measurement of organ weights 
No changes related to the test substance were observed. The increases and decreases observed 
as a result of the measurement of organ weights were determined to have no relationship to 
the dose or to be incidental changes not related to the test substance administration. 
(13) Toxicokinetics 
Dose dependence: When the test substance N-Rephasin⡶ SAL200 was administered 
intravenously to monkeys for 5 days at doses of 10–40 mg/kg, the systemic exposure (to be 
evaluated with AUClast) of N-Rephasin⡶ SAL200 showed a dose-dependent increase. N-Rephasin
⡶ SAL200 showed the maximum blood concentration (Cmax) of the test substance mostly at the 
first blood collection time (0.083–0.2 hr) after the intravenous administration, and then it 
decreased rapidly. 
Effect by repeated administration: The systemic exposure of N-Rephasin⡶ SAL200 after the 
repeated administration at an interval of 12 hours for 5 days (AUClast, Day 5, 2nd dosing) showed 
no difference compared to that at Day 1 (1st dosing). This pattern was also observed for the 
trough level. 
Differences depending on the gender: No differences were observed between the male and 
female animals in the study substance treatment group. 
Consideration 
and conclusion 
To investigate the toxicity of the test substance N-Rephasin⡶ SAL200 after repeated 
intravenous administration for 5 days, the test substance was administered intravenously in 3 
each of male and female cynomolgus monkeys in each group twice daily for 5 days repeatedly 
at doses of 0 (vehicle control group), 10, 20 and 40 mg/kg/day. During the study period, the 
mortality, observation of general symptoms, weight changes, and feed consumption were 
observed, and the temperature measurement, ophthalmic examination, electrocardiogram, 
urinalysis, hematology, blood biochemistry, necropsy findings, and organ weight measurement 
did not show any changes related to the test substance. According to the toxicokinetic results, 
the systemic exposure increased with an increase in the doses administered in male and female 
animals, and the difference in the systemic exposure and the accumulation in the body were 
not observed after the repeated administration for 5 days. In addition, there were no 
differences in the exposure according to the gender of the animals. 
 
 
 

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6.6 Data related to the clinical study 
The study drug (N-Rephasin⡶ SAL200) is an injection that contains 18 mg/mL of SAL-1 as the active ingredient. The 
study drug is a new drug and has no clinical use experience, but its safety was secured and its efficacy was 
demonstrated through preclinical studies. As a result of the Phase 1 clinical study conducted based on these 
demonstrated the safety and tolerability of the study drug [Table 3].  
 
6.6.1 Data related to the Phase 1 clinical study 
 
 [Table 3] Synopsis of the Phase 1 clinical study 
Study title 
A Randomized, Double-Blind, Placebo-Controlled, Single-Dosing, Dose-Escalating Study to 
Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of N-Rephasin⡶ SAL200 
after Continuous Intravenous Infusion in Healthy Volunteers  
Study drug 
N-Rephasin⡶ SAL200 
Study site and 
principal investigator 
Department of Clinical Pharmacology and Therapeutics, Seoul National University College 
of Medicine and Department of Clinical Pharmacology and Therapeutics, Seoul National 
University Hospital  
In Jin Jang, MD, PhD 
Clinical study duration 
November 27, 2013 
Date of Last Completion: February 7, 2014 
Study objective 
To evaluate the safety and explore the characteristics of pharmacokinetics and 
pharmacodynamics after continuous intravenous infusion of N-Rephasin⡶ SAL200 for 1 
hour in healthy male volunteers 
Study method 
This study was conducted as a randomized, double-blind, placebo-controlled, 
single-dosing, dose-escalating clinical study to evaluate the safety and explore the 
characteristics of pharmacokinetics and pharmacodynamics after continuous intravenous 
infusion of N-Rephasin⡶ SAL200 for 1 hour by dose group in healthy volunteers. 
As a preliminary study, 4 subjects were randomized to the 0.1 mg/kg dose group (3 
subjects for study drug and 1 subject for the placebo) to conduct the clinical study. Then, 
8 subjects in the 0.3, 1, 3 and 10 mg/kg dose groups were randomized (6 subjects for 
study drug and 2 subjects for the placebo) to conduct the clinical study. After completion 
of the administration in each dose group, the safety was evaluated to determine whether 
to proceed to the next dose group. 
The subjects deemed eligible for this clinical study were selected by performing 
screening tests, such as history taking, physical examination, and clinical laboratory tests, 
etc. within 4 weeks (Day −28 to Day −2) from a day before the clinical study initiation 
(Day −1) only in volunteers. Then, the subjects visited the research unit of the Seoul 
National University Hospital Clinical Trials Center by 1 p.m. on the day before the clinical 
study initiation (Day −1), and they had a skin test. After the skin test, the subjects who 
did not have specific reactions were admitted to the research unit of the Seoul National 
University Hospital Clinical Trials Center. Subjects who passed the skin test were assigned 
a subject number. The subjects fasted from 10 p.m. on the day of admission (Day −1), 
except for drinking water. The study drug or placebo was infused intravenously in all 
subjects, depending on the relevant treatment group, at around 9 a.m. on the next day of 
the admission, and the clinical study was conducted according to the clinical study 
schedule. After a certain period of time, post-study visit tests were performed in the 
subjects who completed the entire clinical study. 

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Number of subjects 
³ 57 subjects screened 
³ 36 subjects enrolled, 36 subjects received the administration, 34 subjects completed 
Dose group (mg/kg) 
Planned (N) 
Enrolled (N) 
Withdrawn (N) 
0.1 
4 
4 
1 
0.3 
8 
8 
0 
1 
8 
8 
0 
3 
8 
8 
1 
10 
8 
8 
0 
 
Subject eligibility 
 
1. Inclusion criteria 
1) Healthy male adults aged 20 to 45 years at screening 
2) Those whose weigh is ≥ 50 kg and < 90 kg and within the range of ±20% of the 
ideal body weight 
☞ Ideal body weight (kg) = (Height [cm] − 100) × 0.9 
3) Those who fully understood this clinical study after the detailed explanation, 
decided to voluntarily participate, and gave a written consent to comply with 
precautions  
 
2. Exclusion criteria 
1) Those who have clinically significant liver, kidney, nervous system, endocrine 
system, respiratory system, hemato-oncology, cardiovascular system, or mental 
diseases or past history 
2) Those who have had an infectious disease or suspected clinical findings within 30 
days prior to the date of the investigational product administration 
3) Those who are hypersensitive to drugs containing N-Rephasin⡶ SAL200 or other 
drugs (aspirin, antibiotics, etc.) or have a clinically significant hypersensitivity to 
them or who have a past history thereof 
4) Those who have received administration of drugs containing N-Rephasin⡶ SAL200 
5) Those who are antibody-positive to N-Rephasin⡶ SAL200 
6) Those who have SBP < 90 mmHg or DBP < 50 mmHg, or SBP > 150 mmHg or DBP 
> 100 mmHg in vital signs when measured after taking a 3-minute rest in a sitting 
position 
7) Those who have a past history of drug abuse or who are positive to urine drug 
screening 
8) Those who have taken any prescription drugs, oriental medicines or herbal 
medicines within 14 days prior to the date of the investigational product 
administration, or have taken over-the-counter (OTC) drugs or vitamin 
supplements within 7 days (However, if other conditions are appropriate upon 
judgment of the investigator, the subject may be selected as a subject.) 
9) Those who have received administration of other investigational products within 2 
months prior to the date of the investigational product administration 
10) Those who have donated whole blood within 2 months or apheresis blood within 
1 month prior to the date of the investigational product administration, or 
received blood transfusion within 1 month prior to the date of the initial 
administration 
11) Those who smoke cigarettes or who have been found to be nicotine 
metabolite-positive in urinalysis 
12) Those who continuously drink alcohol (exceeding 21 units/week; 1 unit = 10 g of 

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pure alcohol) or who cannot abstain from drinking alcohol and smoking cigarettes 
during hospitalization 
13) Those who are judged ineligible to participate in the clinical study by the 
investigator due to other reasons, including the results of clinical laboratory tests 
14) Those who do not agree to practice contraception using appropriate methods for 
60 days after the date of the administration, or those who do not consent to 
voluntarily report the female partner’s pregnancy to the sub-investigator until 90 
days after the date of the administration  
Method of 
administration of the 
investigational 
product 
Dose group 
(mg/kg) 
Subject 
(N) 
Treatment 
Volume 
0.1 
3 
Study drug, Placebo 
0.0056 ml/kg 
1 
0.0056 ml/kg 
0.3 
6 
Study drug, Placebo 
0.017 ml/kg 
2 
0.017 ml/kg 
1 
6 
Study drug, Placebo 
0.056 ml/kg 
2 
0.056 ml/kg 
3 
6 
Study drug, Placebo 
0.167 ml/kg 
2 
0.167 ml/kg 
10 
6 
Study drug, Placebo 
0.556 ml/kg 
2 
0.556 ml/kg 
 
At around 9 a.m. on Day 1, each of the subject received intravenous infusion of the 
investigational product corresponding to the treatment group for 1 hour continuously on 
an empty stomach. Drinking water was not allowed 1 hour before and after the 
administration, and the subjects kept fasting for 4 hours after starting the administration.  
Clinical evaluation 
Safety evaluation 
- Monitoring of adverse events, such as subject and objective symptoms 
- Physical examination, vital signs, clinical laboratory tests, 12-lead ECG 
 
Pharmacokinetic evaluation 
Blood was collected to evaluate the pharmacokinetics of N-Rephasin⡶ SAL200 after 
intravenous administration of the study drug. 
- Blood sampling (15 times): Pre-dose (0), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 
12, and 24 hours post-dose 
- Endpoints: Cmax, AUClast, AUCinf, tmax, t1/2, CL/F 
Statistical analysis 
Data presentation/Descriptive statistics 
³ 
All demographic information, safety and pharmacokinetic data were summarized 
using descriptive statistics according to appropriate factors, such as dose group and 
treatment group. 
 
Safety and tolerability data 
³ 
About the occurrence of adverse events, the number of cases occurred, number of 
subjects experiencing the cases, severity, seriousness, and causality relationship to 
the study drug were classified using the system organ classes and preferred terms of 
the MedDRA, and they were analyzed by dose group and treatment group in a 
descriptive statistical manner. 
³ 
Results of tests, such as vital signs, electrocardiogram, and clinical laboratory tests 
were reviewed collectively. 

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Pharmacokinetic data 
³ 
For pharmacokinetic parameters, the values were obtained for each subject, and 
their mean, standard deviation, etc. were provided in a descriptive statistical 
manner. 
³ 
The main pharmacokinetic parameters AUClast, AUCinf, and Cmax were calculated using 
a noncompartmental analysis method, and the values corrected by dose 
administered were also analyzed. 
Results 
Study subjects 
A total of 57 volunteers visited the Seoul National University Hospital Clinical Trials 
Center for screening, and 21 of them failed as ineligible subjects. A total of 36 subjects 
received the study drug or the placebo, and 2 of the subjects who received the 
administration withdrew their consent. Accordingly, a total of 34 subjects completed 
the clinical study. Subjects who received the investigational product were included in 
the safety evaluation set, and 27 subjects who received the administration of 
N-Rephasin⡶ SAL200 and completed blood collection for pharmacokinetics were 
included in the set for pharmacokinetic evaluation. 
 
Safety 
A total of 42 adverse events were reported in 12 out of 36 subjects in total who 
received either the study drug or the placebo during this study, and 3 of these cases 
occurred in 1 subject who received the placebo. No adverse events were reported in 
the 0.1 mg/kg dose group. A total of 11 adverse events were reported in the 
0.3–3 mg/kg dose groups, and 6 of these were related to the drug. The severity of the 
reported adverse events were evaluated as “mild” for 5 cases and “moderate” for 1 
case, and all of them recovered without sequelae and disappeared without any 
medical intervention except for 1 case in 1 subject (R207) who was positioned in a 
Trendelenburg position due to syncope that occurred before the administration. It was 
determined that hyperbilirubinemia (Subject R208 in the 0.3 mg/kg dose group), which 
was evaluated as a “moderate” case, was not a clinically significant result considering 
that the relevant level was high at screening, it decreased without any medical 
intervention afterward, and no related adverse events were reported or specific 
findings found during a physical examination.  
28 adverse events occurred in 6 subjects who received the study drug in the 10 mg/kg 
dose group. Of these, 25 cases were found to be related to the drug. Of the adverse 
events that were found to be related to the drug, 23 cases were reported as mild and 2 
cases were reported as moderate. A total of 5 subjects received the administration of a 
drug (acetaminophen) for treatment of adverse events, and all of them recovered 
without sequelae. On the other hand, no subjects discontinued the study due to 
serious adverse events and adverse events.  
Two subjects (subject numbers: R502, R503) who were evaluated as “moderate” felt 
discomfort due to rigors that occurred after the administration, and its severity was 
enough to interfere with other activities of daily living (using computers, reading 
books, etc.). All the relevant subjects received the administration of acetaminophen 
for treatment of adverse events as determined by the investigator, all of them 
recovered without sequelae, and they completed the clinical study.  
Based on the results above, it is evaluated that N-Rephasin⡶ SAL200 is safe and well 
tolerated from 0.1 mg/kg to 3 mg/kg when infused intravenously for 1 hour in healthy 
male volunteers. 
 
Pharmacokinetics 
When N-Rephasin⡶ SAL200 was infused intravenously for 1 hour at doses of 0.1, 0.3, 

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1, 3 and 10 mg/kg, the maximum blood concentration was reached at 25 minutes to 1 
hour, and then it was eliminated rapidly afterwards until 4 hours. Cmax and AUClast, 
which reflect the highest blood concentration and the exposure in the body of 
N-Rephasin⡶ SAL200, showed a pattern of a nonlinear increase pharmacokinetically in 
the dose groups ranging from 0.1 mg/kg to 10 mg/kg. The mean effective half-life of 
the drug, reflecting the mean residual time, was 0.04–1.23 (after baseline correction: 
0.04–0.38), and it tended to increase with an increase in the dose. 
 
 
Pharmacodynamics 
For the pharmacodynamic evaluation of this study, clear zone formation was 
compared after dripping each of the calibration sample prepared with N-Rephasin⡶ 
SAL200 at concentrations of 0–1.0 μg/mL and the serum samples obtained from 
subjects on the medium on which methicillin-resistant Staphylococcus aureus was 
smeared. In the 0.1 mg/kg and 0.3 mg/kg dose groups, no subjects showed results 
similar to the bacteria suppression effect observed in the calibration sample prepared 
with N-Rephasin⡶ SAL200 at 0.05 μg/mL. In the 1 mg/kg and 3 mg/kg dose groups, the 
bacteria suppression effects were similar in the serum sample obtained 1 hour after 
the administration and the calibration samples prepared with N-Rephasin⡶ SAL200 at 
concentrations of 0.1, 0.2 and 0.4 μg/mL. In the 10 mg/kg dose group, the bacteria 
suppression effect of the serum samples obtained at 1 and 1.5 hours after the 
administration in all subjects was similar to the bacteria suppression effect of the 
calibration samples prepared with N-Rephasin⡶ SAL200 at concentrations of 
0.1–0.6 μg/mL. In 3 subjects among them, the results corresponding to the bacteria 
suppression effect of the calibration samples prepared with N-Rephasin⡶ SAL200 at 
concentrations of 0.05–0.1 μg/mL were confirmed in the serum samples obtained 2 
hours after the administration. According to the correlation between the serum 
N-Rephasin⡶ SAL200 concentration of the entire subjects who received the study drug 
and the N-Rephasin⡶ SAL200 concentration of the calibration sample, the calibration 
sample prepared with N-Rephasin⡶ SAL200 at a concentration of 0.1 μg/mL or higher 
has the similar effect to the result of bacteria suppression when the blood 
concentration of N-Rephasin⡶ SAL200 is approximately 9.054 (9.015 after baseline 
correction) μg/mL or higher, and the serum measured 1 hour after the administration 
showed the same bacteria suppression effect as above in all subjects who received 
administration of N-Rephasin⡶ SAL200 at the 1 mg/kg dose or higher.  
 
Conclusion 
The continuous intravenous infusion of N-Rephasin⡶ SAL200 for 1 hour has excellent 
tolerability within the dose range of 0.1–3 mg/kg, and it showed pharmacokinetic 
nonlinearity within the dose range of 0.1–10 mg/kg. In the ex vivo pharmacodynamic 
evaluation, methicillin-resistant Staphylococcus aureus was inhibited as the dose 
increased within the dose range of 0.1–10 mg/kg. 
 
 
 

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7. Code name of the investigational product, etc. or generic name of the active 
ingredient, ingredients and their quantities, formulation, etc. 
7.1 Investigational product 
7.1.1 Study drug  
Product name 
N-Rephasin⡶ SAL200 
Remark 
Content of the 
active ingredient 
100% SAL200 (18 mg/mL as SAL-1) 
 
Formulation and 
appearance 
Injection filled with a colorless clear liquid in a colorless 
transparent vial 
 
Dosage and dosing 
regimen 
A single intravenous injection of N-Rephasin⡶ SAL200 in addition 
to a standard treatment 
 
Storage method 
Store in a freezer (−70 ± 5°C) 
 
Shelf life (effective 
period) 
18 months from the date of manufacture 
 
Manufacturer 
BINEX Co., Ltd. 
Entire 
manufacturing 
process contracted 
 
 
7.1.2 Placebo 
Product name 
INT200 – Placebo (Saline) 
Remark 
Content of the 
active ingredient 
Remaining formulation buffer excluding the active ingredient of 
the study drug 
 
Formulation and 
appearance 
Injection that has the same formulation and appearance as the 
study drug 
 
Dosage and dosing 
regimen 
A single intravenous injection of the placebo in addition to a 
standard treatment 
 
Storage method 
Store in a freezer (−70 ± 5°C)  
 
Shelf life (effective 
period) 
18 months from the date of manufacture 
 
Manufacturer 
BINEX Co., Ltd. 
Entire 
manufacturing 
process contracted 
 
 
7.2 Storage method and shelf life 
Store a sealed container in a freezer (−70 ± 5°C); 18 months from the date of manufacture 
 

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7.3 Packaging and labeling of the investigational product 
7.3.1 Packaging 
Each investigator will receive a sufficient quantity of the below investigational products as necessary from 
iNtRON Biotechnology, Inc., the sponsor of this study.  
Category 
Product name 
Packaging unit 
Ingredients and contents 
Study group 
N-Rephasin⡶ SAL200 
1 mL/vial 
100% SAL200  
(18 mg/mL as SAL-1) 
Control group 
INT200 – Placebo (Saline) 
1 mL/vial 
Remaining 
formulation 
buffer 
excluding the active ingredient of 
the study drug 
 
 
7.3.2 Labeling 
The labels provided by the study site will be used for the study drug and placebo, and if they are not provided, 
the sponsor will provide the study drug and placebo with the label with each of below information entered. The 
relevant visit cycle will be entered separately to distinguish the baseline and treatment visit cycles.  
 
[For Clinical Trial Use Only] 
Identification 
number 
assigned 
to 
the 
investigational product 
[Protocol number] 
[Code name of the product] or [generic name of the active ingredient] 
[Lot number] 
 
[Shelf life] 
 
[Storage method]  
 
Name and address of the Investigational New Drug application holder 
DO NOT USE FOR OTHER PURPOSES THAN CLINICAL TRIALS 
 
 
 
7.3.3 Management and records of the investigational product 
The investigational products (hereinafter referred to as the “clinical drug”) will be manufactured by iNtRON 
Biotechnology, Inc. and supplied to the clinical study site (hereinafter referred to as the “study site”), and they will 
be managed by the clinical trial pharmacist designated by the head of the study site. Whenever the clinical drugs 
are delivered, iNtRON Biotechnology, Inc. will deliver the quality assurance certificate for the clinical drugs to the 
clinical trial pharmacist at each time, and the clinical trial pharmacist must confirm the receipt and quantity of the 
clinical drugs provided by the sponsor and sign in writing. 
The clinical trial pharmacist should properly store and manage the study drugs and the control drugs according to 
the KGCP regulations and the protocol and should communicate with the investigator closely to mutually confirm 
the accountability of all clinical drugs used in the clinical study.  
The clinical drugs must be dispensed according to a prescription signed by the attending physician participating 

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as an investigator in this study, and the initial of the subject, subject number, date of dispensation, quantity, etc. 
should be recorded in the “investigational product accountability log.” 
In addition, the clinical trial pharmacist should accurately record the quantity of the drugs supplied by iNtRON 
Biotechnology, Inc., the quantity of dispensation, and the quantity of remaining drugs, and all drugs not used in the 
clinical study at the end of the study should be returned to the sponsor. 
The clinical research associate should periodically check the quantity of the clinical drugs stored by the clinical 
trial pharmacist in order to confirm the history of use of all clinical drugs. If the clinical study is completed or is 
discontinued in the middle, issues related to the collection or disposal of all clinical drugs shall be handled based on 
the sponsor’s request. 
In any case, the investigator should not supply the clinical drugs and related products to other investigators or 
study sites or use them for any purpose other than that specified in the protocol, unless approved by the sponsor. 
The clinical drug provided to the subjects will be covered by iNtRON Biotechnology, Inc. 
 
 
8. Target disease 
Blood infections (bacteremia) caused by methicillin-susceptible and -resistant Staphylococcus aureus  
 
 
9. Criteria for the inclusion and exclusion of subjects, target number of subjects and its 
rationale 
This clinical study will be conducted in patients with MSSA/MRSA bacteremia caused by Staphylococcus aureus who 
meet the inclusion criteria and do not fall under the exclusion criteria. 
  
9.1 Inclusion criteria 
This clinical study will select those who meet the following conditions as the subjects: 
1) Those with MSSA/MRSA bacteremia who are confirmed to have more than two pairs of Gram-positive bacteria 
in a blood culture performed at 48–96 hours after the start of antibiotic treatment to which S. aureus is 
susceptible 
2) Males and females aged ≥ 19 years 
3) Those who understand the information in the subject information sheet and received the informed consent 
form 
 
9.2 Exclusion criteria 
Patients who fall under any of the following conditions cannot participate in this clinical study: 
1) In the cases that an appropriate antibiotic has not been administered within 48 hours after the occurrence of 
bacteremia (the report time point of Department of Laboratory Medicine) 
2) In the cases that the Gram-positive strain, identified in a blood culture performed at 48–96 hours after the 
start of antibiotic treatment to which S. aureus is susceptible, is not the same strain of S. aureus which was 
cultured when the definite diagnosis of S. aureus bacteremia was made 
3) Those who have passed 48 hours after confirmation of persistent S. aureus bacteremia through a blood culture 
performed at 48–96 hours after the start of antibiotic treatment to which S. aureus is susceptible 

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4) Those who have symptoms of septic shock at the time of acquisition of the informed consent form 
³ In the cases that systolic blood pressure is < 90 mmHg or blood pressure is lower than usual by ≥ 40 mmHg 
despite appropriate fluid treatment is given 
³ In the cases that a hypertensor is required to be used to maintain systolic blood pressure at ≥ 90 mmHg 
5) Those who are infected with mixed bacterial species 
6) Those who are hypersensitive to N-Rephasin⡶ SAL200 or have a clinically significant hypersensitivity to it or 
who have a past history thereof 
7) Pregnant or breastfeeding women and women of child-bearing potential (those who have a possibility to 
become pregnant and do not agree to take appropriate contraceptive measures during the study period) 
8) Those who participated in other clinical studies within 30 days prior to enrollment as subjects 
9) Patients with any conditions that may interfere with study participation or accurate evaluation according to 
the investigator’s judgment 
10) Those who may die within 72 hours due to other serious complications (e.g., cerebral infarction) according to 
the investigator’s judgment 

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9.3 Target number of subjects and its rationale 
This is a Phase IIa clinical study to evaluate the clinical efficacy and safety of N-Rephasin⡶ SAL200 in addition to a 
conventional standard treatment in patients with persistent bacteremia caused by Staphylococcus aureus.  
The primary endpoints are the safety endpoints to be evaluated by presenting a distribution table of the number 
of subjects who experienced at least one side effect (incidence) and distribution tables of the relationship of the 
investigational product to the reported adverse events (distribution tables for severity and the relationship to the 
drug) for each group (study group, control group). Also, the purpose of this study is to obtain baseline data on the 
study drug and control drug.  
The primary evaluation will use descriptive statistics for the study drug and control drug, and no hypothesis 
testing will be performed. The number of subjects required was 20 subjects respectively in the study group and 
control group considering their representativeness, and it has been decided to enroll 25 subjects in each group 
considering a dropout rate of 20%. 
 
Arms 
Drug regimen 
Number of 
subjects for safety 
evaluation 
Number of subjects 
including a dropout rate 
(approximately 20%) 
Control 
group 
Standard treatment for MSSA/MRSA + placebo 
20 
25 
Study 
group 
Standard treatment for MSSA/MRSA + 
N-Rephasin⡶ SAL200 
20 
25 
 
 
In 50 subjects in total, the clinical study will be divided into 2 steps—Step 1 (28 or more and 32 or less subjects) 
and Step 2 (approximately 22 subjects). 
Upon completion of Step 1 of this clinical study at the discretion of the sponsor, the IDMC will perform an interim 
evaluation of the safety and efficacy, and the study will proceed to Step 2, if the investigational product is 
determined to be safe. 
 
Number of subjects in each step 
Step 1 
Interim 
evaluation 
Step 2 
28–32 subjects 
Approximately 
22 subjects 
 
 
10. Duration of the clinical study 
The duration of this study will be 36 months from the date of approval for the clinical study by the IRB.  
However, in the case of a situation that may affect the progress of the clinical study, such as a difficulty in selecting 
subjects, the duration may be changed.  

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11. Methods of the clinical study 
11.1 Design of the clinical study 
This is a multi-center, randomized, double-blind, placebo-controlled, parallel-group, Phase IIa clinical study to 
explore the efficacy and confirm the safety through the confirmation of microbiological eradication of pathogens by 
performing blood cultures in each group after 18 hours (± 6 hours) from the time of administration of the study 
drug or control drug (placebo) after a single intravenous administration of N-Rephasin⡶ SAL200 and the control 
drug (placebo) in addition to treatment with a conventional standard treatment in patients with persistent 
MSSA/MRSA bacteremia despite treatment with a standard treatment. The subjects will be randomized using a 
random code program of the statistical SAS program to design the study to have approximately the same number of 
subjects in the two groups. 
To maintain the blinding status, neither the investigator nor the subject will know to which group each subject is 
assigned while conducting the study. Unblinding will not happen unless a medical emergency occurs, and the 
confidentiality of the assigned groups will be maintained. In the case of unblinding due to an adverse event, etc., it 
must be reported to the IRB and informed to the sponsor.  
 
11.2 Process of the clinical study 
 
<Clinical study schedule> 
 
1) Patients whose S. aureus bacteremia lasts for 48 hours or longer even after the standard treatment for S. aureus 
bacteremia 
2) Randomization according to the study site 
3) The control group will receive a single intravenous injection of the placebo in addition to the standard treatment 
for persistent S. aureus bacteremia. 
4) The study group will receive a single intravenous injection of N-Rephasin⡶ SAL200 at 3 mg/kg in addition to the 
Confirmation of 
persistent 
bacteremia 
N-Rephasinט SAL200 or placebo 
administration 
Susceptible 
antibiotic 
treatment 
initiation 
2nd blood 
culture 
G(+) 
confirmation 
Obtaining 
an informed 
consent 
form 
Blood culture/determine negative conversion in the 
first blood culture 
Blood culture/determine 2 consecutive negative conversions 
Final confirmation of treatment 
success/failure 
1st blood 
culture 
1st blood culture 
MSSA/MRSA 
confirmation 
Standard of care 
initiation 
Last treatment visit 
Follow-up 
Administration of a standard treatment for MSSA/MRSA until confirmation of 2 
consecutive negative conversions 
General examination schedule prior 
to obtaining consent 

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standard treatment for persistent S. aureus bacteremia. 
5) A blood culture is performed 18 hours (± 6 hours) after administration of N-Rephasin⡶ SAL200. 
6) Blood cultures will continue to be performed every 24 hours (± 6 hours) or 48 hours (± 6 hours) after the time 
point of the previous blood culture performed until the results of the blood culture at 2 consecutive days (e.g., 
Day 2 and Day 3, or Day 8 and Day 10) are confirmed as negative conversions (treatment completion) in blood 
cultures 
7) Side effects will be observed at the time point of the first blood culture after administration of N-Rephasin⡶ 
SAL200 or the placebo and at the time point at intervals of 24 hours or 48 hours thereafter 
 
11.3 Randomization of subjects 
A randomization method will be used to guarantee the scientific validity of the clinical study and to ensure that the 
investigator’s personal opinion is not involved in assigning subjects to each treatment group.  
Once the subjects who satisfy the subject inclusion criteria are selected, the investigator will assign the randomization 
numbers to the subjects sequentially in the order of randomization. 
 
For the randomization, a stratified block randomization method, which has been stratified by study site, will be 
used. 
Randomization codes will be generated using the PROC PLAN procedure of SAS (version 9.2). 
The enrolled subjects will be assigned to the study group and control group at a ratio of 1:1 according to the 
randomization codes. 
 
The randomization number will consist of 1 letter of a study site code and 2 digits assigned in the order of 
randomization.  
 
R  
 
 
 
Serial No. 
 
The investigator will use this number to prescribe the investigational product, and the clinical trial pharmacist will 
dispense the investigational product with the number that matches the prescribed assignment number to the subject. 
The subject numbers and randomization numbers of the subjects dropped out from the study will remain 
continuously. In the case of dropping out, the relevant numbers will also drop out. A new subject must be assigned a 
new subject number and randomization number. 
 
11.4 Dosage and method of administration  
Subjects will be determined whether they are eligible for this clinical study at the screening visit. Eligible subjects 
will be assigned randomization numbers, and the clinical study will be conducted according to the schedule of 
clinical study plan. In this step, the drugs used in the following clinical study will be administered: 
 

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Investigational product 
Active ingredient 
Method of administration 
Study drug 
N-Rephasin⡶ SAL200 
SAL-1 18 mg/mL 
A single intravenous injection of N-Rephasin⡶ 
SAL200 in addition to a standard treatment 
Placebo  
Remaining formulation buffer 
excluding the active ingredient of 
the study drug 
A single intravenous injection of the placebo in 
addition to a standard treatment 
 
During the treatment period, the standard treatment for MSSA/MRSA bacteremia will be given, and at the same 
time, a single dose of the study drug (or placebo) will be administered intravenously to the subject. The placebo and 
study drug are in the same kind of containers that cannot be distinguished visually. Each case packaged by serial 
number will be each labeled separately, and the clinical trial pharmacist will deliver them to the investigator 
according to the prescription issued separately. The placebo or study drug will be administered directly to the 
subject.  
 
In 50 subjects in total, the clinical study will be divided into 2 steps—Step 1 (28 or more and 32 or less subjects) 
and Step 2 (approximately 22 subjects). 
Upon completion of the clinical study in subjects in Step 1, the IDMC will perform an interim evaluation of the 
safety and efficacy, and the study will proceed to Step 2, if the investigational product is determined to be safe. 
 
 
 
Step 
Number of subjects 
Dose and method of administration 
1 
Approximately 28 subjects 
(28 or more and 32 or less 
subjects) 
① Calculate the dose in consideration of the body 
weight in order to administer the investigational 
product at a dose of 3 mg/kg. 
 : Weight of the subject (kg) × 3 mg/kg = Dose of the 
investigational product (mg) 
② Dilute the dose calculated in ① in normal saline, 
and prepare the injection to have 110 mL as the volume 
of the entire solution. 
③ Administer the injection solution prepared in ② to 
the subject intravenously at an infusion rate of 
155 mL/hr. 
The IDMC will perform an interim evaluation of the safety and efficacy in subjects in Step 1 and issue a 
report. The safety will be confirmed in the interim evaluation report, and the study will proceed to Step 2 
2 
Approximately 22 subjects 
The study will proceed using the same method of 
administration as in Step 1. 
Total Subjects 
50 subjects 
25 subjects in the study group : 25 subjects in the 
control group 
 
 
 

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11.5 Administration period 
The study drug or placebo will be administered to all randomized subjects once at Day 1 during the clinical study 
period depending on the group to which the subjects are assigned. Along with this, treatment using a standard 
treatment will be performed concomitantly until the blood culture results are confirmed as negative conversions 
(treatment completion) at 2 consecutive days. 
 
11.6 Blinding and unblinding 
This clinical study will maintain the blinding of the investigator and the subject from the information on the type 
of drug assigned to each subject. By maintaining double-blinding of the investigator and subject, the investigator’s 
and subject’s bias in the evaluation of the therapeutic effect and adverse events, etc. can be prevented.  
When unblinding is deemed necessary due to such a reason as an emergency situation threatening the subject’s 
safety, the investigator is required to notify this immediately to the sponsor or the clinical research associate of a 
contract research organization outsourced by the sponsor. The clinical research associate is required to contact the 
relevant study staff member of the sponsor immediately. After receiving the relevant information, the relevant 
study staff member of the sponsor will discuss with the investigator to decide whether or not to unblind and will 
document the decision made. After discussing with the sponsor, the investigator will obtain the investigational 
product information of the relevant subject, check and print the email for notification of unblinding, and keep it in 
the investigator file. In the case that the sponsor cannot be reached immediately, the investigator will open the 
emergency unblinding envelope kept in the file, obtain the investigational product information of the relevant 
subject, write the date and time of opening on the emergency unblinding envelope, sign, and keep it in the 
investigator file. In this case, the investigator will notify the sponsor of the unblinding of double-blinding as soon as 
possible and document the reason for unblinding without having a discussion with the sponsor. 
 
If the investigator becomes aware of the subject’s code during the course of the study, the investigator will 
endeavor to eliminate bias during the efficacy and safety evaluation. 
 
In the case that a serious adverse event such as death occurs, regardless of the unblinding status of the 
investigator, the IDMC may have access to the information of the group to which the relevant subject is assigned 
and evaluate the adverse event, if deemed necessary by the sponsor.  
 
After the end of the study, problems will be resolved through discrepancies (queries) of all data. Once the 
database is confirmed to be complete and accurate, the data will be locked, and the randomization code 
information will be disclosed. Subsequent changes to the database can only be made with the written consent of 
the sponsor and the database manager. 
 
 
11.7 Concomitant medication administration criteria  
11.7.1 Drugs required for concomitant treatments 
This is a comparative clinical study between the monotherapy group in which the standard treatment for 
persistent bacteremia caused by Staphylococcus aureus was administered and the concomitant therapy group in 
which the study drug N-Rephasin⡶ SAL200 was administered in addition to the standard treatment, and it will be 
conducted using the concomitant treatment with the treatments shown below, which are the standard treatments 
for persistent bacteremia caused by Staphylococcus aureus.  

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Standard 
treatment 
type 
Active 
ingredient 
Method of administration 
1. MSSA  
nafcilin 
1-2 g IV q4-6h 
cefazolin 
1-2 g IV q8h 
cefepime 
1-2 g IV q8-12h 
ceftriaxone 
1-2 g IV q12-24h 
cefotaxime 
1-2 g IV q6-8h 
vancomycin 
1 g IV q12h (to be adjusted based on the renal function) 
teicoplanin 
400 mg (6 mg/kg) IV q12h × 3, then 400 mg (6 mg/kg) IV q24h 
linezolid 
600 mg IV or PO q12h 
rifampin 
450-600 mg PO qd 
2. MRSA 
vancomycin 
1 g IV q12h (to be adjusted based on the renal function) 
teicoplanin 
400 mg (6 mg/kg) IV q12h × 3, then 400 mg (6 mg/kg) IV q24h 
linezolid 
600 mg IV or PO q12h 
rifampin 
450-600 mg PO qd 
 
 
 
11.7.2 Medications and treatments allowed to be administered and performed concomitantly 
During this clinical study period, drugs and treatments will not be prohibited separately except for the items in 
Section “11.7.3” below. In addition, drugs that the subject has been taking before participating in this clinical study 
can be continued and their dosage and dosing regimen can be changed even after participating in the clinical study, 
and new drugs and treatments started during the participation period will not be prohibited separately. However, 
the types and increases/decreases in doses of the drugs and treatments should be documented accurately. 
 
 
11.7.3 Medications and treatments prohibited from being administered and performed concomitantly  
The below drugs and treatments will be prohibited during this clinical study period. 
 Investigational products other than for this clinical study 
 In the case that the investigator determines that other drugs and treatments may significantly affect the 
result of the clinical study 
 
11.8 Discontinuation of the administration 
Subjects may withdraw their consent at any time without a justifiable reason. In addition, the investigator may 
discontinue the administration, if the subject’s clinical condition is deemed difficult to proceed with the clinical 
study. Similarly, if the sponsor or relevant government agencies find situations that require discontinuation of the 
clinical study, they may require early termination. Reasons for discontinuation of administration include the 
following: 
1) Withdrawal of consent by the subject 
2) In the case that the investigator determines that it is difficult to proceed with the clinical study due to any 
other reasons (such as serious adverse events) 

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3) Medications and treatments prohibited from being administered and performed concomitantly 
4) Deviation from the inclusion/exclusion criteria (in the case that the blood culture obtained after the 
investigational product administration is infected with other bacterial organisms, the subject will not be 
dropped out due to the criterion “Those who are infected with mixed bacterial species.”) 
5) In the case that the subject does not follow the specified treatment schedule 
In the case of discontinuation of the subject’s drug administration due to the above reasons, the reason for 
discontinuation and the date of implementation should be recorded in the case report form, medical record, etc. of 
the subject. 
 
 
 
 
12. Observation items, clinical test items, and observation test methods  
12.1 Observation items 
Once the eligibility of the subject based on the inclusion and exclusion criteria is confirmed through screening 
tests, the investigational product will be supplied to conduct the clinical study. The planned visits and the plan for 
tests and assessments required at each visit are as shown in [Table 4] Clinical study schedule table.  
The subject will participate in the clinical study for a total of 15 days (screening window period: ±1 day) except for 
the follow-up (W4 ± 5 days). In the case of a subject who complete the study early, the subject will participate in the 
clinical study from the day of screening until the day of early completion (screening window period: ± 1 day). In the 
case of the follow-up (W4 ± 5 days), telephone monitoring will be performed mandatorily, and if the subject is able 
to make a visit, the subject will visit the hospital as an outpatient to have the test items performed. 
Visits other than the treatment visits will be documented in the unscheduled visit CRF, and the purpose of visit 
and the results processed will be documented. Data obtained from these additional visits will be recorded in source 
data as well as in the case report form. If this is reported to the investigator, it should be recorded in the section for 
the occurrence of adverse events that must always be recorded, or in the case of discontinuation of this study, it 
should be recorded in the relevant section in the case report form.  
 
In the case of early termination of the study, the subject will be asked to make the final visit, if possible, to have 
the procedures for the follow-up (W4 ± 5 days) performed and complete the relevant pages in the case report form 
that include an end-of-study form and a confirmation statement form. The primary reason for dropping out 
(adverse event, noncompliance with the protocol, or other reasons) should be specified in the case report form. The 
end-of-study form should be completed even if the subject is not able to make the final visit. 
 
12.1.1 Demographic information 
The demographic information of subjects, such as the name, gender, and age, will be investigated. 
 
12.1.2 Medical history and medication history  
 Medical history: Medical/surgical history, comorbidities, drug hypersensitivity, and history of surgery (within 
the last 1 year) 
 Medication history: The drugs that have been taken since 1 month prior to screening will be investigated.  

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12.1.3 Vital signs 
 Vital signs: Blood pressure, pulse, and temperature  
 
12.1.4 Physical examination 
 Physical examination: This test will use history taking, inspection, palpation, etc. to examine the general 
conditions, skin/mucous membrane, eyes, otorhinolaryngological system, cardiovascular system, respiratory 
system, gastrointestinal system, genitourinary system, nervous system, musculoskeletal system, lymphatic 
system, obstetric and gynecological system, and other body organs. Physical examination will be performed 
at screening and Day 2, and it will be performed at an interval of once in 2 days after Day 2—Days 4, 6, 8, 10, 
12, and 14. It will be performed until negative conversions are confirmed (treatment completion) in blood 
culture/evaluation at 2 days consecutively. 
 
12.1.5 Laboratory tests and pregnancy test 
 Laboratory tests: Hematology, blood biochemistry, urinalysis 
Laboratory tests will be performed at screening and Day 2, and will be performed at Day 7 (± 48 hours) and 
Day 14 (± 48 hours) after Day 2. 
Hematology 
: 
WBC, RBC, Hemoglobin, Platelets 
Blood chemistry 
: 
Total protein, Albumin, Total bilirubin, AST, ALT, ALP, 
Total cholesterol, Serum creatinine 
Urinalysis 
: 
Protein, Glucose, Blood, Ketones 
* In the case that negative conversions (treatment completion) are confirmed at 2 consecutive days before Day 
7, the treatment schedule (Day 1 to Day 14) will be completed after performing these test items.  
 Pregnancy test: A pregnancy test (serum/urine HCG) will be included in the case of women of childbearing 
potential. 
 
12.1.6 Anaphylaxis test and inflammatory cytokine test  
The tests will be outsourced to an external laboratory in order to examine the anaphylaxis and inflammatory 
cytokine aspects of the investigational product, and blood samples for these tests will be collected and stored 
(when collecting blood samples for anaphylaxis testing, use a blood collection tube that contains Futhan 
[FUT-175], which is a protease inhibitor). The anaphylaxis test and inflammatory cytokine test will be performed 
at Day 1 (before the investigational product administration and immediately after the end of the administration), 
Day 2, and Day 7 (± 48 hours). 
 Anaphylaxis test: C3a, C4a, mast cell tryptase 
 Inflammatory cytokine test: IL1b, IL-2, IL-6, TNF-α 
*  In the case that negative conversions (treatment completion) are confirmed at 2 consecutive days before 
Day 7, the treatment schedule (Day 1 to Day 14) will be completed after performing these test items.  
 
12.1.7 Skin test 
The study drug (N-Rephasin⡶ SAL200) will be diluted in normal saline at a concentration of approximately 
0.05% (v/v) in order to make a test solution. Using this solution, a skin test will be performed on one arm. 

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Subjects with an unusual response will drop out from the clinical study, and only those who are negative 
according to the acceptance criteria may be enrolled in this clinical study.  
1) Injection site: Inside the forearm 
2) Method of injection: Place a 26G needle with bevel up, and puncture at an angle of 10 to 15 degrees, but 
only insert the bevel of the needle under the skin. Administer the minimum amount (100 μL at a 
concentration of approximately 0.05% [v/v]) of the diluted solution intradermally to test skin sensitization. 
Observe skin redness, etc. 15 minutes after the injection, and evaluate based on the acceptance criteria.  
3) Acceptance criteria 
(a) If a wheal of at least 3 mm diameter appears along with redness: Positive 
(b) If there is a wheal of at least 3 mm diameter but no redness: Undetermined and re-test required 
(c) If the diameter of a wheal is 3 mm or smaller regardless of redness: Negative 
(d) Retest if the result is equivocal 
 
12.1.8 Blood culture/evaluation (blood collection) 
 Blood cultures: Collection of blood samples for blood cultures will be carried out based on the following 
schedule: the collection at Day 2 will be carried out to fulfill 18 hours (± 6 hours) from the administration of 
the investigational product, the collection at Days 3–8 will be carried out to fulfill 24 hours (± 6 hours) from 
collection of blood samples for blood cultures for the previous time point (once daily), and the collection at 
Days 8–14 will be carried out to fulfill 48 hours (± 6 hours) from collection of blood samples for previous 
blood cultures (once in 2 days). Collection of blood samples for blood cultures will be performed throughout 
the clinical study period until negative conversions (treatment completion) are confirmed at 2 consecutive 
days. 
Two sets of blood samples for blood cultures will be collected (in principle, there should be an interval of at 
least 30 minutes between 2 sets of blood samples, but the time difference is not required, if blood samples 
are collected from different parts).  
1) Select a blood vessel at the site of blood collection, wrap the part with a rubber band, and unwrap after 
checking the vein. Wrap the rubber band at 10 cm above the site of collection, and do not wrap it too 
tight and longer than 2 minutes. 
2) Wipe the area around the skin at the site of blood collection thoroughly with a 70% alcohol swab. 
3) Apply 2% povidone iodine to the area that was wiped with an alcohol swab. 
4) After 2 minutes, draw 10 mL of blood without touching the disinfected area. 
5) After removing the injection needle, press the area with an alcohol swab. 
6) Add 5 mL aseptically to an aerobic culture bottle for culturing. 
7) Add 5 mL aseptically to a 50-mL anaerobic culture bottle for culturing. 
8) Record the subject’s initials, enrollment number, date, time, and site of collection on the culture bottle.  
 
 Evaluation of blood cultures: 
1) If the organism is growing during the culture period, an automated device will sound an alarm, and at 
this time, the growth of the organism can be checked in the laboratory. The laboratory will confirm that 
the bacterium growing is a gram-negative organism or a gram-positive organism, and it will be reported 
in the electronic medical record and informed to the medical staff. Thus, the culture status in the 
automated device will be checked frequently. 
2) The usual blood culture period is 2 to 3 days. 

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12.2 Clinical study schedule 
[Table 4] Clinical study schedule table 
 
 
Observation item 
Screening10 
Treatment 
Follow-up11 
D-1 
D112 
D2 
D3~D13 
D14 
4W ± 5d 
Written consent 
√ 
 
 
 
 
 
Checking on the 
inclusion/exclusion criteria 
√ 
 
 
 
 
 
Randomization1 
 
√ 
 
 
 
 
History of illness 
√ 
 
 
 
 
 
Data on demographic statistics 
√ 
 
 
 
 
 
Vital Signs2 
√ 
√2 
√ 
√ 
√ 
( √ ) 
Physical examination3 
√ 
 
√ 
√3 
√ 
( √ ) 
Laboratory 
tests4, 13 
Hematology 
√ 
 
√ 
√4 
√ 
( √ ) 
Blood chemistry 
√ 
 
√ 
√4 
√ 
( √ ) 
Urinalysis 
√ 
 
√ 
√4 
√ 
( √ ) 
Anaphylaxis test5, 13 
 
√ 
√ 
√5 
 
 
Inflammatory cytokine test5, 13 
 
√ 
√ 
√5 
 
 
Pregnancy test6 
√ 
 
 
 
 
( √ ) 
Skin reaction test 
√ 
 
 
 
 
 
Administration of the 
investigational product7 
 
√ 
 
 
 
 
Administration of drugs required 
for concomitant treatments8 
 
√ 
√ 
√ 
√ 
 
Blood culture/evaluation (blood 
collection)9 
 
 
√ 
√9 
√ 
 
Checking on medication 
history/concomitant medications 
√ 
√ 
√ 
√ 
√ 
√ 
Checking on concomitant 
treatments 
 
√ 
√ 
√ 
√ 
√ 
Adverse events 
 
√ 
√ 
√ 
√ 
√ 
1. Subjects who have passed screening will be assigned a subject number via randomization. 
2. Vital signs will be measured once daily during the remaining treatment period except for Day 1 (including screening), 
and they will be measured 12 times at the following time points at Day 1: 
- Before administration of the investigational product (1 time) 
- 15 and 30 minutes after initiation of the investigational product administration (2 times) 
- Immediately after the end of the investigational product administration, 30 minutes, 1, 2, 3, 4, 8, 16, and 24 hours 
after the administration (9 times) 
3. Physical examination will be performed at screening and Day 2, and it will be performed at an interval of “once in 2 
days” after Day 2 (Days 4, 6, 8, 10, 12, and 14). It will be performed only until when the results of the blood 
culture/evaluation at 2 consecutive days are confirmed (treatment completion) as negative conversions. 
 
 
 
 

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4. Laboratory tests will be performed at screening and Day 2, and will be performed at Day 7 (± 48 hours) and Day 14 (± 48 
hours) after Day 2. 
Hematology 
: 
WBC, RBC, Hemoglobin, Platelets 
Blood biochemistry 
: 
Total protein, Albumin, Total bilirubin, AST, ALT, ALP, Total cholesterol, 
Serum creatinine 
Urinalysis 
: 
Protein, Glucose, Blood, Ketones 
5. The anaphylaxis test and inflammatory cytokine test will be performed at Day 1 (before the investigational product 
administration and immediately after the end of the investigational product administration), Day 2, and Day 7 (± 48 
hours). 
Anaphylaxis test: 
C3a, C4a, Mast Cell Tryptase  
Inflammatory cytokine test: 
IL-1b, IL-2, IL-6, TNF-α 
6. A pregnancy test will be performed as a urine test or a serum hCG test only for women of childbearing potential. 
7. The enrolled subjects will receive administration of the investigational product at Day 1. 
8. Administration of drugs required for concomitant treatment will be among the drugs in “11.7.1 Drugs required for 
concomitant treatments” as determined by the investigator. 
9. Collection of blood samples for blood cultures at Day 2 will be carried out to fulfill 18 hours (± 6 hours) from the 
administration of the investigational product, collection of blood samples for blood cultures at Days 3–8 will be carried 
out to fulfill 24 hours (± 6 hours) from collection of blood samples for blood cultures for the previous time point (once 
daily), and collection of blood samples for blood cultures at Days 8–14 will be carried out to fulfill 48 hours (± 6 hours) 
from collection of blood samples for previous blood cultures (once in 2 days). Collection of blood samples for blood 
cultures will be performed throughout the clinical study period until negative conversions (treatment completion) are 
confirmed at 2 consecutive days. 
10. In the case that a subject has records of the relevant laboratory tests 7 days before screening, patient records may be 
used without performing additional laboratory tests at screening. 
11. The tests for the relevant date will be performed when the subject visits for a follow-up at W4 ± 5 days, and 
concomitant medications, concomitant treatment, and adverse events will be checked via telephone monitoring. In the 
case of the subjects who can visit the hospital as outpatients, vital signs, physical examination, and laboratory tests will 
be performed, and concomitant medications, concomitant treatments, and adverse events will be checked as well.  
12. Subjects who are suitable for the subject eligibility can have procedures for Day −1 and Day 1 simultaneously. 
13. In the case that negative conversions (treatment completion) are confirmed at 2 consecutive days before Day 7, 
laboratory tests, anaphylaxis test and inflammatory cytokine test will be performed additionally. 
 

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12.3 Visit schedule 
The test procedures based on the clinical study schedule are as shown below, and during this participation period, 
subjects will continue the administration of conventional drugs for the “standard treatment” used to treat 
bacteremia. 
12.3.1 Screening (Day −1) 
 After providing a detailed explanation of this clinical study prior to participation of the patient, obtain a 
written consent, and assign the screening no. in the order of enrollment.  
 Investigate the demographic data and medical history (for the medical history, obtain the items within 1 
year prior to participation in the clinical study). 
 Examine vital signs (blood pressure, pulse, and temperature). 
 Perform a physical examination. 
 Medication history: Investigate the drugs taken by the subject within 1 month of obtaining the informed 
consent form (all drugs including oral contraceptives). 
 Obtain blood samples for laboratory testing and urine or blood samples for urinalysis and pregnancy 
testing, and investigate the observation items (perform a pregnancy test in female patients who may be 
pregnant or who have been postmenopausal for less than a year, and enroll only those who are negative as 
subjects). 
Hematology 
: 
WBC, RBC, Hemoglobin, Platelets 
Blood chemistry 
: 
Total protein, Albumin, Total bilirubin, AST, ALT, ALP, 
Total cholesterol, Serum creatinine 
Urinalysis 
: 
Protein, Glucose, Blood, Ketones 
 Perform a skin test to check the sensitivity to the study drug (N-Rephasin⡶ SAL200). 
 Check the inclusion/exclusion criteria for eligibility, and perform procedures in the next visit schedule in 
only the eligible subjects. 
 To use for randomization, identify the type of infecting organism (MRSA, MSSA) and the route of infection 
in the eligible subjects. 
Î The procedures for the day of the screening visit (Day −1) and Day 1 can be performed together, and 
the clinical study can be initiated on the same day as determined by the principal investigator.  
 
 
12.3.2 Administration of the investigational product (Day 1) 
The subject will receive the investigational product and will proceed with the study in the following order: 
 Assign the randomization numbers to the eligible subjects based on the inclusion/exclusion criteria at 
screening. 
 Examine vital signs (blood pressure, pulse, and temperature) at the time intervals stated below. (12 times 
in total) 
• 
Before administration of the investigational product (1 time),  
• 
15 and 30 minutes after initiation of the investigational product administration (2 times),  
• 
Immediately after the end of the investigational product administration (1 time),  
• 
30 minutes, 1, 2, 3, 4, 8, 16, and 24 hours after the end of the investigational product 
administration (8 times) 
 

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 Before administration of the investigational product and immediately after the end of the investigational 
product administration, collect and store blood samples for anaphylaxis testing and inflammatory 
cytokine testing (when collecting blood samples for anaphylaxis testing, use a blood collection tube that 
contains Futhan [FUT-175], which is a protease inhibitor). 
Anaphylaxis test: 
C3a, C4a, mast cell tryptase  
Inflammatory cytokine test: 
IL-1b, IL-2, IL-6, TNF-α 
 
 Administer the investigational product (N-Rephasin⡶ SAL200 or placebo) by intravenous drip infusion 
over approximately 60 minutes. 
 Perform the required concomitant treatments. 
 Investigate the adverse events, concomitant medications, and concomitant treatments.  
* Adverse events will be collected from the time of initiation of the investigational product 
administration until the follow-up visit, and concomitant medications and concomitant treatments will 
be collected from within 1 month prior to obtaining the informed consent form until the follow-up visit 
(W4 ± 5 days).  
 
 
12.3.3 Follow-up observation period (Day 2 to Day 14) 
 
X Day 2 
The subjects will receive treatment for bacteremia with standard treatments until the completion of treatment 
and have follow-up observation until Day 14 or when the results of the blood culture at 2 consecutive days (e.g., 
Day 2 and Day 3, or Day 8 and Day 10) are confirmed as negative conversions (treatment completion), and the 
subjects will proceed with in the following order: 
 
 Examine vital signs (blood pressure, pulse, and temperature). 
 Perform a physical examination. 
 Obtain blood and urine samples for laboratory testing, and investigate the observation items. 
Hematology 
: 
WBC, RBC, Hemoglobin, Platelets 
Blood chemistry 
: 
Total protein, Albumin, Total bilirubin, AST, ALT, ALP, 
Total cholesterol, Serum creatinine 
Urinalysis 
: 
Protein, Glucose, Blood, Ketones 
 Collect and store blood samples for anaphylaxis testing and inflammatory cytokine testing (when 
collecting blood samples for anaphylaxis testing, use a blood collection tube that contains Futhan 
[FUT-175], which is a protease inhibitor). 
Anaphylaxis test: 
C3a, C4a, Mast Cell Tryptase  
Inflammatory cytokine test: 
IL-1b, IL-2, IL-6, TNF-α 
 At the time that 18 hours (± 6 hours) from the administration of the investigational product is satisfied, 
examine for the persistence of bacteremia by performing blood cultures using 2 sets of blood samples 
(10 mL for each sample) collected from the subject. 
 Perform the required concomitant treatments. 
 Investigate the adverse events, concomitant medications, and concomitant treatments.  

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X Day 3 
The subjects will receive treatment for bacteremia with standard treatments until the completion of treatment 
and have follow-up observation until Day 14 or when the results of the blood culture at 2 consecutive days are 
confirmed as negative conversions (treatment completion), and the subjects will proceed with the study in the 
following order: 
 Examine vital signs (blood pressure, pulse, and temperature). 
 At the time that 24 hours (± 6 hours) from the “time of blood collection at Day 2” is satisfied, examine for 
the persistence of bacteremia by performing blood cultures using 2 sets of blood samples (10 mL for each 
sample) collected from the subject. 
 Perform the required concomitant treatments. 
 Investigate the adverse events, concomitant medications, and concomitant treatments.  
 
X Day 4 
The subjects will receive treatment for bacteremia with standard treatments until the completion of treatment 
and have follow-up observation until Day 14 or when the results of the blood culture at 2 consecutive days are 
confirmed as negative conversions (treatment completion), and the subjects will proceed with the study in the 
following order: 
 Examine vital signs (blood pressure, pulse, and temperature). 
 Perform a physical examination. 
 At the time that 24 hours (± 6 hours) from the “time of blood collection at Day 3” is satisfied, examine for 
the persistence of bacteremia by performing blood cultures using 2 sets of blood samples (10 mL for each 
sample) collected from the subject. 
 Perform the required concomitant treatments. 
 Investigate the adverse events, concomitant medications, and concomitant treatments.  
 
X Day 5 
The subjects will receive treatment for bacteremia with standard treatments until the completion of treatment 
and have follow-up observation until Day 14 or when the results of the blood culture at 2 consecutive days are 
confirmed as negative conversions (treatment completion), and the subjects will proceed with the study in the 
following order: 
 Examine vital signs (blood pressure, pulse, and temperature). 
 At the time that 24 hours (± 6 hours) from the “time of blood collection at Day 4” is satisfied, examine for 
the persistence of bacteremia by performing blood cultures using 2 sets of blood samples (10 mL for each 
sample) collected from the subject. 
 Perform the required concomitant treatments. 
 Investigate the adverse events, concomitant medications, and concomitant treatments.  
 
X Day 6 
The subjects will receive treatment for bacteremia with standard treatments until the completion of treatment 
and have follow-up observation until Day 14 or when the results of the blood culture at 2 consecutive days are 
confirmed as negative conversions (treatment completion), and the subjects will proceed with the study in the 

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following order: 
 Examine vital signs (blood pressure, pulse, and temperature). 
 Perform a physical examination. 
 At the time that 24 hours (± 6 hours) from the “time of blood collection at Day 5” is satisfied, examine for 
the persistence of bacteremia by performing blood cultures using 2 sets of blood samples (10 mL for each 
sample) collected from the subject. 
 Perform the required concomitant treatments. 
 Investigate the adverse events, concomitant medications, and concomitant treatments.  
 
X Day 7 
The subjects will receive treatment for bacteremia with standard treatments until the completion of treatment 
and have follow-up observation until Day 14 or when the results of the blood culture at 2 consecutive days are 
confirmed as negative conversions (treatment completion), and the subjects will proceed with the study in the 
following order: 
 Examine vital signs (blood pressure, pulse, and temperature). 
 At the time that 24 hours (± 6 hours) from the “time of blood collection at Day 6” is satisfied, examine for 
the persistence of bacteremia by performing blood cultures using 2 sets of blood samples (10 mL for each 
sample) collected from the subject. 
 Obtain blood and urine samples for laboratory testing, and investigate the observation items. 
Hematology: 
WBC, RBC, hemoglobin, platelets 
Blood chemistry: 
Total Protein, Albumin, Total Bilirubin, AST, ALT, ALP, 
Total Cholesterol, Serum Creatinine 
Urinalysis: 
Protein, Glucose, Blood, Ketone 
 Collect and store blood samples for anaphylaxis testing and inflammatory cytokine testing (when 
collecting blood samples for anaphylaxis testing, use a blood collection tube that contains Futhan 
[FUT-175], which is a protease inhibitor). 
Anaphylaxis test: 
C3a, C4a, mast cell tryptase  
Inflammatory cytokine test: 
IL-1b, IL-2, IL-6, TNF-α 
 Perform the required concomitant treatments. 
 Investigate the adverse events, concomitant medications, and concomitant treatments.  
 
X Day 8 
The subjects will receive treatment for bacteremia with standard treatments until the completion of treatment 
and have follow-up observation until Day 14 or when the results of the blood culture at 2 consecutive days are 
confirmed as negative conversions (treatment completion), and the subjects will proceed with the study in the 
following order: 
 Examine vital signs (blood pressure, pulse, and temperature). 
 At the time that 24 hours (± 6 hours) from the “time of blood collection at Day 7” is satisfied, examine for 
the persistence of bacteremia by performing blood cultures using 2 sets of blood samples (10 mL for each 
sample) collected from the subject. 
 Perform a physical examination. 
 Perform the required concomitant treatments. 

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 Investigate the adverse events, concomitant medications, and concomitant treatments.  
 
X Day 9 
The subjects will receive treatment for bacteremia with standard treatments until the completion of treatment, 
and the subjects will proceed with the study in the following order: 
 Examine vital signs (blood pressure, pulse, and temperature). 
 Perform the required concomitant treatments. 
 Investigate the adverse events, concomitant medications, and concomitant treatments.  
 
X Day 10 
The subjects will receive treatment for bacteremia with standard treatments until the completion of treatment 
and have follow-up observation until Day 14 or when the results of the blood culture at 2 consecutive days are 
confirmed as negative conversions (treatment completion), and the subjects will proceed with the study in the 
following order: 
 Examine vital signs (blood pressure, pulse, and temperature). 
 Perform a physical examination. 
 At the time that 48 hours (± 6 hours) from the “time of blood collection at Day 8” is satisfied, examine for 
the persistence of bacteremia by performing blood cultures using 2 sets of blood samples (10 mL for each 
sample) collected from the subject. 
 Perform the required concomitant treatments. 
 Investigate the adverse events, concomitant medications, and concomitant treatments.  
 
X Day 11 
The subjects will receive treatment for bacteremia with standard treatments until the completion of treatment, 
and the subjects will proceed with the study in the following order: 
 Examine vital signs (blood pressure, pulse, and temperature). 
 Perform the required concomitant treatments. 
 Investigate the adverse events, concomitant medications, and concomitant treatments.  
 
X Day 12 
The subjects will receive treatment for bacteremia with standard treatments until the completion of treatment 
and have follow-up observation until Day 14 or when the results of the blood culture at 2 consecutive days are 
confirmed as negative conversions (treatment completion), and the subjects will proceed with the study in the 
following order: 
 Examine vital signs (blood pressure, pulse, and temperature). 
 Perform a physical examination. 
 At the time that 48 hours (± 6 hours) from the “time of blood collection at Day 10” is satisfied, examine for 
the persistence of bacteremia by performing blood cultures using 2 sets of blood samples (10 mL for each 
sample) collected from the subject. 
 Perform the required concomitant treatments. 
 Investigate the adverse events, concomitant medications, and concomitant treatments.  
 

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X Day 13 
The subjects will receive treatment for bacteremia with standard treatments until the completion of treatment, 
and the subjects will proceed with the study in the following order: 
 Examine vital signs (blood pressure, pulse, and temperature). 
 Perform the required concomitant treatments. 
 Investigate the adverse events, concomitant medications, and concomitant treatments.  
 
X Day 14 (time to determine treatment success/failure) 
The subjects will receive treatment for bacteremia with standard treatments until the completion of treatment, 
and the subjects will proceed with the study in the following order: 
 Examine vital signs (blood pressure, pulse, and temperature). 
 Perform a physical examination. 
 At the time that 48 hours (± 6 hours) from the “time of blood collection at Day 12” is satisfied, examine for 
the persistence of bacteremia by performing blood cultures using 2 sets of blood samples (10 mL for each 
sample) collected from the subject. At Day 14, collect the last blood sample for a blood culture, and if 
negative conversion rates are not confirmed in the blood culture/evaluation at Day 12 and Day 14, 
consider it as a failure to treat S. aureus bacteremia.  
 Obtain blood samples for laboratory testing and urine samples for urinalysis, and investigate the 
observation items. 
Hematology 
: 
WBC, RBC, Hemoglobin, Platelets 
Blood chemistry 
: 
Total protein, Albumin, Total bilirubin, AST, ALT, ALP, 
Total cholesterol, Serum creatinine 
Urinalysis 
: 
Protein, Glucose, Blood, Ketones 
 Perform the required concomitant treatments. 
 Investigate the adverse events, concomitant medications, and concomitant treatments.  
 Evaluate the clinical outcome of the treatment (clinical success or failure). 
 
12.3.4 Follow-up (W4 ± 5 days) 
If the subject is unable to make a visit as an outpatient for this follow-up, adverse events and concomitant 
medications will be checked via telephone monitoring. If the subject is able to make a visit, measurement of vital 
signs, physical examination, and laboratory tests can be performed if necessary through an outpatient visit. In the 
case of subjects who are unable to make an outpatient visit, telephone monitoring will be carried out, and at this 
time, the reason for not being able to make a visit will be documented (even in the case of death or inability to 
make a visit due to other diseases, the relevant subjects will not be dropped out from this clinical study).  
 
The following tests will be performed via telephone monitoring:  
 Investigate the adverse events, concomitant medications, and concomitant treatments.  
 
In the case of subjects who are able to make an outpatient visit, laboratory tests, vital sign measurement, and 
physical examination will be carried out if necessary in the following order: 
 Investigate the adverse events, concomitant medications, and concomitant treatments.  
 Obtain blood samples for laboratory testing and urine samples for urinalysis, and investigate the 
observation items.  

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Hematology 
: 
WBC, RBC, Hemoglobin, Platelets 
Blood chemistry 
: 
Total protein, Albumin, Total bilirubin, AST, ALT, ALP, 
Total cholesterol, Serum creatinine 
Urinalysis 
: 
Protein, Glucose, Blood, Ketones 
 Examine vital signs (blood pressure, pulse, and temperature). 
 Perform a physical examination. 
 
Subjects who drop out at any time during the study will make the termination visit, and the reason for dropping 
out will be documented.  
 
12.4 Unscheduled visit and hospitalization 
In the case that the subject is visiting or hospitalized on a day that is not the scheduled date, adverse events 
related to the study, changes in the concomitant medications, dropout status, outcome of the clinical 
measurement, cases requiring concomitant treatment, etc. should be recorded. The clinical study schedule should 
not be changed due to unscheduled visits. At this time, visits scheduled before the initiation of the clinical study 
are not unscheduled visits. 
 
 
13. Expected side effects and precautions for use 
(1) Adverse events found in the results of the nonclinical studies 
The study drug used in this clinical study is a new drug of a new class, and the absence of drugs of the same or 
similar class makes it difficult to infer side effects. However, as a result of the nonclinical studies and the Phase 1 
clinical study, the adverse events shown below have been reported. 
 
㽡 Rodents  
a. Single-dose study 
- According to the result of a single-dose toxicity study in SD rats, no abnormal findings related to the study 
drug, such as death, general abnormal symptoms, weight changes, and abnormal necropsy findings, were 
observed in all observed items. 
 
b. 2-week repeated dose selection study 
- Urine volume increased, neutrophil decreased, eosinophil decreased, monocyte decreased, basophil 
decreased, lymphocyte increased, TBIL increased, GGT increased, spleen size increased, thymus size increased, 
seminal vesicle weight increased, pituitary gland weight increased 
 
c. 4-week repeat-dose study 
- TCHO increased, PL increased, TG increased, ALB decreased, ALP decreased, proteinuria; edematous findings 
in the pancreas, skeletal muscles or hind limbs; edema according to histopathological examination; kidney 
weight increased, renal tubule dilated, hyaline droplets, cast, and increased hypertrophic zone, middle physis, 
tibia 
 

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㽢 Beagle dogs 
a. 2-week repeated dose selection study 
- Subdued behavior, prone position, respiration rate decreased, vomiting, hypersalivation, ocular pigmentation, 
skin pigmentation, WBC increased, platelet decreased, basophil increased, LUC increased, reticulocyte 
decreased, neutrophil decreased, monocyte increased, leukocyte increased, BUN decreased, TP decreased, 
TBIL decreased, CK decreased, dark red discoloration at the site of administration, mild renal tubular 
degeneration/regeneration 
 
b. 4-week repeat-dose study 
- Vomiting, prone position, lateral recumbent position, subdued behavior, irregular breathing, respiration rate 
increased, feed consumption decreased, rubbing, hypersalivation, platelet decreased, dark red discoloration at 
the site of administration, relative weight of the kidney increased, mild to severe congestion/hemorrhage, 
very mild to mild vasculitis/perivasculitis, very mild to moderate edema and inflammatory cell infiltration 
 
㽣 Monkeys 
a. DES study 
- BUN level increased, creatinine level increased 
 
(2) Adverse events found in the results of the Phase 1 clinical study 
A total of 42 adverse events were reported in 12 out of 36 subjects who received the investigational product 
during the Phase 1 clinical study. All adverse events recovered without sequelae, serious adverse events did not 
occur, and none of the subjects were discontinued from the study due to adverse events.  
a. 0.3 mg/kg dose group 
- Total bilirubin increased 
b. 10 mg/kg dose group 
- Rigors, fatigue, headache, myalgia, tenderness, nausea, dyspepsia 
 
 
14. Discontinuation and dropout, and progress and early termination of the clinical study 
14.1 Discontinuation and dropout criteria for individual subjects 
Subjects have the right to drop out from the clinical study at any time and for any reason without prejudice to 
subsequent treatment. The investigator also has the authority to drop out subjects from the clinical study for the 
benefit of subjects. Unnecessary dropouts should be avoided, as an excessive dropout rate can result in the results of 
the clinical study being unable to be interpreted.  
If the clinical study is discontinued prior to termination of the clinical study, the reason for discontinuation should 
be recorded in the clinical study termination report in the case report form, and the case report form should be 
completed.  
In all cases, the reason for dropout and the date of dropout should be recorded in the CRF and the subject’s medical 
records. It should be followed up whether the reason for dropout is due to adverse events, and if so, it should be 
reported in accordance with the processes described in Section 16.7 “Documentation of adverse events and serious 
adverse events.” For example, if a subject withdraws his or her consent to participate in the study due to recurrence 
of a disease during treatment, “recurrence of the disease” should be recorded in the case report form as a reason for 
dropping out. All subjects who received the clinical drug but did not complete the study in accordance with the 

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protocol should have all tests scheduled for the final visit completed as much as possible. The investigator should 
make best efforts to contact a subject who is lost to follow-up. Attempts to contact such a subject should be recorded 
in the subject’s medical records (e.g., the date and time of a call, a receipt for sending a registered mail). 
 
The subject’s participation in the clinical study may be discontinued for the following reasons:  
1) If it is determined that the situation observed while conducting the clinical study is unreasonable to continue 
the clinical study, the principal investigator should request discontinuation of the clinical study to the 
Institutional Review Board and is able to discontinue the clinical study based on the decision made by the 
Institutional Review Board. 
2) If the sponsor wants to discontinue the clinical study due to reasons such as the safety of the investigational 
product, the sponsor can request discontinuation of the clinical study to the Institutional Review Board and 
discontinue the clinical study based on the decision made by the Institutional Review Board. 
 
The subject may drop out from participation in the clinical study for the following reasons: 
1) In the case that the subject (or the authorized representative) withdraws the consent for participation in the 
clinical study  
2) In the case that surgery or other drugs that may affect the evaluation of the safety and efficacy have been 
carried out or used concomitantly 
3) In the case that the investigator determines that serious adverse events may occur and may cause 
disadvantages to the subject’s health status 
4) In the case that the efficacy evaluation items cannot be observed continuously due to the absence of the 
subject 
5) In the case that the subject dies for reasons unrelated to the clinical study 
6) In the case that the sub-investigator determines that there are other problems in conducting the clinical study 
7) In the case that the subject discontinues contraception due to pregnancy or with an intention to become 
pregnant 
8) In the case that the subject has an exclusion criterion occurred during the clinical study period, the relevant 
subject may be excluded from the clinical study (in the case that the blood culture obtained after the 
investigational product administration is infected with other organisms, the subject will not be dropped out 
due to the criterion “Those who are infected with mixed bacterial species”).  
 
 
14.2 Entry from Step 1 to Step 2 
Proceeding to Step 2 will be determined considering the evaluation results of the IDMC. The IDMC will establish the 
charter and the standard operating procedures separately for its operations and will determine the safety and efficacy 
observed in Step 1 in accordance with the standard operating procedures established.  
An interim analysis to evaluate whether to enter Step 2 will be performed by the IDMC when the number of 
subjects who have terminated the clinical study participation has reached 28 or more and 32 or less, and the safety 
will be evaluated to determine whether to enter Step 2. 
 
 

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14.3 Early termination of the clinical study 
The clinical study may be terminated early for the reasons stated below. The reasons stated below are the cases 
when new information regarding the benefit/risk ratio for subjects of the investigational product obtained has a 
negative direction and include the following: 
1) In the case that conducting the clinical study further after the interim analysis is considered meaningless 
2) In the case that new and important adverse drug reactions have occurred or the incidence and severity of past 
adverse drug reactions are unexpectedly significant 
3) Other safety reasons that negatively affect the benefit/risk ratio of the clinical study 
4) In the case that the sponsor determines that continuation of this clinical study is not justifiable from medical 
and ethical perspectives 
5) In the case that it is determined that the subject enrollment rate at the relevant study site will cause a 
significant setback of the subject enrollment schedule required for this clinical study 
6) In the case that the sale or supply of investigational product is discontinued 
 
If this clinical study is terminated early, a government regulatory agency or the Institutional Review Board will be 
notified in accordance with applicable regulations. 
The clinical study may be discontinued or suspended if requested by the government regulatory agency. 
 
 
14.4 Replacement of subjects who drop out 
Subjects who are terminated early from this clinical study will not be replaced. 
 
 
15. Effectiveness evaluation criteria, and methods of evaluation and interpretation 
15.1 Primary endpoints 
X Safety endpoints 
x Checking on adverse events 
x Laboratory tests 
x Anaphylaxis test, inflammatory cytokine test 
x Physical examination/vital signs 
 
15.2 Secondary endpoints 
X Efficacy Endpoint ①  
x Proportion of patients whose first blood culture performed after administration of the investigational 
product is negative 
X Efficacy Endpoint ②  
x Proportion of patients who die due to S. aureus bacteremia by Day 14 
X Efficacy Endpoint ③  
x Proportion of treatment failure of S. aureus bacteremia by Day 14 (if 2 consecutive negative conversions 
were not observed in blood cultures performed until Day 14) 

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15.3 Statistical analysis methods 
15.3.1 Demographic baseline data 
The background and demographic data of the subjects included in this clinical study will be evaluated by 
treatment group, and the mean, standard deviation, minimum value, maximum value, etc. will be obtained and 
presented for continuous variables, and the frequency and percentage will be presented for categorical variables. 
  
15.3.2 Primary endpoint analysis method 
Safety analysis is performed in the safety set. A distribution table of the number of subjects who experienced at 
least one side effect (incidence) and distribution tables of the relationship of the investigational product to the 
reported adverse events (distribution tables for severity and the relationship to the drug) will be presented for 
each group (study group, control group) to confirm the safety. 
The results of the laboratory tests, anaphylaxis test, inflammatory cytokine test, and vital signs at baseline and 
the last visit will be summarized as mean values and standard deviations, and the changes before and after the 
treatment within each group will be confirmed. Categorical data will be divided into normal and abnormal data 
and summarized as frequency and percentage, and the differences before and after treatment within each group 
will be confirmed.  
 
15.3.3 Secondary endpoint analysis methods 
15.3.3.1 Efficacy Endpoint ①  
x Proportion of patients whose first blood culture performed after administration of the investigational 
product is negative  
The descriptive statistics for the proportion of patients who are negative in the first blood culture after 
administration of the treatment (the rate of negative conversion) will be presented by treatment group. 
Whether the rate of negative conversion in the study group is superior to that in the control group will be 
evaluated in a descriptive statistical manner. 
 
15.3.3.2 Efficacy Endpoint ②  
x Proportion of patients who die due to S. aureus bacteremia at Day 14 after the onset of bacteremia 
(according to the first confirmatory decision of bacteremia). The descriptive statistics for the rate of 
mortality due to S. aureus bacteremia by Day14 will be presented and evaluated by treatment group. 

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15.3.3.3 Efficacy Endpoint ③  
x Proportion of treatment failure of S. aureus bacteremia by Day 14 (if 2 consecutive negative conversions 
were not observed in blood cultures performed until Day 14) 
The descriptive statistics for the treatment failure rate of S. aureus bacteremia by Day14 will be presented 
and evaluated.  
 
 
 
15.4 Statistical analysis sets 
The data obtained from the subjects in this clinical trial will be analyzed largely in three methods: safety set, FAS 
(full analysis set), and PP (per protocol) set. 
 
15.4.1 Safety set 
The safety set is intended for subjects who participated in this clinical study and used the study drug/control 
drug at least once. 
 
 
15.4.2 FAS (Full Analysis Set) 
The FAS is intended for subjects whose bacteremia (blood culture) test results have been confirmed at least 
once after using the study drug/control drug at least once. 
 
 
15.4.3 PP (Per Protocol) 
The PP set is intended for subjects who have completed this clinical study in accordance with the protocol 
among those who are included in the FAS. Among them, those who take medications prohibited from being 
administered concomitantly, those who receive treatments prohibited from being performed concomitantly, and 
those who do not comply with the clinical study schedule except for the F/U visit (however, the noncompliance 
due to death will be included in the PP set) will be excluded. 
 
[Principle of result interpretation] 
For data for efficacy evaluation, the FAS analysis will be the main analysis, and the PP analysis will be performed 
separately to evaluate whether there are differences compared to the PP analysis results. 
Data for safety evaluation will be used to evaluate the safety of this study drug/control drug in the safety set. 
 
 
15.5 Issues related to the statistical analysis and method to handle missing data 
SAS Ver 9.2 will be used as an analysis program. If missing values are generated, observed cases will be analyzed.  

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15.6 Interim analysis 
An interim analysis will be performed when the number of subjects who have terminated the clinical study 
participation has reached 28 or more (but to be performed at or before reaching 32). The main evaluation of the 
interim analysis is for safety purposes, and the efficacy evaluation will also be performed for exploratory purposes. 
The interim analysis and evaluation will be performed by the IDMC.  
The safety will be evaluated by presenting the frequency and pattern (relationship to the investigational product, 
severity, seriousness, etc.) for all adverse events that occurred during the clinical study period for each treatment 
group. The efficacy evaluation will provide proportions for each of the secondary endpoints listed in Section 15.2 
and compare them between the treatment groups.  
 
 
16. Evaluation criteria for safety including side effects, method of evaluation, and 
reporting method 
16.1 Safety evaluation method 
① The safety evaluation items will be evaluated according to the clinical study schedule and “15.3.2 Primary 
endpoint analysis method.” 
In all subjects, the medical history prior to administration of the investigational product, concomitant 
medications, laboratory tests, and measurement of vital signs will be performed. 
In addition, the sub-investigator will record all outliers, which are considered clinically significant, that meet the 
criteria in “16.2 Safety evaluation criteria,” as adverse events or serious adverse events. 
 
 
16.2 Safety evaluation criteria 
16.2.1 Definition of an adverse event (AE) 
An adverse event is any undesired and unintended sign (e.g., abnormality in a laboratory test) or symptom, 
syndrome, or disease that occurs or worsens in a patient or subject receiving the investigational product during the 
observation period of the clinical study. This does not necessarily have to have a causality relationship to the drug. 
In other words, a case that has no causality relationship to the investigational product or the clinical study is 
included in the use of the term “adverse event.”  
Clinically significant abnormal results in diagnostic procedures including abnormal findings of laboratory test 
results (e.g., those requiring unplanned diagnostic procedures/treatments or discontinuation of participation in the 
clinical study) will be considered as adverse events. Therefore, adverse events can be diseases caused by the use of 
a drug regardless of any undesirable and unexpected signs (which may be clinically significant abnormal laboratory 
test results), symptoms or relationship to the drug. 
Worsening of signs or symptoms of the disease being treated is usually measured as a safety endpoint. However, 
if the result is applicable to the definition of a “serious adverse event,” it should be recorded according to the 
procedure (see Section 16.7 “Rules for reporting of serious adverse events”). 
The surgery processes themselves will not be treated as adverse events. They are treatment options for 
conditions requiring surgery. In the case that events requiring surgery occur or are detected during the clinical study 
period, they are adverse events. If the planned surgical procedures allowed in the protocol and the situation(s) that 

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led to take these measures were known prior to initiation of the clinical study, these are not adverse events. In the 
latter case, they should be reported as medical histories. 
 
X Cases that are included in adverse events 
³ 
Disease newly occurred  
³ 
Worsening of existing diseases 
³ 
Effects caused by the clinical study drugs (including the control drug [placebo]): In the case that 
preexisting reactions or conditions worsen or their frequencies increase 
³ 
Effects caused by the clinical study procedures  
³ 
Conditions that are diagnosed or detected after administration of the clinical drug (including the control 
drug [placebo]) even if it is assumed that they were present before initiation of the study 
³ 
In the case that diseases or symptoms observed at the baseline worsen after initiation of the study 
³ 
Complex effects of 2 or more of the factors above  
 
X Cases that are not included in adverse events 
³ 
Temporary pain at the site of blood collection and injection 
³ 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, blood transfusion) 
³ 
In the case that an existing disease or a condition that was present or detected at the beginning of the 
study does not worsen 
³ 
Situations where unexpected medical phenomena do not occur (e.g., hospitalization due to cosmetic 
surgery, hospitalization for personal convenience, etc.) 
³ 
Diseases or conditions that have been studied, conditions that the subject’s condition is not more severe 
than expected, or signs or symptoms not related to the diseases 
³ 
No signs or symptoms resulting from an overdose of the clinical drug or concomitant medications 
 
16.2.2 Definition of an adverse drug reaction 
An adverse drug reaction (ADR) refers to any harmful and unintended reaction that occurred at a certain dose of 
the investigational product where a causality relationship to the investigational product cannot be denied. 
 
16.2.3 Serious adverse event/adverse drug reaction  
A serious adverse event/adverse drug reaction (serious AE/ADR) refers to an adverse event or an adverse drug 
reaction that occurred at a certain dose of the investigational product that falls under any one of the following: 
 
X Cases that are included in serious adverse events 
³ 
In the case that results in death or is life-threatening 
³ 
In the case that requires hospitalization or prolongation of hospitalization  
³ 
In the case that results in permanent or serious disability and dysfunction 
³ 
In the case that results in congenital anomaly or birth defect 
 
X Cases that are not included in serious adverse events 
³ 
Visiting emergency department and staying for within 24 hours  
³ 
Admission to a hospital for a day  
³ 
Prolongation of hospitalization period or transfer to another hospital for treatment of underlying diseases 
that have existed before participation in the study (obtaining of the informed consent form) 
³ 
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In the case of a situation where there is a significant impact on the subject’s well-being and health status besides 
those listed above, the study doctor and relevant experts will make a medical judgement whether or not to 
consider it as a serious adverse event and take appropriate measures accordingly. 
 
16.2.4 Unexpected adverse drug reaction 
An unexpected adverse drug reaction refers to a reaction that shows a difference in the characteristics or degree 
of harm of the adverse drug reaction in view of the available information on the drug such as an investigator’s 
brochure or a package insert of the drug. 
 
16.2.5 Severity of adverse events 
The severity of adverse events will be determined based on the below. 
1) Mild: Symptoms or signs are perceivable, but they can be tolerated without discomfort, and no treatment is 
needed to relieve symptoms, if they do not affect behaviors or functions. 
2) Moderate: Symptoms are uncomfortable enough to interfere with activities of daily living, they affect 
behaviors, and treatment may be needed to relieve symptoms.  
3) Severe: Symptoms cause discomfort that incapacitates from working or performing activities of daily living, 
and treatment is needed to relieve symptoms, if discomfort causes discontinuation of a suspect drug. 
 
16.2.6 Causality relationship of adverse events 
The investigator must also systematically evaluate the causality relationship between the investigational product 
and adverse events according to the criteria listed below.  
The following items should be considered to evaluate the relationship between the drug and adverse events:  
1) Temporal continuity after the drug administration: An adverse drug reaction must occur after the 
investigational product administration. The temporal interval between the investigational product 
administration and the onset of an adverse drug reaction should be evaluated according to the clinical 
circumstances of the event.  
2) Recovery after drug dechallenge, and recurrence after drug rechallenge: Subject’s response after drug 
dechallenge and subject’s response after drug rechallenge (Drug rechallenge will be considered in the aspect 
of the usual clinical stage of a problematic incident.) 
3) Underlying, comorbid, and intercurrent diseases: Reports of each adverse event will be evaluated based on 
the characteristics and stages of the disease being treated and other disease that a subject has.  
4) Concomitant medications and treatments: Other medications or treatments that a subject is receiving should 
be evaluated, as they may be related to the problematic event.  
5) Trend of known responses to drugs of this class: Clinical/preclinical  
6) Pharmacological and pharmacokinetic characteristics of the drug: Pharmacokinetic characteristics 
(absorption, distribution, metabolism, and excretion) of the investigational product should be considered 
along with the pharmacodynamic aspects of the subject. 
 
The evaluation of the relationship between the investigational product administration and adverse events (not 
related, unlikely related, possibly related, probably related, certainly related) will be clinically determined based on 
all information that can be obtained at the time of completing the case report form. Of these, possibly related, 

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probably related, and certainly related will be evaluated as adverse drug reactions. 
 
[Table 5] Causality Relationship Assessment 
Causality 
Term 
Assessment Criteria 
Certainly 
related  
When the temporal order of the investigational product administration and the adverse event 
onset is plausible  
When the adverse event is unexplained by other possible causes (such as diseases or other drugs) 
In the case that discontinuation or dose reduction of the investigational product shows a 
plausible result of the relationship between the event and the drug (the adverse event disappears 
or weakens)  
When an adverse event occurred is known to be definite in the pharmacological and 
symptomatologic aspects of the drugs in the same class as the investigational product (“gray baby 
syndrome” after administration of chloramphenicol, anaphylaxis immediately after rechallenge of 
the previously administered drug, etc.) 
When the event reappears when rechallenged (if performed) 
Probably 
related 
When the temporal order of the investigational product administration and the onset of the 
adverse event or laboratory abnormality is reasonable  
When the adverse event is unlikely to be caused by other possible causes (such as diseases or 
other drugs)  
When discontinuation or dose reduction of the investigational product shows a clinically valid 
result (the adverse event disappears or weakens) 
A result of rechallenge is not mandatory. 
Possibly 
related 
When the temporal order of the investigational product administration and the onset of the 
adverse event or laboratory abnormality is reasonable  
When the adverse event is believed to be caused by the investigational product as much as by 
other possible causes (such as diseases or other drugs)  
When there is no information or information is not apparent upon discontinuation of the 
investigational product administration 
Unlikely 
related 
When the temporal relationship of the investigational product administration and the onset of 
the adverse event or laboratory abnormality is improbable (but not impossible)  
When the adverse event is more plausibly explained by other causes (such as diseases or other 
drugs) than administration of the investigational product 
Not related 
When the subject has not received the investigational product  
When the temporal order of the investigational product administration and the onset of the 
adverse event or laboratory abnormality is impossible 
When there is a definitive cause (e.g., bleeding at the operative site) that can explain the reason  
Unreasonable (e.g., when there is no evidence for the loss of a sense of direction due to the 
investigational product although the patient was hit by a motorcycle, occurrence of cancer a 
couple days after the administration of the investigational product) 
 
 
16.2.7 Exacerbation of underlying diseases or health condition that is already present 
The expected change or expected exacerbation of the underlying disease or preexisting condition will not be 
recorded as an AE unless it meets at least one of the following criteria: 
³ 
When the exacerbated disease becomes an SAE 
³ 
When the investigational product is discontinued, or the dose is decreased or increased 
³ 
When the investigator determines that the disease exacerbated from baseline unexpectedly 
 

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16.3 Observation period  
For the purpose of this clinical study, the duration of adverse event observation will be between the 
administration of the investigational product and the last visit at 4 weeks ± 5 days. 
After the end of the observation period, if the investigator identifies a serious adverse event in the subject and 
considers that it is an adverse event likely to be related to the previous clinical study treatment or related to the 
clinical study procedures, the investigator should contact the sponsor to check how the adverse event should be 
documented and reported. 
 
 
 
16.4 Safety evaluation set 
It will be carried out only in the subjects who received the investigational product at least once. 
 
 
 
16.5 Method, frequency, and time to detect adverse events and serious adverse events 
The initiation of the study is the period after screening, and the end of the reporting period means the follow-up 
visit at W4 ± 5 days after the end of treatment of persistent bacteremia. The investigator should record each 
adverse event promptly and completely in the case report form, and the investigator should record adverse events, 
even if they are determined to be unrelated to the study drug treatment by the investigator. If possible, the 
investigator should try to diagnose based on the symptoms and signs that appear. 
 
 
 
16.6 Documentation of adverse events and serious adverse events 
All adverse events occurring during the study period will be recorded according to the following: 
(1) All adverse events (serious or non-serious, or alert terms) must be recorded in the “Adverse Events” page of 
the case report form.  
(2) If an adverse event is a serious adverse event (see Section 16.2.3), the investigator should complete the 
“Serious Adverse Event Report” form as well as the “Adverse Events” section of the CRF at the time when the 
serious adverse event is confirmed. This form should be sent to the clinical research associate, and then, this form 
will be sent to the pharmacovigilance (PV) staff member of the sponsor by the clinical research associate. 
(3) In other cases where expedited reporting is required without an adverse event, the investigator does not 
need to complete the “Serious Adverse Event Report” form and the “Adverse Events” page of the case report form. 
(4) Adverse events should be described using diagnostic terminologies as much as possible. If a definitive 
diagnosis is made, each signs and symptoms are not required to be recorded unless atypical or extreme symptoms 
have occurred. Each of atypical or extreme symptoms must be reported as separate adverse events. If a definitive 
diagnosis cannot be made, signs and symptoms should be recorded separately. 
 
 

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16.7 Rules for reporting of serious adverse events  
16.7.1 Expedited reporting of serious adverse events  
 In the case of serious adverse events, if the investigator determines that the event corresponds to a “serious 
adverse event” defined in the protocol, it should be reported promptly to the designated pharmacovigilance 
staff members designated by the sponsor and to the IRB as specified below. The reported information 
should be recorded identically in the serious adverse event report and the case report form. 
 
 Submission of serious adverse event reports 
The initial notification of all serious adverse events that newly occur during the clinical study period should be 
submitted immediately after recognizing the occurrence of serious adverse events. The investigator should 
complete a serious adverse event report within 24 hours of recognition and send via email or fax to the 
pharmacovigilance staff members. The contact information of the pharmacovigilance staff members is as follows: 
 
X Sponsor: iNtRON Biotechnology, Inc.  
Person in charge 
Eun Ah Park 
E - mail 
euna0917@intron.co.kr 
Address 
137, Sagimakgol-ro, Jungwon-gu, Seongnam-si, Gyeonggi-do, Republic 
of Korea 
Postal code 
13202 
Telephone number 
+82-31-739-5032 
Fax number 
+82-31-736-7246 
 
 
X Contract research organization: Symyoo Inc. 
Person in charge 
Clinical research associate 
Address 
2nd floor, 6, Hannam-daero 42-gil, Yongsan-gu, Seoul, Republic of Korea 
Postal code 
04417 
Telephone number 
+82-70-4335-5468  
Fax number 
+82-2-749-2050 
+82-2-6442-4753 (eFax) 
 
 
 
熟 In the case that iNtRON Biotechnology, Inc. receives a report of a suspected unexpected serious adverse 
reactions from the investigator, they should promptly report to the Ministry of Food and Drug Safety (MFDS) 
within the following deadline: 
 
① Any suspected unexpected serious adverse reactions that cause death or that are life threatening should be 
reported within 7 days from the day when the sponsor received a report or recognized. If additional information 

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needs to be reported, additional reports should be submitted including the detailed information on the relevant 
adverse drug reaction within 15 days from the day when the sponsor received a report or recognized the 
relevant adverse drug reaction for the first time. 
② All other suspected unexpected serious adverse reactions should be reported within 15 days from the day 
when the sponsor received a report or recognized suspected unexpected serious adverse reactions. 
 
16.7.2 Obligations related to serious adverse events  
☞ Reporting of serious adverse events 
The obligations of each staff member related to “serious adverse events” that occur during the clinical study 
period are as follows: 
 
(1) Obligations of the principal investigator 
In the case that any serious adverse event occurs during the clinical study, the principal investigator should 
report it to the sponsor immediately and provide further reports with detailed information later. In the case that a 
death case has been reported, the principal investigator should provide additional information, such as an autopsy 
report (only if an autopsy was performed) and a death certificate, to the sponsor and the Institutional Review 
Board. In addition, the principal investigator should report serious adverse events occurred during the clinical 
study at the affiliated site or at other sites to the affiliated Institutional Review Board in accordance with the 
requirements for reporting serious adverse events, which are specified by each study site.  
 
(2) Obligations of the sub-investigators 
In the case that a serious adverse event occurs during the clinical study, the sub-investigator should report it to 
the principal investigator and the sponsor immediately and provide additional reports with detailed information 
later.  
 
(3) Obligations of the Institutional Review Board 
The Institutional Review Board should inform the principal investigator of the necessary measures in the case of 
occurrence of suspected unexpected serious adverse reactions or new information that may adversely affect the 
safety of the subject or the conduct of the clinical study.  
 
(4) Obligations of the sponsor 
The sponsor should report all suspected unexpected serious adverse reactions reported from the investigator to 
other related investigators and the Ministry of Food and Drug Safety within “15 days” from the day when the 
sponsor received a report or recognized suspected unexpected serious adverse reactions. However, in the case 
that they cause death or are life threatening, the sponsor should report within “7 days” from the day when the 
sponsor received a report or recognized suspected unexpected serious adverse reactions. If additional information 
needs to be reported, additional reports should be submitted within “15 days” from the day when the sponsor 
received a report or recognized the detailed information. When the sponsor is submitting an adverse drug reaction 
report, the sponsor will attach and submit the information received from the investigator. 
In relation to the above report, the sponsor should periodically report additional safety information until the 
end of the relevant adverse event (disappearance of the relevant adverse event or impossible to follow up). The 
investigator should actively cooperate in providing data and information on the reports. 
In accordance with the ICH GCP regulations, the sponsor should notify the investigator of “matters that may 

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negatively affect the subject’s participation in the clinical study or that may result in a change in the approval of 
the Institutional Review Board for continuation of the clinical study,” and especially should inform the investigator 
of suspected unexpected serious adverse reactions (SUSARs). 
 
(5) Immediate reporting to the sponsor by the investigator  
Serious adverse events and adverse events that require expedited reporting to the pharmacovigilance staff 
member should be recorded in the “Serious Adverse Event Report” form. This form must be reported to the 
sponsor and contract research organization within 24 hours. The “Serious Adverse Event Report” form and 
recording instructions will be provided in the investigator study file. 
The initial report should be prepared as complete as possible, including the detailed information on intercurrent 
diseases and (serious) adverse events and the evaluation of causality relationship to the investigational product. 
Information that is not obtained at the time of completing the initial report (e.g., the adverse event end date or 
the laboratory test result obtained after the initial report) should be recorded in the “Serious Adverse Event 
Report” form at the follow-up. 
If a non-serious adverse event becomes a serious adverse event, it should be recorded in the “Serious Adverse 
Event Report” form and should be reported to the sponsor immediately. 
 
 
16.8 Follow-up on adverse events  
While the subject is participating in the clinical study, the investigator should ensure that proper medical 
treatment is given for all adverse events, including clinically significant laboratory test results related to the study. If 
medical treatment is needed for adverse events perceived by the investigator, the subject should be informed. 
The follow-up information should only include new (updated and/or additional) information that reflects the 
situation at the time of the investigator’s signature. The follow-up period for adverse events in this clinical study is 
to be 1 month after the subject’s last visit. In the case of a chronic disease or death of a subject due to other 
adverse events, etc., these cases may be terminated with the result as “recovering” or “not recovered,” and 
therefore, the follow-up does not require the result to be in the “recovered” category. 
 
 
16.9 Emergency 
In the case of a deviation from the protocol due to an emergency, the investigator should call and inform the 
sponsor, iNtRON Biotechnology, Inc, of the deviation as soon as possible, and determine whether the relevant 
subject should continue or discontinue to be in the clinical study. The details of the protocol deviation and its 
reason should be recorded in detail in the case report form or the protocol deviation (violation) form.  
 
 
 
17. Informed consent form 
The investigator should obtain a written informed consent form [Attachment 1] after providing sufficient 
information in accordance with the Declaration of Helsinki and KGCP before enrolling the patient in the clinical study.  
 

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The Institutional Review Board (IRB) should review the informed consent form and subject information sheet to be 
used by the investigator. It is the responsibility of the principal investigator to obtain the informed consent form from 
the patient or his/her legally authorized representative before initiating any act or treatment that is not the patient’s 
usual care. 
The informed consent form and subject information sheet should include all information required by the ICH, KGCP 
and applicable regulations. In addition, ethical principles based on the KGCP and Declaration of Helsinki should be 
followed. The informed consent form should also include the statement “iNtRON Biotechnology, Inc., the sponsor, and 
the Ministry of Food and Drug Safety will directly access the subject’s medical records.” Prior to initiation of the study, 
the investigator should obtain approval from the Institutional Review Board (IRB) for the written informed consent 
form and other information to be provided to the subject.  
In the case that the clinical study includes subjects recruited after obtaining consent only from their authorized 
representative (e.g., minor, patient with severe dementia) or without obtaining consent (e.g., emergency), the 
investigator should explain the clinical study to the subject in person to the extent that the subject can understand it, 
and if possible, the investigator should have the subject sign and date the informed consent form as soon as possible.  
 
If it is impossible for the subject to provide informed consent, the consent from the subject’s authorized 
representative should be obtained. In the case that it is impossible for the subject to provide informed consent and 
authorized representative doesn’t exist, the method of subject recruitment should be specified in the protocol and/or 
elsewhere. The investigator should obtain a written approval from the Institutional Review Board to protect the rights, 
safety and well-being of such a subject and to comply with applicable regulations in relation to the subject’s 
participation. The subject or the subject’s authorized representative should be informed about the clinical study as 
soon as possible. 
The investigator should provide a copy of the informed consent form and a copy of the written subject information 
sheet, which explains the clinical study using terms that can be easily understood rather than using professional jargon, 
to the subject or the authorized representative. After giving the subject or the subject’s authorized representative 
time to ask questions about the details of the clinical study, the investigator should have the subject or the subject’s 
authorized representative sign and date the informed consent form in person, and if necessary, the person who 
discussed together when obtaining the informed consent form should also sign and date in person. The subject or the 
authorized representative should receive a copy of the informed consent form signed prior to participation in the 
study and a copy of the other written subject information sheet provided to the subject.  
If the subject or the authorized representative is an illiterate, an impartial witness should be present during the 
course of obtaining consent.  
After the subject or the authorized representative provides consent verbally and signs, if possible, the impartial 
witness should sign and date the informed consent form in person to testify that the information was accurate and 
the subject or the authorized representative understood and provided consent based on their free will.  
 
The informed consent form and any other information provided to the subject or the authorized representative 
should be changed and provided whenever important information related to the subject’s consent is newly obtained, 
and the Institutional Review Board’s opinion should be obtained prior to use. The investigator or a person designated 
by the investigator should fully explain all the valid aspects of the clinical study and new information related to the 
subject’s willingness to continue participating in the clinical study to the subject or the subject’s authorized 
representative. Mutual exchange of opinions such as this should be recorded.  

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While the subject is participating in the clinical study, the newly updated informed consent form and written 
subject information sheet should be provided for the subject. 
 
 
18. Subject indemnification policy 
In the case that the subject experiences adverse events that have causality relationship to the study drug used in 
this clinical study despite the investigator has been conducting the clinical study in compliance with all laws and 
regulations and strictly in accordance with the protocol and various related literature, recommendations and 
suggestions provided by iNtRON Biotechnology, Inc, iNtRON Biotechnology, Inc. will implement and reimburse the 
reasonable treatment cost in accordance with the indemnification policy for victims [Attachment 2] submitted to the 
IRB of the study site. See the subject indemnification policy document. 
 
 
19. Examination and treatment criteria for subjects after the clinical study 
The test fees and the investigational product for the schedule planned for this study will be paid by iNtRON 
Biotechnology, Inc. only for the subjects who participate during the clinical study participation period. The 
examination and treatment of the subjects whose clinical study participation has been discontinued or terminated will 
be based on the general examination and treatment principles of the infectious diseases field. In other words, 
different types of treatments, procedures, and drug therapies will be performed depending on the subject’s condition 
and the doctor’s decision.  
 
 
20. Measures for protection of the subject safety 
This clinical study will be conducted scientifically and ethically in accordance with the Korea Good Clinical Practice 
(KGCP) and laws related to clinical studies. In addition, this clinical study will be conducted not only to respect the 
dignity and interests of human being in accordance with the Declaration of Helsinki but also to prevent disadvantages 
to the subject as well. 
The Institutional Review Board of the study site will evaluate/approve this protocol according to the Korea Good 
Clinical Practice and will evaluate regularly to check whether this clinical study is being conducted in accordance with 
the protocol. 
  
Before enrolling the subject in the clinical study, the investigator will check the health condition of each subject to 
confirm that the subject can participate in the study, and if there was an adverse event in the previous cycle prior to 
the administration for the next cycle, the investigator will check whether the adverse event has recovered and 
continue the study. In addition, the investigator will fully understand the investigational product and will put the best 
effort to ensure the safety of the subject. 
  
In the case that the subject experiences adverse events due to the clinical study, the subject will receive appropriate 
medical treatment until recovery, and iNtRON Biotechnology, Inc. will indemnify against the injuries caused by the 
investigational product in accordance with the “indemnification policy for victims [Attachment 2].” 

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20.1 Study site 
The head of the study site should fully equip the laboratory and professional personnel required for the conduct of 
the relevant clinical study for each step and should prepare perfectly to conduct the relevant clinical study 
appropriately. 
  
20.2 Principal investigator 
The principal investigator should fully understand the adverse events, precautions, etc. that are stated in this 
protocol in advance and report to the Institutional Review Board and the sponsor immediately in case of serious 
adverse events, etc. during the clinical study. 
 
 
20.3 Sub-investigators 
They should understand the expected adverse events, precautions for use, etc. that are stated in this protocol in 
advance and report to the principal investigator and the sponsor immediately in case of serious adverse events, etc. 
while conducting the clinical study. 
 
20.4 Sponsor 
The sponsor will designate a medical monitor to promote the safety of subjects participating in this clinical study. 
The medical monitor will conduct the review while blinded and will perform the following activities:  
x 
Reviewing SAEs/SUSARs, and if necessary, performing separate evaluation in combination with the 
investigator’s evaluation  
x 
Attending the IDMC meeting if necessary (to attend only where blinding can be maintained) 
x 
Reviewing the safety section of the clinical study report 
 
 
 
 
21. Other matters required to conduct the clinical study safely and scientifically 
21.1 Approval of the Institutional Review Board (IRB)  
Prior to initiation of this clinical study, the investigator should obtain a written approval from the Institutional 
Review Board for the protocol, informed consent form, data and process related to the subject recruitment (e.g., 
advertisement), and written subject information sheet to be provided to the subject. The investigator should 
provide the investigator’s brochure, a copy of the overview of the drug applied for approval (for marketed products, 
the package insert), the information to be provided to the subject, the most recent information, etc. to the 
Institutional Review Board. The investigator should provide the clinical study report, the most recent information, 
and other information (e.g., safety update, amendments, notification letters) to the Institutional Review Board 
according to applicable regulations or in-hospital procedures. The investigator should also submit the approval 

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letter obtained from the Institutional Review Board to iNtRON Biotechnology, Inc. before the clinical drug is 
supplied. If an audit is conducted by the study site or the Institutional Review Board in relation to this clinical study, 
the investigator should inform this to iNtRON Biotechnology, Inc. immediately. In this case, the investigator should 
inform iNtRON Biotechnology, Inc. regarding the result after the audit. 
 
 
 
21.2 Approval of the protocol and the protocol amendment  
Prior to initiation of the clinical study, the protocol, subject information sheet, informed consent form, and other 
relevant documents will be submitted to the IRB along with an application for a review (cover letter or a form) that 
contains the list of submitted documents, date of submitted documents issued, institution from which approval 
needs to be obtained (or region or district under jurisdiction). If applicable, these documents may be submitted to 
the regulatory authorities, as required by the legal requirements in the relevant country.  
The sponsor may supply the clinical drug to the investigator to initiate the study only after obtaining all 
documents required ethically and legally. These documents should also include a list of IRB members whose 
occupations and qualifications are indicated. If the IRB does not disclose a list of members, a request should be 
made to issue a document confirming that the members will be composed based on the KGCP. The IRB approval 
letter should include the records of the clinical study title, clinical study number, study site (region if needed), and 
amendment number and other documents reviewed, if applicable. The approval letter should include the 
documentation of the date when the approval was determined, and it should include the official signature of a 
member. All ethical and legal requirements should be met before the first subject is enrolled in the clinical study. 
Amendments to the protocol and administrative changes should be reported to the IRB and, if applicable, to the 
regulatory authorities, as required by the legal requirements in the relevant country. The protocol amendment 
should be evaluated to determine if official approval is required and to determine whether the informed consent 
form should be revised.  
The investigator should keep all the records of information exchange with the IRB, and if applicable, the 
investigator should keep the records of information exchange documented between the coordinating investigator 
and the IRB. This is also applied to the information exchange between the investigator (or the coordinating 
investigator, if applicable) and the regulatory authorities.  
  
 
21.3 Compliance with the protocol and amendments to the protocol 
This clinical study will be conducted in accordance with the approved protocol. All amendments to the protocol 
should be discussed with the sponsor, iNtRON Biotechnology, Inc., and the protocol amendment should be 
completed by the sponsor (or the contract research organization). The investigator should not apply any of these 
amendments to the protocol before they are reviewed and approved by the Institutional Review Board, except for 
the cases to prevent harm to the subjects immediately. Serious protocol deviations should be recorded in the case 
report form.  
If any of these modifications or amendments to the protocol are applied before obtaining approval from the 
Institutional Review Board in order to prevent harm to the subject immediately, these modifications or 
amendments should be submitted to the Institutional Review Board (for review and approval in the future), the 

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sponsor, the contract research organization, and the Ministry of Food and Drug Safety (if required by applicable 
regulations) as soon as possible. Then, the chairperson or the secretary of the Institutional Review Board should 
send a signed approval document to the sponsor. 
If the protocol amendments are minor, it is sufficient for the investigator to just notify the Institutional Review 
Board. However, if the fundamental study design is being changed or if the possibility of risks to the subject is 
increasing,  
① the informed consent form should be revised and submitted to the Institutional Review Board to be reviewed 
and approved, 
② consent should be obtained again from the subjects already recruited using a newly changed informed 
consent form if such a change affects the subjects, and  
③ the new informed consent form should be used to obtain consent from newly recruited subjects. 
 
 
21.4 Protection of subjects 
The sponsor, contract research organization, and investigator should thoroughly monitor the subject’s 
progression of disease for the safety of the subject, and if the risks to the subject safety are expected, the relevant 
subject should be excluded from the clinical study and appropriate measures should be taken. 
This study guarantees the confidentiality of all subjects, and records and evaluates using the subject number (ID) 
assigned during the study process. The subjects will be informed of this confidentiality guarantee for subjects. The 
principal investigator will keep the completed informed consent form. By signing this agreement, the investigator 
has agreed to obtain the informed consent form from the subject participating in the study. 
 
21.5 Monitoring 
The purposes of monitoring are as follows: 
1) To protect the rights and welfare of subjects 
2) To determine whether the reported clinical study-related data are accurate, complete, and verifiable when 
compared with the source documents 
3) To confirm whether the clinical study is conducted in accordance with the protocol approved by the Minister 
of Food and Drug Safety and the Institutional Review Board as well as the KGCP 
 
Therefore, the clinical research associate will regularly visit the study site during the study progression in order to 
confirm whether the principal investigator is complying with the approved protocol, whether source documents 
and other clinical study-related records are maintained to be accurate, complete and up to date, and whether all 
adverse events have been properly reported within the deadlines specified in the KGCP and the protocol. Also, the 
clinical research associate will visit the study site for purposes to check the storage (preservation) condition and 
quantity of the investigational product, and to confirm the accuracy, completeness, and consistency of case report 
forms, source documents and other clinical study-related documents (including electronic documents) by checking 
whether the clinical study data required by the protocol are being recorded in the case report forms accurately and 
whether the information in the case report forms is consistent with the source documents.  
The clinical research associate acts as the key communicator between the sponsor and the principal investigator. 
 

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When the clinical research associate visits the study site or contacts the study staff member via telephone, fax or 
email, the relevant facts and information should be reported to the sponsor in writing. The monitoring report 
should include the following: 
1) Date and location where monitoring is carried out, name of the clinical research associate, investigator (or 
the name of a person who came in contact)  
2) Descriptions of a summary of what the clinical research associate has identified and clinically significant 
findings or events, deviations from the protocol, etc. or problems, and action taken or to be taken to 
maintain compliance with the protocol 
The clinical research associate should report data related to the safety of the subjects that has been identified 
through the monitoring process to the sub-investigator (investigator) who can make medical judgement, and the 
sub-investigator (investigator) will finally determine the following recommendations resulting from the data safety 
monitoring:  
• 
Recommendation whether to continue or discontinue the study 
• 
Recommendation for the recruitment/selection/preservation and management of subjects, the 
improvement of protocol compliance, and the data management and quality control process in order to 
ensure the integrity of the study 
• 
Recommendation of ways to reduce the risks of adverse events, etc. by evaluating the information on 
risks that exceed the benefits related to the investigational product, the adverse events, or the effect 
that is below the expectation 
• 
Review of the completeness of data, etc. by receiving reports of monitoring results related to protocol 
deviations, dropout, etc. when such cases occur 
 
The principal investigator should agree and cooperate to allow the clinical research associate or the delegate of 
this task to have access to the location of the investigational products stored and the clinical study-related 
documents (including electronic documents), and the clinical research associate can review all CRFs and written 
consents.  
 
21.6 Case report forms 
Source documents include all documents (including electronic documents), data, and records that contain source 
data such as hospital records, medical records, subject’s records, memos, pathological test results, subject’s diaries, 
assessment checklists, drug dispense records, data recorded on automated test equipment, test certificates and 
their official copies, microfiches, microfilms, radiological examination data, magnetic tapes, and pathological 
laboratory record data. Source data include any information contained in the original or an official copy of the 
original in which the relevant clinical findings, observations, and other actions required to reproduce or evaluate 
the clinical study are recorded.  
Therefore, all information collected and recorded in the subject’s case report form (CRF) should be prepared 
based on the source documents and source data and should be consistent with this information. A description 
should be attached to any information that does not match the source documents.  
The investigator should ensure that the data contained in the case report form or any other report are accurate, 
complete, legible, and timely. In the case of changing or correcting information in the documented or electronic 
case report form, the records of any changes or corrections should be stored. 

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The clinical research associate will visit the study site at appropriate intervals to perform the duties to compare 
the case report forms and source documents. For this, the investigator should agree and cooperate to allow the 
clinical research associate to access source documents. Once the data to be recorded are obtained, the case report 
form should be completed as soon as possible. 
The form of the case report form is the web-CRF, and the extent of authorization to use will be set and an ID will 
be assigned based on the scope of work of the investigator, CRA, CRC, etc. Only the clinical study staff members will 
have access to the web-CRF using the ID and PW, and the principal investigator should maintain confidentiality of 
the records that can identify the subject in order to ensure that subject’s personal life and confidentiality is 
guaranteed in accordance with applicable regulations. 
 
Other clinical study-related data (such as various source data and correspondence) should be properly signed and 
dated in accordance with the general Korea Good Clinical Practice (KGCP). 
 
After the clinical study is terminated and data are transferred from the investigator to iNtRON Biotechnology, Inc., 
the relevant data will go through a verification process. If necessary, iNtRON Biotechnology, Inc. may request the 
clinical study staff member to verify or modify the data.  
 
21.7 Preservation of records  
The principal investigator will keep all documents related to the study, including the reports submitted to the 
Ministry of Food and Drug Safety, the Institutional Review Board, and iNtRON Biotechnology, Inc. Also, according to 
Article 30 Paragraph 2 of the Regulation on Safety of Pharmaceuticals, etc., the investigator should keep the 
protocol and the records and data related to the conduct of the clinical study (including electronic documents) for 3 
years from the date of licensure for manufacturing, selling, importing products. 
In the case that the investigator is unable to continue storing the documents due to appointment to another 
department or retirement, the study-related documents should be transferred to a mutually agreed designee (e.g., 
another investigator who participated in the clinical study, the Institutional Review Board), and in such a case, the 
sponsor should be notified in writing. 
 
The investigator should contact the sponsor of the clinical study-related documents in order to obtain a written 
approval letter from the sponsor prior to the destruction. If the sponsor determines that the preservation of the 
data is no longer necessary, the sponsor will inform the principal investigator in writing. 
The investigator should obtain a written approval letter from the sponsor prior to the destruction of the 
documents. The investigator should keep the records of use of the study drug, copies of case report forms (or 
electronic files), source data, etc. related to the clinical study for the period specified in the relevant regulations 
(KGCP basis: to be kept for 3 years from the date of licensure or the date of deletion of the conditions of 
permission) and the period specified by the sponsor, whichever is longer. The essential documents of the clinical 
study include the following: 
 
① All informed consent forms signed 
② Subject identification code list*, screening log (if applicable), enrollment log 

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③ Records of any contact between the investigator and the IEC/IRB 
④ Composition of the IRB 
⑤ Records of any contact between the investigator and the sponsor (or the contract research organization)  
⑥ Recorded list of the investigators and staff members delegated to perform important clinical study tasks and 
their roles and signatures  
⑦ CRFs of all subjects and copies of documents related to the changes 
⑧ Investigational product accountability log  
⑨ Records of the storage of body fluids or tissue samples (if applicable) 
⑩ All other source documents (subject’s medical records, hospital records, laboratory test records, etc.) 
⑪ All documents corresponding to Section 8 of the ICH E6 Guideline for KGCP (essential documents for the 
conduct of clinical studies) 
 
In general, these documents will be kept by the investigator. If the investigator cannot perform these obligations, 
the sponsor must be notified to perform an alternative, and this should be documented in detail. 
 
21.8 Maintaining data and subject records 
21.8.1 Maintaining confidentiality of data 
The investigator should treat all information provided by iNtRON Biotechnology, Inc. in relation to this clinical 
study as confidential. In addition, in the case of disclosing this information to the Institutional Review Board or 
similar professional committees or related organizations and to people working at such organizations, the relevant 
information must be provided after they fully understand about maintaining the confidentiality of the information. 
 
21.8.2 Maintaining subject records 
The investigator should treat all personal information related to the subjects who are involved in this clinical 
study as confidential. However, if the Ministry of Food and Drug Safety or equivalent health authorities request 
that the study documents related to the subjects be reviewed or copied to verify the records in the case report 
forms, the investigator should accept this. 
 
21.9 Termination of the clinical study  
Upon completion of the clinical study, the relevant clinical study must be terminated at the study site. The 
sponsor or the investigator may discontinue the clinical study at any time, but early termination of the study 
should be done after having a sufficient consultation. In accordance with the regulations in the relevant country, it 
may be necessary to report to the IEC/IRB and regulatory authorities, at the end of the clinical study period. 
Clinical study-related supplies should be collected, destroyed, or stored as requested by the sponsor. 
 
21.10 Reporting of early termination or discontinuation of the clinical study 
The sponsor, the investigator, or the relevant regulatory agencies may discontinue the entire or part of the study 

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at any time, but the compliance process should be consulted. 
The clinical study can be discontinued unexpectedly in the event of a safety issue while conducting the clinical 
study. The study can also be discontinued even when the overall risk–benefit evaluation is not favorable for 
continuing the study. 
If the study is terminated early or discontinued, the investigator should notify the subjects promptly to allow 
them to have proper treatment and follow-up care. Furthermore, the investigator or the sponsor should 
immediately notify the IRB of the detailed information in writing. The regulatory agencies should be informed 
according to the relevant regulations of each country. 
If the risk–benefit evaluation changes after the study is discontinued, it should be provided to the IRB in the case 
that the new evaluation can affect the follow up plan on the subjects who participated in the study. In such a case, 
the measures required to protect the subjects should be described. 
 
21.11 Deviation from the protocol 
No protocol deviation should occur. If a deviation occurs, the principal investigator should notify the clinical 
research associate and review and discuss the deviation. All deviations should be documented, and the reason, date, 
action taken, impact on the subject and the study should be documented. These documents should be kept in the 
investigator’s study file and the sponsor’s study file. 
 
21.12 Essential documents 
Before initiating the study, in other words, before obtaining consent from the first subject, the investigator 
should provide the following documents to iNtRON Biotechnology, Inc.: 
 
① Curriculum vitae of the principal investigator and sub-investigators (signed and dated currently and/or 
supported by notarization documents) 
② Signed and dated agreement for the final protocol 
③ Signed and dated agreement for the actual protocol amendment (if applicable) 
④ Approval/favorable comments from the IRB that clearly define the documents reviewed (protocol, actual 
protocol amendment, subject information sheet/informed consent form, other written information provided 
to subjects, and subject recruitment procedures) 
⑤ Copies of the subject information sheet, informed consent form, other written information, and subject 
recruitment advertisement that are approved by the IRB (if applicable) 
⑥ IRB members/composition list 
⑦ Financial agreement(s) 
⑧ Signed IRB receipt 
⑨ Approval letter from the regulatory agencies and/or notification if required 
 
 

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22. Use of the study result 
By signing this protocol, the principal investigator and the investigator agree to use the results of this study for 
purposes such as registration, presentation, and provision of information for medical and pharmaceutical experts. If 
necessary, the name, address, and qualifications of the investigator may be notified to the government authorities. 
The result of this clinical study will be presented in academic journals or academic conferences, and the sponsor has 
the right to review the information to be presented prior to presentation or submission of the clinical study result.  
All information related to the study drug and the unpublished information provided by the sponsor, such as 
indications, formulations, and preparation methods of the study drug and other academic data related to the study 
drug are confidential and solely owned by the sponsor. The investigator will use the relevant information only for 
the purpose of conducting this study. Unless a prior written approval is obtained from the sponsor, the investigator 
will agree that it will not be used for any other purposes.  
The original CRFs completed will be solely owned by the sponsor. By signing the protocol, the investigator will 
agree to the sponsor’s use of the study results for the domestic and overseas application for approval of drugs, 
presentation and use as information for medical and pharmaceutical professionals. The name, address, and 
qualifications of the investigator will be reported to the regulatory authorities.  
The information obtained during this clinical study at the discretion of iNtRON Biotechnology, Inc. may be 
provided to other investigators who are conducting other clinical studies using this clinical drug. 
Although it is the opposite from the information described in the protocol, iNtRON Biotechnology, Inc. will agree 
with the investigator’s right to publish the study results. All data and results obtained in this clinical study are 
owned by iNtRON Biotechnology, Inc., and the publications should state the participation of the principal 
investigator, staff members who assisted him/her, and other investigators who participated in this clinical study. 
Any scientific paper, presentation, communication, or other study-related information described in this protocol 
should be submitted to the chief executive officer of iNtRON Biotechnology, Inc. to review the information before 
submitting it for publication or presentation. The reviewed information will be provided within 4 weeks after the 
application of the manuscript. The guidelines for the copyright aims to follow the guidelines of the ICMJE 
(International Committee of Medical Journal Editors). In addition, when there is a request for a patent application 
or measures for the sponsor to firmly establish its ownership, the investigator will postpone the presentation for an 
additional 90 days. 
 
Upon termination of the study, one or more manuscripts for joint publication will be prepared by the investigator 
and iNtRON Biotechnology, Inc. collaboratively. The copyrighted investigator will be requested to initiate and 
approve the publication. The completion of the clinical study report (CSR) is the responsibility of Symyoo Inc. and 
iNtRON Biotechnology, Inc. One principal investigator responsible for reviewing the CSR and signing the 
investigator’s signature section will be designated by iNtRON Biotechnology, Inc. 
 
If there is a disagreement about the publication, the publication should reflect the opinions of both the 
investigator and iNtRON Biotechnology, Inc. fairly and sufficiently. 
 
 
23. Responsibilities 
Symyoo Inc. and iNtRON Biotechnology, Inc. are responsible for completion of the protocol, case report form, 
supply of the clinical drug and other study materials, monitoring, data management, statistical analysis, procedures of 
iNtRON Biotechnology, Inc., consent form for internal uses, and the clinical study report (CSR) specified in the recent 

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KGCP guidelines. 
The investigator is responsible for conducting the clinical study. If any responsibilities are delegated, the 
investigator should have a list of properly qualified persons to whom the investigator has delegated specific important 
responsibilities related to the study. 
The investigator will take all technical and organized security measures needed to prevent accidental or undesirable 
damage, loss, or deterioration of data. The investigator will prevent unauthorized access to any data or other data 
processing that is not permitted by applicable laws. 
In the case that there is a request from iNtRON Biotechnology, Inc., the investigator will provide iNtRON 
Biotechnology, Inc. with the necessary information which can confirm that such technical and organized security 
measures are being implemented. 

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24. Literature references 
1. Jeong HJ, Kim WJ, Kim MJ, Park SC. Nosocomial infection surveillance in the intensive care unit. Kor J Infect Dis. 
1995;27:105-117 
2. Kundsin RB. Documentation of airborne infection during surgery. Ann N Y Acad Sci. 1980;350:251-261 
3. Etiene J, Fleurette J, Ninet JF, Favet P, Gruer LD. Staphylococcus endocarditis after dental extraction. Lancet. 
1986;2:511-512 
4. Etiene J, Brun Y, Fleurette J. Staphylococcus lugdunensis endocarditis. J Clin Pathol. 1989;42:892-893 
5. Frency J, Brun Y, Bes M, Meugnier H, Grimont F, Grimon PAD, Newi C, Fleurette J. Staphylococcus lugdunensis sp. 
and Staphylococcus schleiferi sp. novel two species from human clinical specimens. Int Syst Bacteriol. 
1998;38:168-172 
6. Seung-Ho Han et al., Monitoring of Methicillin-Resistant Staphylococcus aureus in Nasal Swabs Obtained fron 
Dental Clinic Healthcare Providers and Medical Environments Nurses. Int J Oral Biology. 2010;35:7-12 
7. Jane D. Siegel, MD et al., the Healthcare Infection Control Practices Advisory Committee, Management of 
Multidrug-Resistant Organisms In Healthcare Settings, 2006 
8. Lee HM, Yong DG, Lee KW et al. Antimicrobial Resistance of Clinically Important Bacteria Isolated from 12 
Hospitals in Korea in 2004. Korean Journal of Clinical Microbiology 2005; 8 (1): 66–73 
9. Eun Ja Park et al., Analysis of Economic Outcome of Methicillin-Resistant Staphylococcus aureus(MRSA) 
Bacteremia Using Retrospective Case-Control Study, Kor. J. Clin. Pharm 2007;17:59-64 
10. Alexander Sulakvelidze et al., Bacteriophage Therapy, Antimicrobial Agents and Chemotheraphy, 2011;649-659 
11. Mark Fenton et al., Recombinant bacteriophage lysins as antibacterials, Bioengineered Bugs, 2010;1:9-16 
12. Richard M. Carlton, Phage Therapy: Past History and Future Prospects, Archivum Immunologiae et Therapiae 
Experimentalis, 1999;47:267-274 
13. Korean Intellectual Property Office, Patent Registration Notification, Registration Number: 10-0781669. 
Bacteriophage Having Killing Activity Specific to Staphylococcus aureus, Patentee: iNtRON Biotechnology, Inc. 
14. Korean Intellectual Property Office, Patent Registration Notification, Registration Number: 10-0759988. 
Antimicrobial Protein Specific To Staphylococcus aureus, Patentee: iNtRON Biotechnology, Inc. 
15. J. W. Costerton et al., Biofilms, the Customized Microniche, J Bacteriol 1994;176:2137-2142 
16. Korean Intellectual Property Office, Patent Registration Notification, Registration Number: 10-0910961. 
Bacteriophage or Lytic Protein Derived From the Bacteriophage Which Effective For Treatment of Staphylococcus 
aureus Biofilm, Patentee: iNtRON Biotechnology, Inc. 
17. Thien-Fah C Mah, Mechanisms of biofilm resistance to antimicrobial agents, Trends in Microbiology, 2001;9:34-39 
18. Julie A. Wu et al., Lysostaphin disrupts Staphylococcus aureus and Staphylococcus epidermidis biofilms on artificial 
surfaces. Antimicrobial Agents and Chemotherapy. 2003;47:3107-3414 
19. Catherine Liu et al., Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of 
Methicillin-Resistant Staphylococcus aureus, IDSA Guidelines, 2011 
20. Jae-Seok Kim, M.D. et al., Antimicrobial Resistance Profiles of Staphylococcus aureus Isolated in 13 Korean 

Protocol No. ITB-101 
  
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Hospitals, Korean J Lab Med 2004;24:223-229 
21. Goldrick B et al., First reported case of VRSA in the United States, Am J Nurs, 2002;102(11):17 
22. Francisco M. Marty et al., Emergence of Clinical Daptomycin-Resistant Staphylococcus aureus Isolate during 
treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia and Osteomyelitis. J Clin Microbiol. 
2006;44(2):595-597 
23. Yoong, P., R. Schuch, D. Nelson, and V. A. Fischetti. Identification of a broadly active phage lytic enzyme with lethal 
activity against antibiotic resistant 
Enterococcus faecalis and Enterococcus faecium. J. Bacteriol. 
2004;186:4808-4812 
24. Soo youn Jun et al., Comparison of the Antibacterial Properties of Phage Endolysins SAL-1 and LysK, 
2011;55:1764-1767 
25. Nelson D, Loomis L, Fischetti VA. Prevention and elimination of upper respiratory colonization of mice by group A 
streptococci by using a bacteriophage lytic enzyme. Proc Natl Acad Sci USA 2001; 98:4107-4112  
26. Jado I, Lopez R, Garcia E, Fenoll A, Casal J, Garcia P. Phage lytic enzymes as therapy for antibiotic-resistant 
Streptococcus pneumoniae infection in a murine sepsis model. J Antimicrob Chemother 2003; 52:967-973 
27. Loeffler JM, Djurkovic S, Fischetti VA. Phage lytic enzyme Cpl-1 as a novel antimicrobial for pneumococcal 
bacteremia. Infect Immun 2003; 71:6199-6204 
28. McCullers JA, Karlstrom A, Iverson AR, Loeffler JM, Fischetti VA. Novel strategy to prevent otitis media caused by 
colonizing Streptococcus pneumoniae. PLoS Pathog 2007; 3:28 
29. Loessner MJ. Bacteriophage endolysins-current state of research and applications. Curr Opin Microbiol 
2005;8:480-487 
30. Fischetti VA. Bacteriophage lysins as effective antibacterials. Curr Opin Microbiol 2008; 11:393-400 
31. Loeffler JM, Nelson D, Fischetti VA. Rapid killing of Streptococcus pneumoniae with a bacteriophage cell wall 
hydrolase. Science 2001; 294:2170-2172 
32. Schuch R, Nelson D, Fischetti VA. A bacteriolytic agent that detects and kills Bacillus anthracis. Nature 2002; 
418:884-889 
33. Jan Borysoyski et al., Bacteriophage Endolysins as a Novel Class of Antibacterial Agents, Exp Biol Med 2006; 
231:366-377 
34. Vincent A Fischetti, Using phage Lytic Enzymes to Control Pathogenic Bacteria, BMC oral Health 2006, 6(Suppl 
I):S16 
35. William Wiley Navarre et al., Multiple Enzymatic Activities of the Murein Hydrolase from Staphylococcal Phage 
Φ11, The Journal of Biological Chemistry 1999; 274(22):15847-15856 
36. Juan A Hermoso et al, Taking aim on bacterial pathogens: from phage therapy to enzybiotics, Current Opinion in 
Microbiology 2007, 10:1-12 
37. Vincent A Fischetti et al., Reinventing phage therapy: are the parts greater than the sum?, Nature Biotechnology 
2006; 24(12):1508-1511 
38. Van Hal et al., Predictors of Mortality in Staphylococcus aureus Bacteremia, Clinical Microbiology Reviews 2012; 

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25(2):362-386 
 
Attachments 
 
 
[Attachment 1] Subject Information Sheet and Informed Consent Form  
[Attachment 2] Indemnification Policy for Victims  
[Attachment 3] Data and Safety Monitoring Plan