Conditions: Influenza A
Keywords: efficacy safety
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 228
Healthy volunteers: no

Brief summary:
This study is a Phase IIb, Randomized, Double-blind, Multicenter, Placebo-controlled study evaluating the efficacy and safety of CT-P27 in subjects with acute uncomplicated influenza A infection.

Detailed description:
This study is a Phase IIb, Randomized, Double-blind, Multicenter, Placebo-controlled study. All enrolled subjects will be given a single dose of 90 mg/kg CT-P27, 45 mg/kg CT-P27, or placebo intravenously over 90 minutes (±15 minutes) on Day 1 and then followed by Day 110.

Arms:
arm 1: CT-P27 will be administrated once in IV infusion. arm 2: CT-P27 will be administrated once in IV infusion. arm 3: Placebo will be administrated once in IV infusion.

Interventions: intervention 1: CT-P27 90 mg/kg intervention 2: CT-P27 45 mg/kg intervention 3: Placebo
Intervention descriptions: intervention 1: Influenza A treatment drug. intervention 2: Influenza A treatment drug. intervention 3: Placebo.

Protocol document:
Prot_000.pdf: 
CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 1 of 91 
31 January 2018 
 
 
 
 
Clinical Study Protocol 
A Phase IIb, Randomized, Double-blind, Multicenter, Placebo-controlled 
Study Evaluating the Efficacy and Safety of CT-P27 in Subjects with Acute 
Uncomplicated Influenza A Infection 
 
Protocol Number: 
CT-P27 2.2 
Date of Protocol: 
31 January 2018 
Version: 
5.0 
Protocol Amendment No.: 
Amendment 4,  dated 31 January 2018 
Product: 
CT-P27 
Study Phase: 
Phase IIb 
Sponsor: 
■■■■■■■■■ 
  
Sponsor Contact: 
■■■■■■■■■ 
SAE Reporting and Data Center: 
■■■■■■■■■ 
 
Confidentiality Statement 
This confidential information in this document is provided to you as an Investigator or 
consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee. Your acceptance of this document constitutes 
agreement that you will not disclose the information contained herein to others without written 
authorization from the Sponsor. 




CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 3 of 91 
31 January 2018 
 
 
 
 
SYNOPSIS 
Name of Sponsor/Company: 
CELLTRION, Inc. 
Name of Finished Product: 
CT-P27 
Name of Active Ingredient: 
Human monoclonal antibodies CT-P22 and CT-P23 
Title of Study: 
 
A Phase IIb, Randomized, Double-blind, Multicenter, Placebo-controlled Study 
Evaluating the Efficacy and Safety of CT-P27 in Subjects with Acute 
Uncomplicated Influenza A Infection 
Protocol No: 
 
CT-P27 2.2 
Study Site(s): 
 
■■■■■■■■■  
Study Duration:  
Approximately 16 weeks 
Phase: 
IIb 
Test Product, Dose and Mode of Administration: 
CT-P27 45 mg/kg or 90 mg/kg dose by single IV infusion over 90 minutes (±15 minutes) 
Reference Therapy, Dose and Mode of Administration: 
Placebo by single IV infusion over 90 minutes (±15 minutes) 
Objectives: 
Primary Objective:  
 
To evaluate efficacy as determined according to the time to resolution of respiratory and constitutional 
symptoms of influenza and fever 
Secondary Objectives 
 
To evaluate the additional efficacy and safety of CT-P27, including potential effects on the incidence 
of antibody-dependent enhancement (ADE)  
Exploratory Objectives:  
 
To assess the pharmacokinetics (PK) of CT-P27 components (CT-P22 and CT-P23)  
 
To assess immunogenicity  
 
To assess the characterization of isolated influenza viruses 
Sample Size: 
Approximately 183 subjects with acute uncomplicated influenza A infection will be randomly assigned to the 
45 mg/kg CT-P27, 90 mg/kg CT-P27 or placebo groups (70 subjects per CT-P27 treatment groups and 43 
subjects in placebo group).  
Main Selection Criteria: 
Male or female subjects with a diagnosis of influenza A by a rapid influenza diagnostic test and onset of illness 
no more than 48 hours prior to the planned administration of study drug will be considered for enrollment in 
the study if they meet all of inclusion criteria and none of the exclusion criteria. 
Inclusion Criteria:  
Each subject must meet all the following criteria to participate in this study: 
1. Subject is a male or female and aged 19 to 64 years, inclusive. 
2. Subject can voluntarily provide a written informed consent. 
3. Onset of illness no more than 48 hours prior to the planned administration of study drug. If the 
adjustments of visit schedule is required, additional 12 hours can be allowed (Maximum onset of 
illness: 60 hours).  


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 4 of 91 
31 January 2018 
 
 
 
 
Note: time of onset of illness is defined as the earlier of either (a) the time when the body temperature 
was first measured as ≥38.0oC (≥100.4oF) or (b) the time when the subject experienced the presence 
of at least two symptoms that are respiratory and/or constitutional (moderate to severe in intensity). 
4. As reported by the subject and recorded on the Flu-iiQ™ completed at screening, the subject has at 
least two of the following symptoms (moderate to severe in intensity):  
a) Respiratory symptom (cough, sore throat, or nasal congestion) or 
b) Constitutional symptom (headache, feeling feverish, body aches and pains, or fatigue). 
5. Subject has a fever ≥38.0oC or ≥100.4oF at screening or a history of fever within the 24 hours prior to 
screening and has received treatment with an antipyretic(s) in the 6 hours prior to screening. 
6. Subject is diagnosed with influenza A at screening, using the Sponsor-supplied or agreed in advance 
rapid influenza diagnostic test. And if there is available test result confirmed as influenza A prior to 
obtaining written informed consent and that result was from the influenza diagnostic test which is 
agreed with Sponsor in advance, that test result can be allowed.  
7. For both male and female subjects, the subject and his/her partner (if of childbearing potential) agree 
to use a highly effective method of contraception during the study and for 5 months after the 
administration of study drug. 
a) Male and female subjects and their partner who have been surgically sterilized for less than 6 
months prior to the date of informed consent must agree to use a highly effective method of 
contraception during the study and for 5 months after the administration of study drug. 
b) Menopausal females must have experienced their last menstrual period more than 12 months 
prior to the date of informed consent to be classified as not of childbearing potential. 
8. Subject's body mass index (BMI) is of <35.0 kg/m2 and weight is of ≤99.9 kg. 
Exclusion Criteria: 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Subject is not likely to complete all required study visits or procedures for any reason, in the opinion of 
the Investigator. 
2. Subject has received a treatment with another investigational medical product or participated in another 
clinical trial within 30 days (or 5 half-lives, whichever is longer). 
3. Subject has previous exposure to any anti-influenza monoclonal antibody therapy including CT-P27 prior 
to study drug administration. 
4. Subject has a history of hypersensitivity to any monoclonal antibody or has a known hypersensitivity to 
any of the treatment components. 
5. Subject is taking antiviral treatment for influenza (e.g., zanamivir, oseltamivir, rimantadine, amantadine, 
peramivir, or ribavirin) or has a history of using these antivirals within 14 days prior to the administration 
of study drug. 
6. Subject has been immunized against influenza with live attenuated or inactivated virus vaccine within 21 
days prior to the administration of study drug. 
7. Subject has a medical condition including one or more of the following: 
a. 
Positive influenza B or influenza A+B infection. 
b. History or presence of congestive heart failure with symptoms consistent with New York Heart 
Association Class III or IV functional status within 12 months prior to study drug administration. 
c. 
Presence of clinically significant abnormality on a 12-lead electrocardiogram (ECG) at screening 
that, in the Investigator's clinical judgment, may compromise the safety of the subject or affect 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 5 of 91 
31 January 2018 
 
 
 
 
the outcome of the study. These include, but are not limited to, a PR interval >200 msec, a 
corrected QT interval [QTc] >450 msec for male subjects and >470 msec for female subjects, or 
any evidence of heart block, right bundle branch block, or left bundle branch block. 
d. History or presence of any clinical condition or evidence of organ dysfunction that may affect 
either the subject’s ability to participate in the study or the study result, in the opinion of the 
Investigator. 
e. 
Subjects with abnormal liver function values. These will include aspartate transaminase (AST), 
alanine transaminase (ALT) or alkaline phosphatase (ALP) ≥ 3 × ULN at screening. 
f. 
Subject with abnormal renal function values (serum creatinine ≥ 1.7 × ULN with creatinine 
clearance level ≤ 75mL/min at screening). 
g. In the opinion of the Investigator, the subject has active tuberculosis. 
h. Uncontrolled diabetes mellitus (defined as known by the case of HbA1c >8%). 
i. 
Uncontrolled hypertension (defined as known by the case of systolic blood pressure (SBP) ≥160 
mmHg or diastolic blood pressure (DBP) ≥100 mmHg).  
j. 
Documented, known current infection with hepatitis B, hepatitis C, or human immunodeficiency 
virus (HIV). 
k. Severe infection within 30 days prior to the administration of study drug that required parenteral 
antibiotic use or hospitalization. 
l. 
Any uncontrolled acute or chronic clinically significant respiratory disease (e.g., chronic 
obstructive pulmonary disease, cystic fibrosis, bronchiectasis, asthma, or bacterial pneumonia). 
m. History of malignancy within 2 years prior to study drug administration (with the exception of 
treated basal cell carcinoma of the skin or carcinoma in situ of the cervix) or current active 
malignancy. 
8. Subject is currently hospitalized or currently requires hospitalization due to severity of illness or has any 
plan for elective hospitalization within 1 month after study drug administration. 
9. Subject requires oxygen therapy due to underlying disease or influenza infection. 
10. Subject has a history of bone marrow or solid organ transplantation. 
11. Subject uses systemic steroids or other immunosuppressant (except oral steroid up to 5-10 mg/day, 
methotrexate up to 10 mg/week). 
12. Subject requires routine/intermittent hemodialysis or peritoneal dialysis. 
13. Subject is pregnant or breastfeeding.    
14. Subject is not eligible for the study participation for whatever reason (including clinical laboratory 
results) in the opinion of the Investigator, or shows evidence of a condition (psychological, emotional 
problems, any disorders or resultant therapy) that is likely to invalidate informed consent, or limited the 
ability of the subject to comply with the protocol requirements in the opinion of the Investigator, or 
unable to understand the protocol requirements, instructions and study related restrictions, the nature, 
scope and possible consequences of the clinical study, or is unable to give written informed consent or to 
comply fully with the protocol.                                                                                                                          
Methodology:  
This is a Phase IIb, multicenter, placebo-controlled, randomized, double-blind, parallel-arm study to evaluate 
the efficacy and safety of 2 different doses of CT-P27 (45 mg/kg and 90 mg/kg) in subjects with acute 
uncomplicated influenza A infection. This proof-of-concept study will provide dose-ranging information for 
the subsequent clinical development of the drug. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 6 of 91 
31 January 2018 
 
 
 
 
No study procedures will be performed prior to informing the subject about the study and obtaining written 
informed consent. However, any test result which was obtained within the allowed screening period can be 
used as screening data for subject’s convenience. It is critical that subjects receive treatment with study drug 
no more than 48 hours after the onset of symptoms (window of +12 hours is allowed). For most subjects, 
obtainment of the informed consent form (ICF), screening for eligibility, randomization, and treatment will 
occur on the same day. Though obtainment of the ICF may occur on the day prior to screening, randomization 
or treatment, it must be within 24 hours before the administration of study drug. 
To be eligible for enrollment, subjects must have a positive test result for influenza A by a rapid influenza 
diagnostic test. At screening, nasopharyngeal swab samples will be collected for two times to be used for rapid 
influenza diagnostic test and virology assessment. The enrollment process is presented in Figure S1. 
Figure S1 Enrollment Process 
 
Approximately 183 subjects with influenza A to be enrolled in the study will be randomly assigned to 1 of 3 
groups, 45 mg/kg CT-P27, 90 mg/kg CT-P27, or placebo (70 subjects per CT-P27 treatment groups and 43 
subjects in placebo group). Randomization will be stratified by flu vaccination history within a year (Yes vs 
No) and participation in PK sub-study (Yes vs No). A schematic diagram of subject assignment is presented in 
Figure S2. 
Figure S2 Schematic diagram of Subject Assignment 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 7 of 91 
31 January 2018 
 
 
 
 
 
All enrolled subjects will be given a single dose of 45 mg/kg CT-P27, 90 mg/kg CT-P27, or placebo 
intravenously over 90 minutes (±15 minutes) on Day 1 and then followed by Day 110.  
A PK sub-study will be performed on the subjects who signed informed consent to participate in a PK sub-
study. Of total number of subjects to be enrolled, approximately 53 subjects (20 subjects per CT-P27 treatment 
groups and 13 subjects in placebo group) will be included in the Subgroup (PK) Cohort, and additional PK 
samples from the subjects in this cohort will be collected according to the schedule of assessments. A schematic 
diagram for the study cohorts is presented in Figure S3. 
Figure S3 Schematic Diagram for the Study Cohorts 
 
Subjects may be admitted in a hospital from Day 1 (before study drug administration) to Day 3 (after 
completion of the 48 hours assessments) if it is deemed necessary upon the judgement of the investigator. 
Study visits: 
 
Subjects who are included in Whole Study Cohort and are hospitalized: 4 planned study visits 
 
Subjects who are included in Whole Study Cohort but are not hospitalized: 6 planned study visits 
 
Subjects who are included in the Subgroup (PK) Cohort and are hospitalized: 7 planned study visits 
 
Subjects who are included in the Subgroup (PK) Cohort but are not hospitalized: 9 planned study 
visits 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 8 of 91 
31 January 2018 
 
 
 
 
Efficacy Assessment: 
The completion of the Influenza Intensity and Impact Questionnaire (Flu-iiQ™) and the recording of body 
temperature will take place at screening for baseline assessments. After study drug administration, subjects 
will be instructed to complete the Flu-iiQ™ and the body temperature in the diary twice a day (at approximately 
12-hour intervals) from Day 1 to Day 8 (in the morning [between 6 and 10 AM, approximately] and in the 
evening [between 6 and 10 PM, approximately]) and body temperature of subject will be also taken by site 
personnel at site at screening, Day 1 (prior to infusion), Day 2, Day 3, Day 5 and Day 8. 
Nasopharyngeal swab samples will be used for viral shedding based on quantitative polymerase chain reaction 
(qPCR) and cell culture. Those samples will be taken at screening, Day 2 (24 hours [±4 hours] after the start 
of the study drug infusion), Day 3 (48 hours [±4 hours] after the start of the study drug infusion), Day 5 (96 
hours [±4 hours] after the start of the study drug infusion), and Day 8 (168 hours [±4 hours] after the start of 
the study drug infusion). Laboratory confirmation of influenza A infection will be defined as a positive result 
by qPCR or cell culture. 
The following efficacy parameters will be assessed as primary and secondary efficacy endpoints: 
Primary Efficacy Endpoint:  
The primary efficacy endpoint is defined as the time from the administration of study drug to resolution of 
influenza symptoms and fever. 
Resolution of symptoms has occurred if the following influenza symptoms (as recorded on the Flu-iiQ™) are 
mild in intensity or none for at least 24 hours. 
 
Respiratory symptoms (cough, sore throat, and nasal congestion). 
 
Constitutional symptoms (headache, feeling feverish, body aches and pains, and fatigue). 
Resolution of fever is defined as: 
 
Body temperature of <37.0oC for at least 24 hours. 
Secondary Efficacy Endpoints:  
 
Time to resumption of normal activity as reported in Domain 2 of the Flu-iiQ™. 
 
Time to return to normal body temperature (<37.0oC) for at least 24 hours. 
 
Time to resolution of individual symptoms for at least 24 hours as recorded on the Flu-iiQ™. 
 
Severity of symptoms as recorded on the Flu-iiQ™. 
 
Viral shedding in nasopharyngeal swab samples. 
 
Incidence of secondary complications of influenza. 
 
Quality of Life (QoL) measures as reported in Domain 3 and Domain 4 of the Flu-iiQ™. 
Safety Assessment: 
For safety evaluations, subjects will be followed up from the time the ICF is signed until Day 110 
(approximately 5 half-lives) after the administration of study drug. Safety assessments will occur throughout 
the study.  
Adverse events (AE) or concomitant medications that are verified by the investigator will be recorded on the 
eCRF. Up to Day 8, any AE or concomitant medication will also be recorded by subjects on their diaries and 
the investigators will refer to the records for information. If there is any AE or concomitant medication after 
Day 8, subjects will be instructed to contact the principal investigator or sub-investigator at any time. 
If symptoms have not relieved up to Day 3, chest x-ray will be performed to determine presence of secondary 
complications of influenza A infection. 
Subjects with suspicious ADE will be required to assess virus titer using the nasopharyngeal swab sample, Flu-
iiQ™ and body temperature up to Day 8 after the day of ADE occurrence. If symptoms have not resolved or 
have worsened up to Day 8 after the day of ADE occurrence, same procedures will repeat.  


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 9 of 91 
31 January 2018 
 
 
 
 
The following safety parameters are determined as secondary safety endpoints: 
 
Treatment-emergent adverse events (TEAEs) 
 
Treatment-emergent serious adverse events (TESAEs) 
 
TEAEs leading to treatment discontinuation 
 
Clinical laboratory analyses (hematology, biochemistry, and urinalysis laboratory tests) 
 
Vital sign measurements  
 
ECGs 
 
Physical examination findings 
 
ADEs 
Exploratory Assessment: 
Blood sampling for PK analysis will be collected from the subjects on: 
 
Day 1 at pre-infusion (within 15 minutes prior to the beginning of the infusion), the end of infusion 
(+15 minutes), 1 hour (±15 minutes) after the end of the infusion,  
 
Day 2 (24 hours [±4 hours] after the start of the study drug infusion), 
 
Day 3 (48 hours [±4 hours] after the start of the study drug infusion),  
 
Day 8 (168 hours [±4 hours] after the start of the study drug infusion), 
 
Day 15 (±2 days),  
 
Days 29, 57 and 110 (±5 days) or at End-of-Study (EOS) visit  
Blood sampling for Immunogenicity assessment will be collected on Day 1(at pre-infusion) and Day 110 (± 
5days) or EOS visit.  
For the subjects with Influenza A confirmed by qPCR or cell culture, genotypic analysis on Hemagglutinin 
(HA) and Neuraminidase (NA) genes, and phenotype characterization of potential escape variants with regard 
to CT-P27 will be assessed using the nasopharyngeal swab samples.  
Blood sampling for assessment of anti-influenza antibodies (Hemagglutination inhibition) will be collected on 
Day 1(at pre-infusion) and Day 29(± 5days) or EOS visit (if a subject is early terminated from the study) in 
Subgroup (PK) Cohort. 
Additional genotyping tests could be conducted if it is required from a regulatory or medical perspective.  
The following parameters are determined as exploratory endpoints: 
 
PK profiles 
o 
AUC0-∞: Area under the concentration-time curve in serum from time zero extrapolated to infinite 
time 
o 
AUC0-last: Area under the concentration-time curve from time zero to the last quantifiable 
concentration 
o 
Cmax: Maximum observed serum concentration 
o 
tmax: Time of maximum concentration 
o 
Clast: Last observed quantifiable concentration 
o 
λz: Apparent terminal elimination rate constant 
o 
t1/2: Apparent terminal elimination half-life 
o 
MRT: Mean residence time 
o 
CL: Systemic clearance from serum after IV dosing 
o 
Vz: Apparent volume of distribution during the terminal elimination phase after IV dosing 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 10 of 91 
31 January 2018 
 
 
 
 
 
Anti-drug specific antibodies for CT-P27 component antibodies (CT-P22 and CT-P23) 
 
HI antibody 
 
Genotype and phenotype of isolated influenza virus 
Sample Size Assumptions: 
This study is designed to obtain effect sizes of 2 different CT-P27 treatment groups and placebo group based 
on the time from the administration of study drug to resolution of influenza symptoms and fever. 
For this proof-of-concept dose-ranging study, assuming 90% of subjects are included in the eligible infected 
population, the total eligible sample size of 164 (63 eligible infected subjects per CT-P27 treatment groups and 
38 subjects in placebo group) achieves 80% power to detect 1.8 days of reduction for the primary endpoint of 
time to resolution with 5% two-sided significance level and standard deviation (SD) of 3 days using a 
Wilcoxon’s rank-sum test.  
Considering a dropout rate of 10%, this study will need 183 subjects to be enrolled to achieve 164 evaluable 
subjects. 
For an effect size of 1.5 days of reduction in time to resolution with SD of 2.9 days, the total sample size could 
be increased to about 250 to achieve at least 80% statistical power with 5% two-sided significance level. 
Data Analysis: 
Statistical Analysis:  
Statistical analyses will be carried out ■■■■■■■■■. Clinical parameters measured in this study will 
be described using descriptive statistics (including number [n], mean, median, SD, minimum, and maximum) 
for quantitative variables and frequency counts and percentages for qualitative variables. Data will be listed in 
data listings.  
The detailed method about the statistical analysis will be described in a statistical analysis plan (SAP), which 
will be finalized prior to database lock and unblinding of the treatment codes. Changes from analyses planned 
in this protocol will be documented in the SAP. Any deviations from the planned analysis as described in the 
SAP will be justified and recorded in the final clinical study report. 
Analysis Populations:  
 
Intent-to-Treat (ITT) Population: defined as all subjects randomized to study drug or placebo. 
 
Intent-to-Treat Infected (ITTI) Population: defined as all randomized subjects with confirmed influenza A 
by qPCR or cell culture. 
 
Safety Population: defined as all randomized subjects receiving any amount of CT-P27 or placebo.  
 
Pharmacokinetic Population: defined as approximately 53 subjects (20 per CT-P27 treatment groups and 
13 in placebo group) in Subgroup (PK) Cohort and all randomized subjects with confirmed influenza A 
by qPCR or cell culture who received a complete dose of study drug, with at least one post-dose PK 
sample.  
Efficacy Analyses:  
The primary efficacy endpoint will be analyzed on the ITTI population using a Wilcoxon’s rank-sum test to 
assess differences between treatments, if every subject were followed until resolution of influenza symptoms 
and fever. The statistically significant difference of time to resolution of influenza symptoms and fever between 
placebo and CT-P27 based on Wilcoxon rank-sum test will be presented by p-values. If there is any censoring, 
the primary efficacy endpoint will be analyzed using Log-rank test, and Kaplan-Meier plots will be presented. 
The secondary efficacy endpoints will be analyzed on both ITTI and ITT populations. Time to resumption of 
normal activity, return to normal body temperature (<37.0oC) and resolution of individual symptoms will be 
analyzed using a Kaplan Meier model. Severity of symptoms, Incidence of secondary complications of 
influenza, viral shedding and QoL by Flu-iiQ™ will be summarized by treatment groups. 
Safety Analyses:  


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 11 of 91 
31 January 2018 
 
 
 
 
Adverse events will be coded to system organ class and preferred term according to the Medical Dictionary for 
Regulatory Activities. Adverse events will be graded for severity based on Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. Adverse events will be summarized using frequency tables presented 
by treatment group. The results of other safety analyses will be presented using descriptive statistics or shift 
tables, as appropriate. All safety analyses will be based on the safety population. 
Exploratory Analyses:  
Pharmacokinetic parameters will be computed by non-compartmental methods using ■■■■■■■■■. 
Pharmacokinetic parameters for CT-P27 components (CT-P22 and CT-P23) will be summarized at each dose 
level (45 mg/kg and 90 mg/kg) using descriptive statistics and will include AUC0–last, AUC0-, Cmax, Clast, tmax, 
t1/2, λz, MRT, CL, and Vz. Summary statistics will include the number of observations (n), mean, SD, median, 
minimum, maximum, geometric mean, and coefficient of variation (CV%). All PK analyses will be based on 
the PK population. Dose proportionality for CT-P22 and CT-P23 will be assessed for Cmax and AUC0-last the 
Power model. For each of the parameters assessed, a plot of the log-transformed parameter value against the 
log-transformed dose will be constructed including the fitted line from the linear regression and the line of 
unity slope. The 95% confidence interval (CI) or P-value for the slope will be presented. 
Anti-drug specific antibodies for CT-P27 component antibodies, genotype, phenotype, and HI antibody will 
be summarized by treatment group and time point. Analysis of anti-drug specific antibodies for CT-P27 
component antibodies will be performed using safety population, and analysis of HI antibody will be performed 
using PK population. Analysis of genotype and phenotype will be performed using ITTI population. 
 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 12 of 91 
31 January 2018 
 
 
 
 
TABLE OF CONTENTS 
SPONSOR SIGNATURE FOR PROTOCOL APPROVAL ...............................................2 
LIST OF TABLES .................................................................................................................16 
LIST OF FIGURES ...............................................................................................................16 
1.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................17 
2.0 
INTRODUCTION......................................................................................................20 
2.1 
Background Information ..............................................................................20 
2.1.1 
Treatment for Influenza .....................................................................20 
2.1.2 
Investigational Product ......................................................................20 
2.1.3 
Non-Clinical Studies .........................................................................21 
2.1.4 
Effects in Humans .............................................................................22 
2.1.4.1 
Phase I Studies .................................................................22 
2.1.4.2 
Phase II Study ..................................................................22 
2.1.4.3 
Efficacy in Humans .........................................................23 
2.1.4.4 
Safety in Humans ............................................................23 
2.2 
Rationale for Current Study .........................................................................24 
2.3 
Hypothesis .......................................................................................................25 
2.4 
Risk Assessment .............................................................................................25 
2.4.1 
Potential Risks and Risk Mitigation ..................................................25 
2.4.2 
Potential Benefits ...............................................................................26 
3.0 
STUDY OBJECTIVES ..............................................................................................27 
3.1 
Primary Objective ..........................................................................................27 
3.2 
Secondary Objectives.....................................................................................27 
3.3 
Exploratory Objectives ..................................................................................27 
4.0 
INVESTIGATIONAL PLAN ...................................................................................28 
4.1 
Summary of Study Design .............................................................................28 
4.2 
Discussion of Study Design ............................................................................37 
4.3 
Selection of Study Cohort ..............................................................................37 
4.3.1 
Inclusion Criteria ...............................................................................37 
4.3.2 
Exclusion Criteria ..............................................................................38 
4.3.3 
Disease Diagnostic Criteria ...............................................................40 
4.3.4 
Subject Withdrawal ...........................................................................41 
4.3.5 
Study and Site Termination ...............................................................41 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 13 of 91 
31 January 2018 
 
 
 
 
5.0 
STUDY TREATMENTS ...........................................................................................43 
5.1 
Treatments Administered .............................................................................43 
5.2 
Identity of Investigational Product(s) ..........................................................43 
5.3 
Packaging and Labelling ...............................................................................44 
5.4 
Precautions and/or Overdose ........................................................................45 
5.5 
Method of Assigning Subjects to Treatment Group ...................................45 
5.6 
Selection of Doses in the Study .....................................................................45 
5.7 
Selection and Timing of Dose for Each Subject ..........................................45 
5.8 
Blinding ...........................................................................................................46 
5.8.1 
Emergency Unblinding ......................................................................46 
5.9 
Prior and Concomitant Treatments .............................................................46 
5.9.1 
Prohibited Prior Medications .............................................................47 
5.9.2 
Prohibited Concomitant Medication ..................................................47 
5.9.3 
Permitted Drugs .................................................................................47 
5.10 
Medical Care of Subjects after End of Study ..............................................48 
5.11 
Treatment Compliance ..................................................................................48 
5.12 
Study Drug Accountability, Dispensing and Destruction ..........................48 
6.0 
EFFICACY, SAFETY, EXPLORATORY PHARMACOKINETIC 
AND OTHER ASSESSMENTS ................................................................................49 
6.1 
Efficacy Measures and Procedures ..............................................................49 
6.1.1 
Diaries ................................................................................................49 
6.1.1.1 
Flu-iiQ™ .........................................................................49 
6.1.1.2 
Body Temperature ...........................................................50 
6.1.2 
Nasopharyngeal Swabs ......................................................................50 
6.1.3 
Rapid Influenza Diagnostic Testing ..................................................50 
6.1.4 
Viral Shedding ...................................................................................51 
6.1.5 
Secondary Complications of Influenza .............................................51 
6.2 
Safety Measures and Procedures ..................................................................51 
6.2.1 
Definition of Adverse Events ............................................................51 
6.2.1.1 
Definition of Serious Adverse Event ...............................53 
6.2.1.2 
Definition of Suspected Unexpected Serious 
Adverse Reaction (SUSAR) ............................................54 
6.2.1.3 
Lack of Efficacy as an AE or SAE ..................................54 
6.2.1.4 
Evaluation of AEs ............................................................54 
6.2.1.5 
Recording and Follow-up of AEs and SAEs ...................56 
6.2.1.6 
Reporting of a Serious Adverse Event and a 
SUSAR ............................................................................57 
6.2.1.7 
Reporting of Serious Adverse Events to 
Regulatory Authorities and Investigators ........................57 
6.2.2 
Contraception ....................................................................................58 
6.2.3 
Pregnancy ..........................................................................................59 
6.2.4 
Clinical Laboratory Evaluations ........................................................60 
6.2.5 
Antibody-dependent Enhancement ...................................................61 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 14 of 91 
31 January 2018 
 
 
 
 
6.2.6 
Vital Signs and Body Temperature ...................................................62 
6.2.7 
Hypersensitivity Reactions ................................................................63 
6.2.8 
Physical Findings and Other Safety Assessments .............................63 
6.3 
Exploratory Assessments...............................................................................64 
6.4 
Demographics and Medical History .............................................................65 
6.5 
Appropriateness of Measurements ...............................................................65 
7.0 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................66 
7.1 
Data Management/Coding ............................................................................66 
7.2 
Quality Assurance Audit ...............................................................................68 
8.0 
STATISTICS ..............................................................................................................69 
8.1 
Determination of Sample Size .......................................................................69 
8.2 
Study Endpoints .............................................................................................69 
8.2.1 
Primary Efficacy Endpoints ..............................................................69 
8.2.2 
Secondary Efficacy Endpoints ..........................................................70 
8.2.3 
Secondary Safety Endpoints ..............................................................70 
8.2.4 
Exploratory Endpoints .......................................................................71 
8.3 
Statistical Methods .........................................................................................72 
8.4 
Analysis Populations ......................................................................................72 
8.4.1 
Intent-to-Treat Population .................................................................72 
8.4.2 
Intent-to-Treat Infected Population ...................................................73 
8.4.3 
Safety Population ...............................................................................73 
8.4.4 
Pharmacokinetic Population ..............................................................73 
8.5 
Statistical Analyses.........................................................................................73 
8.5.1 
Primary Efficacy Analysis .................................................................73 
8.5.2 
Secondary Efficacy Analyses ............................................................74 
8.5.3 
Exploratory Analyses ........................................................................75 
8.5.4 
Safety Analyses .................................................................................77 
8.5.4.1 
Adverse Events ................................................................77 
8.5.4.2 
Clinical Laboratory Evaluations ......................................78 
8.5.4.3 
Vital Signs Measurements, Physical Findings, 
and Other Safety Evaluations ..........................................78 
8.5.5 
Subject Baseline Characteristics ........................................................78 
8.6 
Data to be Analyzed .......................................................................................78 
8.6.1 
Missing Data ......................................................................................79 
8.7 
Interim Analyses ............................................................................................79 
9.0 
ETHICS ......................................................................................................................80 
9.1 
Institutional Review Board or Independent Ethics Committee ................80 
9.2 
Ethical Conduct of the Study ........................................................................80 
9.3 
Subject Information and Informed Consent ...............................................81 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 15 of 91 
31 January 2018 
 
 
 
 
10.0 
STUDY ADMINISTRATION ..................................................................................82 
10.1 
Administrative Structure ..............................................................................82 
10.2 
Data Handling and Record Keeping ............................................................82 
10.3 
Direct Access to Source Data/Documents ....................................................83 
10.4 
Investigator Information ...............................................................................83 
10.4.1 
Investigator Obligations ....................................................................83 
10.4.2 
Protocol Signatures ............................................................................83 
10.4.3 
Publication Policy ..............................................................................83 
10.5 
Financing and Insurance ...............................................................................84 
11.0 
STUDY MANAGEMENT .........................................................................................85 
11.1 
Monitoring ......................................................................................................85 
11.1.1 
Data Safety Monitoring Board ..........................................................85 
11.1.2 
Monitoring of the Study ....................................................................85 
11.1.3 
Inspection of Records ........................................................................85 
11.2 
Management of Protocol Amendments and Deviations .............................86 
11.2.1 
Modification of the Protocol .............................................................86 
11.2.2 
Protocol Deviations ...........................................................................86 
11.3 
Study Termination .........................................................................................87 
11.4 
Final Report ....................................................................................................87 
12.0 
REFERENCES ...........................................................................................................88 
13.0 
APPENDICES ............................................................................................................89 
13.1 
Appendix 1: Signature of Investigator .........................................................90 
13.2 
Appendix 2: Flu-iiQ™ ...................................................................................91 
 
 
 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 16 of 91 
31 January 2018 
 
 
 
 
List of Tables 
Table 1 
Schedule of Assessments .................................................................................33 
Table 2 
CT-P22 and CT-P23 Molecular Formula and Weight .....................................44 
Table 3 
Clinical Laboratory Tests .................................................................................61 
Table 4 
Administrative Structure ..................................................................................82 
 
 
List of Figures 
Figure 1      Enrollment Process ...............................................................................................28 
Figure 2      Schematic Diagram of Subject Assignment .........................................................29 
Figure 3      Schematic Diagram for the Study Cohorts ...........................................................30 
Figure 4      Flow chart of Antibody-Dependent Enhancement (ADE) ...................................62 
 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 17 of 91 
31 January 2018 
 
 
 
 
1.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF 
TERMS 
Abbreviation 
Definition 
ADA 
Anti-drug antibodies 
ADE 
Antibody-dependent enhancement 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve  
AUC0-last 
Area under the concentration-time curve from time zero to the 
last quantifiable concentration 
AUC0-∞ 
Area under the concentration-time curve in serum from time zero 
extrapolated to infinite time 
AUMC0-∞ 
Area under the first moment-time curve in serum from time zero 
extrapolated to infinite time 
BLQ 
Below the limit of quantitation 
BUN 
Blood urea nitrogen 
CK 
Creatine kinase 
CL 
Systemic clearance from serum after intravenous dosing  
Clast 
Last observed quantifiable concentration 
Cmax 
Maximum observed serum concentration 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
Coefficient of Variation 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EOS 
End of Study 
EU 
European Union 
FDA 
Food and Drug Administration 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 18 of 91 
31 January 2018 
 
 
 
 
Flu-iiQ™ 
Influenza Intensity and Impact Questionnaire 
GCP 
Good Clinical Practice 
HA 
Hemagglutinin 
Hb 
Hemoglobin 
HCT 
Hematocrit  
HI 
Hemagglutination inhibition 
HIV 
Human immunodeficiency virus  
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat  
ITTI 
Intent-to-treat Infected  
IV 
Intravenous 
IWRS 
Interactive Web Response System 
λz 
Apparent terminal elimination rate constant 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean residence time 
NA 
Neuraminidase 
NAb 
Neutralizing antibodies  
OTC 
Over-the-counter 
PK 
Pharmacokinetic  
PD 
Pharmacodynamics  
PT 
Preferred term 
QoL 
Quality of Life 
qPCR 
Quantitative polymerase chain reaction  
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 19 of 91 
31 January 2018 
 
 
 
 
SD 
Standard deviation 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Apparent terminal elimination half-life 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
tmax 
Time of maximum concentration 
US 
United States  
Vz 
Apparent volume of distribution during the terminal elimination 
phase after intravenous dosing 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 20 of 91 
31 January 2018 
 
 
 
 
2.0 INTRODUCTION 
2.1 
Background Information 
Influenza is an acute, contagious respiratory illness caused by viruses of the Orthomyxoviridae 
family. Influenza spreads around the world in seasonal epidemics. Symptoms range from mild 
to severe and generally include fever, sore throat, muscle pains, headache, tiredness, and cough. 
The disease is generally self-limiting: most people recover in less than 2 weeks. However, 
some groups of patients, notably the elderly, young children, pregnant women, and people with 
health conditions such as asthma, congestive heart failure, or a weakened immune system 
caused by disease or medication, have increased susceptibility to influenza-related 
complications. These can result in hospitalization and sometimes death. In Europe, recorded 
annual mortality from influenza in the 27 countries of the European Union (EU) ranged from 
851 to 7,077 (EUROSTAT, the Statistical Office of the EU). In the United States (US), it has 
been estimated that influenza may cause approximately 3,000 to 49,000 deaths and result in 
approximately 200,000 hospitalizations.1 
2.1.1 
Treatment for Influenza 
The two classes of antiviral drugs used against influenza are neuraminidase (NA) inhibitors 
(oseltamivir, zanamivir, and peramivir) and M2 protein inhibitors (amantadine derivatives). 
Neuraminidase inhibitors are currently preferred for flu infections as they are less toxic and 
more effective; however, they may be associated with the development of resistant virus 
strains.2-5 There are currently no approved therapeutic biologics specifically for subjects with 
acute uncomplicated influenza A infection or serious and life-threatening complications of 
influenza A infections. To address this unmet medical need, CELLTRION (hereinafter referred 
to as the Sponsor) is developing CT-P27 for the treatment of influenza A. 
2.1.2 
Investigational Product 
CT-P27 is a 1:1 mixture of two human Immunoglobulin G (IgG) 1 monoclonal antibodies, CT-
P22 and CT-P23 that target an exogenous protein. These antibodies were selected from 
convalescent subjects and have been shown to neutralize influenza strains belonging to the 
H1N1 and H3N2 groups, as well as other potential pandemic clades like H2N2, H5N1, H7N9, 
and H9N2. CT-P27 drug product is believed to neutralize viral activity by binding to a 
conserved stem region of the viral HA protein, which is mediated through binding of the fusion 
peptide of virus HA to the endosomal membrane at low pH environment. 
The CT-P27 antibody mixture was developed as a concentrate for dilution, to be administered 
by intravenous (IV) infusion in a clinical setting. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 21 of 91 
31 January 2018 
 
 
 
 
2.1.3 
Non-Clinical Studies 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■ 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 22 of 91 
31 January 2018 
 
 
 
 
2.1.4 
Effects in Humans 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■. 
2.1.4.1 
Phase I Studies 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■ 
2.1.4.2 
Phase II Study 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 23 of 91 
31 January 2018 
 
 
 
 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■ 
2.1.4.3 
Efficacy in Humans 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■ 
2.1.4.4 
Safety in Humans 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 24 of 91 
31 January 2018 
 
 
 
 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■ 
2.2 
Rationale for Current Study 
A previous Phase II study (Study CT-P27 2.1) demonstrated trends favoring the efficacy of 
low doses of CT-P27 on viral shedding measures and total symptom scores in healthy 
volunteers. The proposed Phase IIb study will evaluate the efficacy and safety of two doses of 
CT-P27 (45 mg/kg and 90 mg/kg) in subjects with acute, uncomplicated influenza A. This 
study was designed to obtain an effect size of CT-P27 in comparison to placebo based on time 
to resolution of influenza symptoms and fever (see Section 8.1). Information on effect size, as 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 25 of 91 
31 January 2018 
 
 
 
 
well as the safety, efficacy, and PK of CT-P27 at 45 mg/kg and 90 mg/kg will be used in the 
selection of doses in subsequent studies. 
2.3 
Hypothesis 
The primary hypothesis is that time to resolution of influenza symptoms and fever is shorter in 
subjects receiving CT-P27 at 45 mg/kg and 90 mg/kg than in subjects receiving placebo. 
2.4 
Risk Assessment 
2.4.1 
Potential Risks and Risk Mitigation 
Since CT-P27 is a mixture of two monoclonal antibodies, typical AEs of monoclonal antibody 
therapy might be expected. 
However, the overall risks of allergic reactions posed by CT-P27 are expected to be low based 
on the type of product (i.e., monoclonal antibodies that target an exogenous protein). This 
expectation was supported by available non-clinical and clinical data as outlined above (also 
see the Investigator’s Brochure). 
Based on non-clinical data, free CT-P22 and CT-P23 are not expected to cause unwanted 
immune system activation via FcRIIIa binding on effector immune system cells. Therefore, 
ADE is not expected. In the limited clinical experience with CT-P27, there were no 
anaphylactic reactions and only a few infusion-related TEAEs (headache, rash) were reported. 
Furthermore, the immunogenicity against CT-P27 components appeared to be extremely low. 
To minimize the effects of an immune- or infusion-related reaction, study drug will be 
administered slowly, over a 90-minute period (±15 minutes). Emergency drugs and equipment 
suitable for assistance during anaphylactic reactions will be available during infusion with 
study drug. 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 26 of 91 
31 January 2018 
 
 
 
 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■ 
This study will be performed in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) guidelines and applicable local regulatory requirements. 
2.4.2 
Potential Benefits 
There may be no direct benefit to the subjects participating in this trial. However, there is 
currently an unmet need for additional treatment options for influenza A. Therefore, the results 
of this study may assist in the development of a new treatment for influenza A. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 27 of 91 
31 January 2018 
 
 
 
 
3.0 STUDY OBJECTIVES 
3.1 
Primary Objective  
The primary objective is to evaluate efficacy as determined according to the time to resolution 
of respiratory and constitutional symptoms of influenza and fever.  
3.2 
Secondary Objectives 
The secondary objective is to evaluate the additional efficacy and safety of CT-P27, including 
potential effects on the incidence of antibody-dependent enhancement (ADE). 
3.3 
Exploratory Objectives 
 
To assess the pharmacokinetics (PK) of CT-P27 components (CT-P22 and CT-P23)  
 
To assess immunogenicity. 
 
To assess the characterization of isolated influenza viruses. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 28 of 91 
31 January 2018 
 
 
 
 
4.0 INVESTIGATIONAL PLAN 
4.1 
Summary of Study Design 
This is a Phase IIb, multicenter, placebo-controlled, randomized, double-blind, parallel-arm 
study to evaluate the efficacy and safety of two doses of CT-P27 (45 mg/kg and 90 mg/kg) in 
subjects with acute uncomplicated influenza A infection. This proof-of-concept study will 
provide dose-ranging information for the subsequent clinical development of the drug. 
No study procedures will be performed prior to informing the subject about the study and 
obtaining written informed consent. However, any test result which was obtained within the 
allowed screening period can be used as screening data for subject’s convenience. It is critical 
that subjects receive treatment with study drug no more than 48 hours after the onset of 
symptoms (window of +12 hours is allowed). For most subjects, obtainment of the informed 
consent form (ICF), screening for eligibility, randomization and treatment will occur on the 
same day. Though obtainment of the ICF may occur on the day prior to screening, 
randomization or treatment, it must be within 24 hours before the administration of study drug. 
To be eligible for enrollment, subjects must have a positive test result for influenza A by a 
rapid influenza diagnostic test. At screening, nasopharyngeal swab samples will be collected 
for two times to be used for rapid influenza diagnostic test and virology assessment. The 
enrollment process is presented in Figure 1. 
Figure 1      Enrollment Process 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 29 of 91 
31 January 2018 
 
 
 
 
Approximately 183 subjects with influenza A to be enrolled in the study will be randomly 
assigned to 1 of 3 groups, 45 mg/kg CT-P27, 90 mg/kg CT-P27, or placebo (approximately 70 
subjects per CT-P27 treatment groups and 43 subjects in placebo group). Randomization will 
be stratified by flu vaccination history within a year (Yes vs No) and participation in PK sub-
study (Yes vs No). A schematic diagram of subject assignment is presented in Figure 2. 
Figure 2      Schematic Diagram of Subject Assignment 
All enrolled subjects will be given a single dose of 45 mg/kg CT-P27, 90 mg/kg CT-P27, or 
placebo intravenously over 90 minutes (±15 minutes) on Day 1 and then followed by 110 days.  
A PK sub-study will be performed on the subjects who signed informed consent to participate 
in a PK sub-study. Of total number of subjects to be enrolled, approximately 53 subjects (20 
subjects per CT-P27 treatment groups and 13 subjects in placebo group) will be included in 
the Subgroup (PK) Cohort, and additional PK samples from the subjects in this cohort will be 
collected according to the schedule of assessments. A schematic diagram for the study cohorts 
is presented in Figure 3.  
 
 
 
 
 
 
 
 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 30 of 91 
31 January 2018 
 
 
 
 
Figure 3      Schematic Diagram for the Study Cohorts 
 
Subjects may be admitted in a hospital from Day 1 (before study drug administration) to Day 
3 (after completion of the 48 hours assessments) if it is deemed necessary upon the judgement 
of the investigator. 
Study visits: 
 
Subjects who are included in Whole Study Cohort and are hospitalized: 4 planned 
study visits 
 
Subjects who are included in Whole Study Cohort but are not hospitalized: 6 planned 
study visits 
 
Subjects who are included in the Subgroup (PK) Cohort and are hospitalized: 7 
planned study visits 
 
Subjects who are included in the Subgroup (PK) Cohort but are not hospitalized: 9 
planned study visits 
 
Efficacy Assessment: 
The completion of the Influenza Intensity and Impact Questionnaire (Flu-iiQ™) (see Appendix 
2 for a copy of the questionnaire and Section 6.1.1.1 for details describing the questionnaire) 
and the recording of body temperature will take place at screening for baseline assessments. 
After study drug administration, subjects will be instructed to complete the Flu-iiQ™ and the 
body temperature in the diary twice a day (at approximately 12-hour intervals) from Day 1 to 
Day 8 (in the morning [between 6 and 10 AM, approximately] and in the evening [between 6 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 31 of 91 
31 January 2018 
 
 
 
 
and 10 PM, approximately]) and body temperature of subject will be also taken by site 
personnel at site at screening, Day 1 (prior to infusion), Day 2, Day 3, Day 5 and Day 8.  
Nasopharyngeal swab samples will be used for viral shedding based on quantitative 
polymerase chain reaction (qPCR) and cell culture. Those samples will be taken at screening, 
Day 2 (24 hours [±4 hours] after the start of the study drug infusion), Day 3 (48 hours [±4 
hours] after the start of the study drug infusion), Day 5 (96 hours [±4 hours] after the start of 
the study drug infusion), and Day 8 (168 hours [±4 hours] after the start of the study drug 
infusion). Laboratory confirmation of influenza A infection will be defined as a positive result 
by qPCR or cell culture. 
Safety Assessment: 
For safety evaluations, subjects will be followed up from the time the ICF is signed until Day 
110 (approximately 5 half-lives) after the administration of study drug. Safety assessments will 
occur throughout the study.  
Adverse events (AE) or concomitant medications that are verified by the investigator will be 
recorded on the eCRF. Up to Day 8, any AE or concomitant medication will also be recorded 
by subjects on their diaries and the investigators will refer to the records for information. If 
there is any AE or concomitant medication after Day 8, subjects will be instructed to contact 
the Principal Investigator or sub-Investigator at any time. 
If symptoms have not relieved up to Day 3, chest x-ray will be performed to determine presence 
of secondary complications of influenza A infection. 
Subjects with suspicious ADE will be required to assess virus titer using the nasopharyngeal 
swab sample, Flu-iiQ™ and body temperature up to Day 8 after the day of ADE occurrence. 
If symptoms have not resolved or have worsened up to Day 8 after the day of ADE occurrence, 
same procedures will repeat. 
Exploratory Assessment: 
Blood sampling for PK analysis will be collected from the subjects on: 
 Day 1 at pre-infusion (within 15 minutes prior to the beginning of the infusion), the 
end of infusion (+15 minutes), 1 hour (±15 minutes) after the end of the infusion,  
 Day 2 (24 hours [±4 hours] after the start of the study drug infusion),  
 Day 3 (48 hours [±4 hours] after the start of the study drug infusion),  
 Day 8 (168 hours [±4 hours] after the start of the study drug infusion) 
 Day 15 (±2 days),  
 Days 29, 57 and 110 (±5 days) or at EOS visit  
Blood sampling for Immunogenicity assessment will be collected on Day 1 (at pre-infusion) 
and Day 110 (±5 days) or EOS visit.  
For the subjects with Influenza A confirmed by qPCR or cell culture, genotypic analysis on 
Hemagglutinin (HA) and Neuraminidase (NA) genes, and phenotype characterization of 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 32 of 91 
31 January 2018 
 
 
 
 
potential escape variants with regard to CT-P27 will be assessed using the nasopharyngeal 
swab samples.  
Blood sampling for assessment of anti-influenza antibodies (Hemagglutination inhibition) will 
be collected on Day 1 (at pre-infusion) and Day 29 (± 5days) or EOS visit (if a subject is early 
terminated from the study) in Subgroup (PK) Cohort. The Schedule of Assessments is 
presented in Table 1. 
 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
 
Page 33 of 91 
31 January 2018 
 
 
 
 
 
 
 
Table 1 
Schedule of Assessments  
Evaluation 
Screening 
1 
Treatment  
Post-Treatment  
Day 1 
Day 2  
Day 3 
Day 5 
Day 8 
Day 15 
(±2 days) 
Day 29 
(±5 days) 
Day 57 
(±5 days) 
Day 110 / EOS 
visit22 
(±5 days) 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
Demographic, medical history, and height 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
 
 
 
 
 
 
 
 
 
Physical examination and weight 
X 
 
 
 
 
 
 
 
 
X 
Hepatitis B/C and HIV tests (local)  
X 2 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (local) 2 
X 4 
 
 
 
 
 
 
 
 
X  
Clinical laboratory analyses 5 (local) 
X 6 
 
 
X  
 
X 
 
 
 
 
Vital Signs (blood pressure, heart rate, respiratory rate) 7 
X 
X 
X 
X 
X 
X 
 
 
 
X 
12-Lead ECG 8 
X 
 
 
 
 
X 
 
 
 
X 
Chest x-ray 9 
X 
 
 
(X)10 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Infusion of CT-P27 or placebo 11 
 
X 
 
 
 
 
 
 
 
 
Blood sampling for PK (only Subgroup [PK] Cohort) 12 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Blood sampling for immunogenicity  
 
X13 
 
 
 
 
 
 
 
X 
Blood sampling for HI antibody(only Subgroup [PK] 
Cohort) 
 
X13 
 
 
 
 
 
X 
 
 
Monitoring for immediate hypersensitivity 14 
 
X 
 
 
 
 
 
 
 
 
Collection of a nasopharyngeal swab 15 
X 
 
X 
X 
X 
X 
 
 
 
 
 
Rapid influenza diagnostic test 16 
x 
 
 
 
 
 
 
 
 
 
 
Virus titer (qPCR and Cell culture) 
x 
 
x 
x 
x 
x 
 
 
 
 
 
The characterization of isolated influenza 
viruses  
x 
 
(x) 
 
 
 
 
Physician assessment 17 
X 
 
X 
X 
X 
X 
 
 
 
X 
Flu-iiQ™ 18 
X 
X 
 
 
 
 
Body Temperature 19 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Concomitant medication 20 
X 
X (continuously throughout the study) 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
 
Page 34 of 91 
31 January 2018 
 
 
 
 
Evaluation 
Screening 
1 
Treatment  
Post-Treatment  
Day 1 
Day 2  
Day 3 
Day 5 
Day 8 
Day 15 
(±2 days) 
Day 29 
(±5 days) 
Day 57 
(±5 days) 
Day 110 / EOS 
visit22 
(±5 days) 
Adverse events 21 
X 
X (continuously throughout the study) 
ADE=antibody-dependent enhancement; AE=adverse event; ECG=electrocardiogram; eCRF=electronic case report form; EOS=End of Study; Flu -iiQ™=Influenza Intensity and 
Impact Questionnaire; HI=hemagglutination inhibition; HIV=Human immunodeficiency virus; PK=pharmacokinetic 
Note: The assessments designated with an (X) will only be performed in selected subjects under the conditions explained in the footnotes. 
1. 
For most subjects, obtainment of the informed consent form (ICF), screening for eligibility, randomization and treatment will occur on the same day. 
Though obtainment of the ICF may occur on the day prior to screening, randomization or treatment, it must be within 24 hours before the administration 
of study drug.  
2. 
Hepatitis B surface antigen, Hepatitis B surface antibody, Hepatitis C virus antibody, and HIV will be assessed at screening in all subjects (mandatory). 
The results of these tests are not intended as eligibility assessments, but collected to provide baseline information. 
3. 
For females of child-bearing potential only. 
4. 
Urine pregnancy test will be performed at screening. If the urine pregnancy test gives equivocal results, a serum pregnancy test will be performed prior to 
study drug administration. Subjects with a positive test result will be excluded from the study. 
5. 
Clinical laboratory analysis will be performed at screening and on Day 3, Day 8. All clinical laboratory analysis will be performed at the local laboratory. 
The laboratory tests to be performed are presented in Table 3. 
6. 
Clinical laboratory results will not be used for assessment of eligibility, but to establish baseline values.  
7. 
Vital sign will be performed at screening, Day 1 (prior to infusion), Day 2 (±4 hours), Day 3 (±4 hours), Day 5 (±4 hours), Day 8 (±4 hours) and Day 110 
(±5 days) after the start of the study drug infusion. Blood pressure (sitting) and heart rate will be measured after the subject has rested (sitting quietly) for 
at least 5 minutes. 
8. 
12-Lead ECGs will be performed at screening, on Day 8 (±4 hours), and Day 110 (±5 days) (or EOS visit in early termination case).  
9. 
Chest x-rays to evaluate the lower respiratory tract will be performed at screening and if the Investigator considers it is clinically appropriate, chest x-rays 
to evaluate the lower respiratory tract will be performed during the study. 
10. If symptoms have not relieved up to Day 3, chest x-ray will be performed to determine presence of secondary complications of influenza A infection. 
11. Treatment with study drug must occur no more than 48 hours after the onset of symptoms. If the adjustments of visit schedule is required, additional 12 
hours can be allowed (Maximum onset of illness: 60 hours).  
12. PK blood sampling at: 
• Day 1: pre-infusion (within 15 minutes prior to the beginning of study drug infusion), at the end of infusion (within 15 minutes after the end of study 
drug infusion), and 1 hour (±15 minutes) after the end of the study drug infusion. 
• Day 2: 24 hours (±4 hours) after the start of the study drug infusion. 
• Day 3: 48 hours (±4 hours) after the start of the study drug infusion. 
• Day 8: 168 hours (±4 hours) after the start of the study drug infusion. 
• Day 15 (±2 days), Day 29 (±5 days), Day 57 (±5 days), and Day 110 (±5 days)/EOS visit. 
13. Day 1: prior to the study drug infusion. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
 
Page 35 of 91 
31 January 2018 
 
 
 
 
14. On Day 1, vital signs (including blood pressure and heart rate, respiratory rate), body temperature and ECG will be assessed at the time points listed 
below, and the subject will be monitored continuously over the period for possible immediate hypersensitivity reactions. 
• Vital sign and body temperature 
o 
Pre-infusion (within 15 minutes prior to the beginning of the infusion). 
o 
30 minutes (±15 minutes) after the beginning of the infusion. 
o 
Within 15 minutes after the end of the infusion. 
o 
2 hour (±15 minutes) after the end of the infusion. 
• Vital sign, body temperature and ECG 
o 
1 hour (vital sign, body temperature: ±15 minutes, ECG: −30/+60 minutes) after the end of the infusion. 
Emergency drugs and equipment suitable for assistance during anaphylactic reactions will be available during infusion with study drug. 
15. When collecting the nasopharyngeal swabs, nasopharyngeal swabbing will be performed by trained site personnel. A nasopharyngeal swab sample will be 
obtained from all subjects up to Day 8 on the following schedule:  
 Screening (Nasopharyngeal swab samples will be collected for two times to be used for rapid influenza diagnostic test and virology assessment.) 
 Day 2: 24 hours (±4 hours) after the start of the study drug infusion. 
 Day 3: 48 hours (±4 hours) after the start of the study drug infusion. 
 Day 5: 96 hours (±4 hours) after the start of the study drug infusion. 
 Day 8: 168 hours (±4 hours) after the start of the study drug infusion. 
16. Sponsor-supplied or agreed in advance rapid influenza diagnostic test material will be used. And if there is available test result confirmed as influenza A 
prior to obtaining written informed consent and that result was from the influenza diagnostic test which is agreed with Sponsor in advance, that test result 
can be allowed. At screening, testing must be performed within 24 hours before study drug administration. Subjects with a negative test resul t by rapid 
diagnostic test, who have onset of symptoms within 48 hours (window of +12 hours is allowed) before study drug administration, can be rescreened only 
once. 
17. The Investigator or designee will perform a symptom-directed physical examination (which should include, at a minimum, the examination of ear, nose, 
throat, sinuses, and lungs) and assessment for potential complications of influenza. 
18. The subject will record the results of the Flu-iiQTM in the diary. 
 Flu-iiQTM will be recorded once by the subject at the screening visit and will be recorded twice a day (at approximately 12-hour intervals) from Day 1 
to Day 8 (in the morning [between 6 and 10 AM, approximately] and in the evening [between 6 and 10 PM, approximately]). 
19. Body temperature which a subject experiences in prior to screening will be collected and body temperature taken with any type of thermometer w ill be 
acceptable. However, from the screening period, Sponsor-supplied thermometer will be used. 
 Temperature will be measured by subject; It will be recorded twice a day (at approximately 12-hour intervals) from Day 1 to Day 8 (in the morning 
[between 6 and 10 AM, approximately] and in the evening [between 6 and 10 PM, approximately]). 
 Temperature will be measured by site personnel at site: at screening, Day 1 (prior to infusion), Day 2 (±4 hours), Day 3 (±4 hours), Day 5 (±4 hours) 
and Day 8 (±4 hours). 
 These will be used for assessment of endpoint.  
20. Use of all medications, from 30 days prior to randomization and up until Day 110/EOS visit, will be recorded in the subject’s eCRF. 
21. AEs will be collected from the date the informed consent form is signed until Day 110/EOS visit. 
22. EOS visit will be done at Day 110. But if a subject is early terminated from the study, EOS visit will be done to assess safety parameters at any time. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
 
Page 36 of 91 
31 January 2018 
 
 
 
 
 
Schedule of Assessments (Unscheduled Visits Subjects with suspicious ADE) 
Evaluation 
Suspicious ADE Assessment 
Day of occurrence1 
Day 2  
Day 3 
Day 5 
Day 8 5 
Collection of a nasopharyngeal swab 
X 
X 
X 
X 
X 
 
Virus titer (qPCR and Cell 
culture) 2 
x 
x 
x 
x 
x 
 
The characterization of isolated 
influenza viruses  
x 
(x) 
Flu-iiQTM3 
X 
Body Temperature4 
X 
1. 
The day of suspicious ADE occurrence. 
 Symptoms have not resolved or have worsened up to Day 8 (168 hours) after the administration of study drug in the opinion of the Investigator. 
 The subject develops a secondary influenza-like illness after Day 8 (168 hours). 
2. 
Nasopharyngeal swab will be collected once a day up to Day 8 on the following schedule:  
• 
Day of occurrence 
• 
Day 2: 24 hours (±4 hours) 
• 
Day 3: 48 hours (±4 hours) 
• 
Day 5: 96 hours (±4 hours) 
• 
Day 8: 168 hours(±4 hours) 
3. 
Flu-iiQ™ and the body temperature in the diary twice a day up to Day 8 (168 hours) from Day 1 to Day 8 (in the morning [between 6 and 10 AM, 
approximately] and in the evening [between 6 and 10 PM, approximately]). 
4. 
Body temperature will be assessed by Sponsor-supplied thermometer. 
5. 
If symptoms have not resolved or have worsened up to Day 8 after the day of ADE occurrence, same procedure will repeat. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0 
Page 37 of 91 
31 January 2018 
 
 
 
 
4.2 
Discussion of Study Design 
This study uses a standard randomized, placebo-controlled study design. The study is designed 
to determine the effect size of two doses of CT-P27. 
The selection of the study Cohort is appropriate for the evaluation of CT-P27 in subjects with 
acute, uncomplicated influenza A. 
Placebo-controlled trials are appropriate in settings and Cohorts where the expected serious 
risk of non-treatment is small. For trials evaluating treatment of uncomplicated mild to 
moderate influenza, placebo-controlled rather than non-inferiority designs will be used because 
the risks associated with receiving placebo are low, and the efficacy of available treatment is 
modest (1 day difference in time to symptom improvement), variable, and cannot be predicted 
well enough to support an adequate non-inferiority margin. The variable clinical course of 
influenza in any given season, as well as the potential for differences in pathogenicity and host 
immunity as new influenza strains emerge and change over time, also makes uncontrolled data 
or historical controls difficult to interpret and inadequate to support efficacy of investigational 
drugs. 
The doses were selected based on PK/PD modelling. The higher dose (90 mg/kg) was 
evaluated in a Phase I study. No significant adverse effects of treatment were observed. 
The primary and secondary efficacy endpoints are consistent with the Food and Drug 
Administration (FDA) document, “Guidance for Industry: Influenza: Developing Drugs for 
Treatment and/or Prophylaxis” 6. 
4.3 
Selection of Study Cohort 
Approximately 183 subjects will be enrolled (see Section 8.1). The study Cohort will consist 
of male and female subjects with acute uncomplicated influenza A who can be enrolled, 
screened, randomized, and treated with study drug no more than 48 hours following the onset 
of symptoms. 
4.3.1 
Inclusion Criteria 
Each subject must meet all the following criteria to participate in this study: 
1. Subject is a male or female and aged 19 to 64 years, inclusive.  
2. Subject can voluntarily provide a written informed consent. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 38 of 91 
31 January 2018 
 
 
 
 
3. Onset of illness no more than 48 hours prior to the planned administration of study drug. 
If the adjustments of visit schedule is required, additional 12 hours can be allowed 
(Maximum onset of illness: 60 hours).  
Note: time of onset of illness is defined as the earlier of either (a) the time when the body 
temperature was first measured as ≥38.0oC (≥100.4oF) or (b) the time when the subject 
experienced the presence of at least two symptoms that are respiratory and/or constitutional 
(moderate to severe in intensity). 
4. As reported by the subject and recorded on the Flu-iiQ™ completed at screening, the 
subject has at least two of the following symptoms (moderate to severe in intensity):  
a) Respiratory symptom (cough, sore throat, or nasal congestion) or 
b) Constitutional symptom (headache, feeling feverish, body aches and pains, or 
fatigue). 
5. Subject has a fever ≥38.0oC or ≥100.4oF at screening or a history of fever within the 24 
hours prior to screening and has received treatment with an antipyretic(s) in the 6 hours 
prior to screening. 
6. Subject is diagnosed with influenza A at screening, using the Sponsor-supplied or agreed 
in advance rapid influenza diagnostic test. And if there is available test result confirmed as 
influenza A prior to obtaining written informed consent and that result was from the 
influenza diagnostic test which is agreed with Sponsor in advance, that test result can be 
allowed 
7. For both male and female subjects, the subject and his/her partner (if of childbearing 
potential) agree to use a highly effective method of contraception during the study and for 
5 months after the administration of study drug. 
a) Male and female subjects and their partner who have been surgically sterilized for 
less than 6 months prior to the date of informed consent must agree to use a 
highly effective method of contraception during the study and for 5 months after 
the administration of study drug. 
b) Menopausal females must have experienced their last menstrual period more than 
12 months prior to the date of informed consent to be classified as not of 
childbearing potential. 
8. Subject's body mass index (BMI) is of <35.0 kg/m2 and weight is of ≤99.9 kg. 
4.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 39 of 91 
31 January 2018 
 
 
 
 
1. Subject is not likely to complete all required study visits or procedures for any reason, in 
the opinion of the Investigator. 
2. Subject has received a treatment with another investigational medical product or 
participated in another clinical trial within 30 days (or 5 half-lives, whichever is longer). 
3. Subject has previous exposure to any anti-influenza monoclonal antibody therapy 
including CT-P27 prior to study drug administration. 
4. Subject has a history of hypersensitivity to any monoclonal antibody or has a known 
hypersensitivity to any of the treatment components. 
5. Subject is taking antiviral treatment for influenza (e.g., zanamivir, oseltamivir, rimantadine, 
amantadine, peramivir, or ribavirin) or has a history of using these antivirals within 14 days 
prior to the administration of study drug. 
6. Subject has been immunized against influenza with live attenuated or inactivated virus 
vaccine within 21 days prior to the administration of study drug. 
7. Subject has a medical condition including one or more of the following: 
a) Positive influenza B or influenza A+B infection. 
b) History or presence of congestive heart failure with symptoms consistent with New 
York Heart Association Class III or IV functional status within 12 months prior to 
study drug administration. 
c) Presence of clinically significant abnormality on a 12-lead ECG at screening that, 
in the Investigator's clinical judgment, may compromise the safety of the subject or 
affect the outcome of the study. These include, but are not limited to, a PR interval 
>200 msec, a corrected QT interval [QTc] >450 msec for male subjects and >470 
msec for female subjects, or any evidence of heart block, right bundle branch block, 
or left bundle branch block. 
d) History or presence of any clinical condition or evidence of organ dysfunction that 
may affect either the subject’s ability to participate in the study or the study result, 
in the opinion of the Investigator. 
e) Subjects with abnormal liver function values. These will which include aspartate 
transaminase (AST), alanine transaminase (ALT) or alkaline phosphatase (ALP) ≥ 
3 × ULN at screening. 
f) Subject with abnormal renal function values (serum creatinine ≥ 1.7 × ULN with 
creatinine clearance level ≤ 75mL/min at screening).  
g) In the opinion of the Investigator, the subject has active tuberculosis. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 40 of 91 
31 January 2018 
 
 
 
 
h) Uncontrolled diabetes mellitus (defined as known by the case of HbA1c >8%).  
i) Uncontrolled hypertension (defined as known by the case of systolic blood 
pressure (SBP) ≥160 mmHg or diastolic blood pressure (DBP) ≥100 mmHg). 
j) Documented, known current infection with hepatitis B, hepatitis C, or human 
immunodeficiency virus (HIV). 
k) Severe infection within 30 days prior to the administration of study drug that 
required parenteral antibiotic use or hospitalization. 
l) Any uncontrolled acute or chronic clinically significant respiratory disease (e.g., 
chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis, asthma, or 
bacterial pneumonia). 
m) History of malignancy within 2 years prior to study drug administration (with the 
exception of treated basal cell carcinoma of the skin or carcinoma in situ of the 
cervix) or current active malignancy. 
8. Subject is currently hospitalized or currently requires hospitalization due to severity of 
illness, or has any plan for elective hospitalization within 1 month after study drug 
administration. 
9. Subject requires oxygen therapy due to underlying disease or influenza infection. 
10. Subject has a history of bone marrow or solid organ transplantation. 
11. Subject uses systemic steroids or other immunosuppressant (except oral steroid up to 5-10 
mg/day, methotrexate up to 10 mg/week). 
12. Subject requires routine/intermittent hemodialysis or peritoneal dialysis. 
13. Subject is pregnant or breastfeeding. 
14. Subject is not eligible for the study participation for whatever reason (including clinical 
laboratory results) in the opinion of the Investigator, or shows evidence of a condition 
(psychological, emotional problems, any disorders or resultant therapy) that is likely to 
invalidate informed consent, or limited the ability of the subject to comply with the protocol 
requirements in the opinion of the Investigator, or unable to understand the protocol 
requirements, instructions and study related restrictions, the nature, scope and possible 
consequences of the clinical study, or is unable to give written informed consent or to 
comply fully with the protocol. 
4.3.3 
Disease Diagnostic Criteria 
The subjects will be screened for the presence of influenza A using a rapid influenza diagnostic 
test no more than 24 hours before treatment with study drug. The presence of influenza A will 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 41 of 91 
31 January 2018 
 
 
 
 
be confirmed with qPCR or cell culture in only enrolled subject. Subjects who are positive for 
influenza A on the rapid influenza diagnostic test but negative on qPCR or cell culture will 
continue in the study and be followed up for safety purposes. 
4.3.4 
Subject Withdrawal 
All subjects are free to withdraw from participation in the study at any time, for any reason, 
specified or unspecified, and without prejudice to further treatment. If a subject chooses to 
withdraw from the study, they will be encouraged to return to the site for safety reasons to 
complete the assessments planned for EOS visit 
The Investigator will ensure that all reasonable attempts (telephone calls, contact with primary 
care physician, certified letter) are made to obtain follow-up safety information on subjects 
who do not return to the site for study visits or are lost to follow-up. 
Subjects who are withdrawn from the study after randomization will not be replaced. 
Subjects who withdraw from the study after dosing will be advised by the Investigator to 
continue contraception restrictions for 5 months after the administration of study drug. 
The Investigator will ensure that the reasons for withdrawal are documented on the subject’s 
medical records (source documents) and in the electronic Case Report Form (eCRF). If the 
subject withdraws due to an AE, the details of the AE must be entered on the AE section of the 
eCRF. If the reason for subject withdrawal is not known, the subject must be contacted and 
followed up in order to establish whether the reason for withdrawal was an AE, and if so, this 
must be reported in accordance with the procedures outlined in Section 6.2.1.5. 
4.3.5 
Study and Site Termination 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to, the following:  
 The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects. 
 Enrollment is unsatisfactory. 
 A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product. 
The Sponsor will notify the Investigator if the study is placed on hold, or if the Sponsor decides 
to discontinue the study or development program. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 42 of 91 
31 January 2018 
 
 
 
 
The Sponsor has the right to replace a site at any time. Reasons for replacing a site may include, 
but are not limited to, the following: 
 Excessively slow recruitment. 
 Poor protocol adherence. 
 Inaccurate or incomplete data recording. 
 Non-compliance with the ICH guideline for GCP. 
 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 43 of 91 
31 January 2018 
 
 
 
 
5.0 STUDY TREATMENTS 
5.1 
Treatments Administered 
Subjects in this study will receive a single IV dose of the following:  
 CT-P27 45 mg/kg 
 CT-P27 90 mg/kg  
 
Placebo  
An infusion solution of 0.9% w/v sodium chloride will be used for subject infusion. The bag 
will be gently inverted to mix the solution in order to avoid foaming. Parenteral solutions will 
be inspected visually for particulates and discoloration prior to administration and 
administration will not be performed if any particulates and discoloration are found. The 
detailed method about mixing the solution will be described in a guideline, which will be 
available at all site. 
All study drugs will be administered as IV infusions over 90 minutes (±15 minutes). 
5.2 
Identity of Investigational Product(s) 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■ 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 44 of 91 
31 January 2018 
 
 
 
 
Table 2 
CT-P22 and CT-P23 Molecular Formula and Weight 
 
CT-P22 
CT-P23 
■■■■■■■■■■■■■
■■■■■ 
■■■■■■■■■ 
■■■■■■■■■ 
■■■■■■■■■■■■■
■■■■■ 
■■■■■■■■■ 
■■■■■■■■■ 
 
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■ 
5.3 
Packaging and Labelling 
Investigational medicinal products will be packaged and labelled for each subject according to 
local legal requirements. 
A label will be attached to the outside of each kit, as well as to the container. The text will be 
in compliance with local regulatory requirements and may include some of the following 
information: 
 Protocol number 
 Contents and quantity 
 Lot number 
 Kit number 
 Directions for use  
 Investigator’s name 
 Storage instructions 
 Caution statement (“for clinical trial use only”) 
 Sponsor’s contact name and address 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 45 of 91 
31 January 2018 
 
 
 
 
 Expiry date 
All supplies of CT-P27 must be stored at a refrigerated temperature between 2°C and 8°C . The 
temperature must be monitored. Until dispensed to the subjects, the CT-P27 will be stored in 
a securely locked area, accessible to authorized personnel only.  
5.4 
Precautions and/or Overdose 
There are no specific antidotes to CT-P27. Treatment of an overdose should be symptomatic. 
Subjects who develop severe infusion-related reactions must have infusion terminated 
immediately, and the subject will be treated according to the best standards of care. These 
subjects will be followed up until stabilized, or until the reaction resolves. 
During infusion of study drug, emergency drugs and equipment suitable for assistance during 
anaphylactic reactions will be available during infusion with study drug. 
5.5 
Method of Assigning Subjects to Treatment Group 
Once the subject has provided an informed consent and meets all the inclusion criteria and 
none of the exclusion criteria, the study site will request the study drug assignment using the 
Interactive Web Response System (IWRS).  
All randomized subjects will be managed by IWRS. To randomize a subject, the study site will 
access the IWRS interlocking with electronic data capture system. The subject identifying 
information (e.g. gender, year of birth and/or date of birth) and the stratification factors are 
provided to gain the randomization number and investigational product allocation. 
Randomization information which includes randomization ID, regime name, regime ratio, date 
and time of randomization, and stratum name generated by IWRS will be delivered to the 
Sponsor.  
5.6 
Selection of Doses in the Study 
Given the safety profile in clinical studies, and PK/PD modelling analysis using PK data from 
clinical and non-clinical studies, the efficacious doses for humans are expected to be in the 
range of 45 to 90 mg/kg. 
5.7 
Selection and Timing of Dose for Each Subject 
All subjects will receive a single dose of study drug as randomized. As the study drug is 
administered at the study site, there are no specific instructions to be given to the subject as to 
how or when to take the study drug. It is critical that the infusion with study drug begins within 
48 hours after the onset of influenza symptoms (window of +12 hours is allowed). 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 46 of 91 
31 January 2018 
 
 
 
 
5.8 
Blinding 
The clinical trial will be performed in a double-blind manner. The study drug (CT-P27 and 
placebo) will be handled by a delegated unblinded pharmacist before the drug administration 
and will be administered by blinded personnel, with physically blind condition. 
The study blind will not be broken except in a medical emergency (where knowledge of the 
investigational medicinal product administered would affect the treatment of the emergency) 
or regulatory requirement (e.g., for SAE or death). 
If the blind is broken, the date, time, and reason must be recorded in the subject’s eCRF and 
any associated AE report. 
5.8.1 
Emergency Unblinding 
Under normal circumstances, the blind will not be broken. The blind will be broken only if 
specific emergency treatment would be dictated by knowing the study drug status of the subject.  
The Investigator may, in an emergency, determine the identity of the study drug by using the 
applicable procedure in the IWRS.  
The date, time, and reason for the unblinding must be documented in the appropriate field of 
the eCRF. The Sponsor and the Medical Monitor must be informed as soon as possible.  
Suspected unexpected SAEs, which are subject to expedited reporting, will be unblinded 
before submission to the regulatory authorities, if required. 
The overall randomization code will be broken only for reporting purposes. The unblinded 
analyses will be performed by the CRO or unblinded biostatisticians from the Sponsor. Only 
relevant CRO biostatisticians, medical writers, and the Sponsor will be unblinded at this stage. 
However, the subjects and investigators will remain blinded; all other study personnel will 
remain blinded until the end of the study. Final determination of the analysis sets will occur 
prior to finalizing the database for each analysis.  
The randomization code will not be revealed to study subjects, parents or guardians, study site 
staff, or Investigators. 
5.9 
Prior and Concomitant Treatments 
Use of all medications (drugs taken from 30 days prior to randomization until Day 110 or EOS 
visit) will be recorded in the subject’s eCRF. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 47 of 91 
31 January 2018 
 
 
 
 
The subjects will record concomitant medications in the subject diaries. Use of any medication 
during the study reported on the diary, reported to the Investigator, or prescribed by the 
Investigator will be transferred to the eCRF. 
5.9.1 
Prohibited Prior Medications 
At screening, subjects with any of the following will be ineligible for enrollment. 
 An investigational medical product in another clinical trial within 30 days (or 
5 half-lives, whichever is longer) prior to study drug administration. 
 A previous exposure to anti-influenza monoclonal antibody therapy. 
 Previous antiviral treatment for influenza (e.g., zanamivir, oseltamivir, rimantadine, 
amantadine, peramivir, or ribavirin) at screening or has a history of using these 
antivirals within 14 days prior to study drug administration. 
 Live attenuated or inactivated virus vaccine within 21 days prior to study drug 
administration. 
5.9.2 
Prohibited Concomitant Medication 
The use of the following medication is prohibited from Day 1 until Day 110/EOS visit: 
 Live attenuated or inactivated influenza vaccine. 
 Systemic immunosuppressants. 
 Other influenza anti-virals (such as amantadine, rimantadine, zanamivir, oseltamivir, 
peramivir, or ribavirin). 
 Other investigational drugs. 
5.9.3 
Permitted Drugs 
During the study, unless contraindicated, subjects may take acetaminophen/paracetamol, 
levodropropizine and chlorpheniramine for symptom relief according to the label’s prescribing 
information and at dosages that do not exceed the manufacturer’s recommendations. Those 
medication for symptom relief would be prescribed by investigators as P.R.N (pro re nata). 
The investigator should train the subject to administer maximum twice a day as much as 
possible. And administration of the medication during the study should be reported on the diary. 
Subject will be not allowed to use other drugs for symptom relief except 
acetaminophen/paracetamol, levodropropizine and chlorpheniramine. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 48 of 91 
31 January 2018 
 
 
 
 
If these drugs are taken, details concerning the dose and duration of treatment will be recorded 
in the subject’s medical records (source documents) and in the eCRF.  
5.10 Medical Care of Subjects after End of Study 
The Sponsor will not provide any additional care to subjects after they leave the study. Subjects 
who require additional care will be encouraged to seek treatment from their personal physician. 
5.11 Treatment Compliance  
The Investigator or designee will administer/supervise the administration of study drug at the 
study site. Therefore, compliance will not be assessed as an outcome measure. The subject’s 
date of treatment, dose, and duration of infusion will be recorded in the subject’s medical 
records (source documents) and in the eCRF. 
5.12 Study Drug Accountability, Dispensing and Destruction 
It is the responsibility of the Investigator to ensure that all study drug received at the study site 
will be inventoried and accounted for throughout the study and the result recorded in the drug 
accountability form maintained at the study site. Contents of the study drug containers must 
not be combined. The drug accountability will be verified by the monitor during onsite 
monitoring visits. Study drug will be stored in a limited access area or in a locked cabinet under 
appropriate environmental conditions. 
The Investigator agrees not to supply the study drug to any person other than sub-Investigators, 
designated study site personnel, and the subjects participating in the study. Study drug may not 
be re-labelled or reassigned for use by other subjects unless approved by the Sponsor.  
The Investigator will destroy empty or partially used vials as well as the cartons after 
reconstitution per site standard operating procedure, and keep tear-off labels for accountability. 
The Investigator agrees to neither dispense the study drug from, nor store it at, any site other 
than the study sites agreed upon with the Sponsor. On a country-specific basis, permission may 
be granted for local disposition, with supporting documentation. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 49 of 91 
31 January 2018 
 
 
 
 
6.0 EFFICACY, SAFETY, EXPLORATORY 
PHARMACOKINETIC AND OTHER ASSESSMENTS 
6.1 
Efficacy Measures and Procedures 
The methods used to obtain efficacy data are described below. Efficacy endpoints are discussed 
in Section 8.2. 
The timing of each assessment and study procedure is presented in Table 1. 
6.1.1 
Diaries 
Subjects will be issued a diary on Day 1 and will be required to record the diary from Day 1 to 
Day 8. The study site staff will instruct the subjects on the use of the diary. Subjects will be 
told to bring their completed diary each time they return to the study site. Study staff will 
review the entries in the diary (Flu-iiQ™ questionnaire, recording of body temperature, 
adverse event and concomitant medication). If the subject is not compliant in regard to filling 
out the diary (omissions, discrepancies, or other difficulties), instructions on how to use the 
diary may be repeated. Study site staff should encourage the subject to complete the diary and 
remind the subject of the importance of following study procedures while at home.  
6.1.1.1 
Flu-iiQ™ 
The Flu-iiQ™ is a validated questionnaire with four domains. These include the 1) intensity 
of influenza symptoms, 2) impact on activities, 3) effects on feelings and 4) concerns due to 
influenza. Subjects are offered four choices, ranging from the most positive response (e.g., 
none or not at all) to the most negative choice (e.g., severe or great difficulty). Scores for 
influenza symptoms are none, mild, moderate, and severe.  
The Flu-iiQ™ will be completed by subject at screening. After study drug administration, 
subjects will be instructed to complete the Flu-iiQ™ twice a day (at approximately 12-hour 
intervals) from Day 1 to Day 8 (in the morning [between 6 and 10 AM, approximately] and in 
the evening [between 6 and 10 PM, approximately]). 
The results of the first two domains of the Flu-iiQ™ (those assessing symptoms and the impact 
of influenza on activities) will be used in the assessment of primary and secondary efficacy 
endpoints (see Section 8.2). The results of the 3rd and 4th domain (impact on feelings and 
concerns) will be evaluated as QoL measures. A copy of the Flu-iiQ™ is included in Appendix 
2. Information obtained from the diary will be transferred to the eCRF. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 50 of 91 
31 January 2018 
 
 
 
 
6.1.1.2 
Body Temperature  
The Sponsor will supply a thermometer to each subject along with directions for the use of the 
thermometer. Body temperature will be taken by subject twice a day (at approximately 12-hour 
intervals) from Day 1 to Day 8 (in the morning [between 6 and 10 AM, approximately] and in 
the evening [between 6 and 10 PM, approximately)] and it will be taken by site personnel at 
site at screening, Day 1 (prior to infusion), Day 2, Day 3, Day 5 and Day 8. 
These results will be recorded in the diary or source document at site and transferred to the 
eCRF. 
Body temperature will also be taken at site visits as indicated in Table 1. 
6.1.2 
Nasopharyngeal Swabs 
The Sponsor will provide nasopharyngeal swabs for use during the study. Samples from these 
swabs will be used to obtain samples for qPCR and cell culture, to confirm influenza A 
infection and evaluate viral shedding and to assess genotype, phenotype, and to assess antiviral 
resistance. 
A nasopharyngeal swab sample will be obtained from all subjects and will be collected for two 
times to be used for rapid influenza diagnostic test and virology assessment at screening. 
Nasopharyngeal samples will be obtained at each subsequent study visit: Day 2 (24 hours [±4 
hours] after the start of the study drug infusion), Day 3 (48 hours [±4 hours] after the start of 
the study drug infusion), Day 5 (96 hours [±4 hours] after the start of the study drug infusion), 
and Day 8 (168 hours [±4 hours] after the start of the study drug infusion). 
The time selected for taking the swabs will be similar at each study visit (e.g., in the morning 
(between approximately 6 A.M. and 10 A.M.) or in the evening (between approximately 6 P.M. 
and 10 P.M.). 
Under some circumstances additional nasopharyngeal swabbing may occur. If the subject 
meets the definition for suspicious ADE (see Section 6.2.5), the subject will have additional 
swabs taken (at scheduled or unscheduled visits, as necessary) until Day 8 (168 hours) after 
the day of ADE occurrence. 
6.1.3 
Rapid Influenza Diagnostic Testing 
The Sponsor will supply the site a rapid influenza diagnostic test at screening to assess 
eligibility for the study. If there is available test result confirmed as influenza A prior to 
obtaining written informed consent and that result was from the influenza diagnostic test which 
is agreed with Sponsor in advance, that test result can be allowed. Subjects who have negative 
test results, but who have influenza-like symptoms, can be rescreened only once. The diagnosis 
of influenza A will be confirmed by a positive qPCR or cell culture result. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 51 of 91 
31 January 2018 
 
 
 
 
Results of rapid diagnostic testing will be recorded on the eCRF. 
6.1.4 
Viral Shedding 
Viral shedding will be determined using qPCR and cell culture; samples for these evaluations 
will be obtained from nasopharyngeal swabs taken during the study (see Section 6.1.2). 
The methods for qPCR and cell culture will be described in a separate laboratory procedure 
manual. 
The results obtained from the laboratory will be recorded in the virology laboratory database 
and transferred to the Sponsor.  
6.1.5 
Secondary Complications of Influenza 
The presence of secondary complications of influenza A infection will be determined by the 
Investigator’s assessment of the subject’s clinical condition. Complications may include, but 
are not limited to, bacterial or other viral upper or lower respiratory tract infections, including 
otitis media, sinusitis, bronchitis, and pneumonia. 
Secondary complications of influenza A infection will be considered as AEs or as adverse drug 
reactions based on the assessment of causal relationship with the study drug. If any of the 
secondary complications meet any of the SAE criteria, they will also be reported as SAEs. 
Secondary complications will be treated according to the local standard of care. 
6.2 
Safety Measures and Procedures 
6.2.1 
Definition of Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a subject enrolled 
(i.e., when the ICF is signed) into this study regardless of its causal relationship to study drug. 
Subjects will be instructed to contact the Principal Investigator or sub-Investigator at any time 
after the ICF is signed if any symptoms develop. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease. 
An AE includes a/an: 
a) Exacerbation of a pre-existing condition or disease. 
b) Increase in frequency or intensity of a pre-existing condition. 
c) Condition first detected or diagnosed after informed consent.  


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 52 of 91 
31 January 2018 
 
 
 
 
d) Continuous persistent pre-existing disease or symptoms that worsen after the subject 
provides informed consent. 
An AE does not include a/an: 
a) Medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, transfusion); 
the condition that leads to the procedure is an AE. Any complications of the procedure 
are also considered to be AEs. 
b) Pre-existing disease or conditions present or detected at the start of the study that do 
not worsen. 
c) Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalizations for cosmetic elective surgery, social and/or convenience admissions). 
d) The disease or disorder being studied or signs or symptoms associated with the disease 
or disorder, unless more severe or frequent than expected for the subject’s condition. 
e) Overdose of either study drug or concurrent medication without any signs or symptoms. 
Medical history and any medical conditions that are present prior to informed consent will be 
recorded as medical history and not be reported as an AE. 
Any signs and symptoms of influenza A infection throughout the study, including the screening 
period, will be captured on the Flu-iiQ™ and the body temperature in the diary. 
A TEAE is defined as 1) a new event that occurs during or after treatment with study drug or 
2) any event present at baseline that worsens in either intensity or frequency after exposure to 
study drug. 
If laboratory test abnormalities occur after the start of the administration of study drug, only 
clinically significant results will be considered to be TEAEs. The clinically significant 
laboratory results include those that: 
 Result in discontinuation from the study. 
 Require treatment or any other therapeutic intervention. 
 Require further diagnostic evaluation (excluding a repetition of the same procedure to 
confirm the abnormality). 
 Are associated with clinical signs or symptoms judged by the Investigator to have a 
clinically significant impact. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 53 of 91 
31 January 2018 
 
 
 
 
6.2.1.1 
Definition of Serious Adverse Event 
A serious adverse event (SAE) is defined as any AE occurring at any dose that results in any 
of the following outcomes: 
a) Death - the death was an outcome of an AE. 
b) Life-threatening - the subject was at substantial risk of dying at the time of AE 
occurrence.   
c) Inpatient hospitalization or prolongation of existing hospitalization. 
d) A disability/incapacity - the AE resulted in a substantial disruption of a person’s ability 
to conduct normal life functions, i.e., the AE resulted in a significant, persistent or 
permanent change, impairment, damage or disruption in the subject’s body 
function/structure, physical activities and/or quality of life. 
e) A congenital anomaly in the offspring of a subject who received drug - it is suspected 
that exposure to study drug prior to conception or during pregnancy may have resulted 
in an adverse outcome in the child. 
f) Other SAEs: Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered SAEs when, based upon appropriate 
medical judgment, they may jeopardize the subject or require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
A distinction will be drawn between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria above. An AE that is severe in intensity is not 
necessarily an SAE. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 54 of 91 
31 January 2018 
 
 
 
 
Clarifications:  
 Any SAE that occurs after informed consent is signed will be reported.  
 Life-threatening means that the subject is, in the view of the Investigator, at immediate 
risk of death from the event as it occurs. This definition does not include an event that, 
had it occurred in a more severe form, might have caused death. 
 Hospitalization for elective treatment of a pre-existing condition that does not worsen 
during the study is not considered an AE.  
 Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization, the event is an SAE. 
 Inpatient hospitalization means the subject has been formally admitted to a hospital for 
medical reasons (even if for less than 24 hours). However, this does not include the 
hospitalization due to the study treatment / procedure. 
 Emergency room visit; the subject was seen and treated in the emergency room, and 
following treatment, subject was released. The Principle Investigator will assess if the 
event is considered a medically significant event.  
6.2.1.2 
Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., for applicable product information, include the Investigator's 
Brochure for an unapproved investigational product or the package insert/summary of product 
characteristics for an approved product). Therefore, if a treatment-related SAE occurs and it 
was not mentioned in the applicable product information, then it will be reported as a SUSAR 
(see Section 6.2.1.6).  
6.2.1.3 
Lack of Efficacy as an AE or SAE 
Lack of efficacy is not considered as an AE in clinical trials. However, disease-related 
complications will be reported as an AE.  
6.2.1.4 
Evaluation of AEs  
Each AE is to be evaluated for duration, severity, seriousness, and causal relationship to the 
investigational drug. The action taken and the outcome must also be recorded. 
Seriousness 
The event will be evaluated to determine if it meets the criteria for an SAE, as described in 
Section 6.2.1.1. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 55 of 91 
31 January 2018 
 
 
 
 
Severity/Intensity 
The severity of the AE will be characterized according to the following criteria based on the 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03: 
 
Grade 1  
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
 
Grade 2  
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate activities of daily living. 
 
Grade 3  
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living. 
 
Grade 4  
Life-threatening consequences; urgent intervention indicated. 
 
Grade 5  
Death related to AE. 
When evaluating an AE that recurs over time (for example, a specific AE reported multiple 
times in the diary), the Investigator will review the AE for changes in severity over the time 
period being assessed. The most severe grade will be assigned to that AE. 
Relationship/Causality 
The Investigator will assess the causality/relationship between the study drug and the AE and 
record that assessment in the eCRF. One of the following categories will be selected based on 
medical judgment, considering the definition below and all contributing factors. However, for 
the summarization of data, all categories other than unrelated will be considered as related to 
study drug. 
 Definite: A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to drug administration, and which cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the drug 
(dechallenge) will be clinically plausible. The event must be definitive 
pharmacologically or phenomenologically, using a satisfactory rechallenge procedure 
if necessary. 
 Possible: The relationship suggests that the association of the AE with the study drug 
is unknown; however, the AE is not reasonably supported by other conditions. 
 Probable: The relationship suggests that a reasonable temporal sequence of the AE with 
drug administration exists and, in the Investigator’s clinical judgment, it is likely that a 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 56 of 91 
31 January 2018 
 
 
 
 
causal relationship exists between the drug administration and the AE, and other 
conditions (concurrent illness, progression, or expression of disease state or 
concomitant medication reactions) do not appear to explain the AE. 
 Unrelated: There is not a reasonable possibility that the study drug caused the AE. 
 Not Assessable: All efforts will be made to classify the AE according to the above 
categories. The category “unknown” (unable to judge) may be used only if the causality 
is not assessable, (e.g., because of insufficient evidence, conflicting evidence, 
conflicting data, or poor documentation). 
6.2.1.5 
Recording and Follow-up of AEs and SAEs 
All AEs/SAEs, regardless of the relationship to study drug, will be assessed and recorded from 
the date the ICF is signed until Day 110 (approximately 5 half-lives) after the administration 
of study drug.  
Subjects will be trained on the recording of AEs into their diary up to Day 8, and this 
information will be transferred to the eCRF after verification of the investigator. If there is any 
AE after Day 8, subjects will be instructed to contact the Principal Investigator or sub-
Investigator at any time. Any AE occurring during the study must be documented in the 
subject’s medical records, in accordance with the Investigator’s normal clinical practice, and 
on the AE page of the eCRF. SAEs that occur during the study must be documented in the 
subject’s medical record and on the SAE page of the eCRF. Serious adverse event reporting is 
discussed in Section 6.2.1.6. 
A separate set of SAE pages will be used for each SAE. However, if at the time of initial 
reporting multiple SAEs that are temporally and/or clinically related are present, they may be 
reported on the same SAE page. 
All AEs/SAEs will be recorded individually in the study subject’s own words (verbatim) unless, 
in the opinion of the Investigator, the AEs/SAEs constitute components of a recognized 
condition, disease, or symptom. The Investigator will attempt to establish a diagnosis of the 
event based on signs, symptoms, and/or other clinical information. In such cases, the diagnosis 
will be documented as the AE and/or SAE rather than the individual signs/symptoms. 
If a clinically significant abnormal laboratory finding or other abnormal test result meets the 
definition of an AE or SAE, then the AE eCRF page or SAE eCRF page must be completed, 
as appropriate. A diagnosis (if known), or clinical signs and symptoms (if diagnosis is 
unknown), rather than the clinically significant abnormal laboratory finding or test result, will 
be entered on the AE or SAE eCRF page. If no diagnosis is known and clinical signs and 
symptoms are not present, then the abnormal finding will be recorded. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 57 of 91 
31 January 2018 
 
 
 
 
Treatment-related AEs and treatment-related SAEs will be followed up until resolution or 
medical condition stabilizes.  
6.2.1.6 
Reporting of a Serious Adverse Event and a SUSAR 
Any SAE (including death due to any cause and SUSARs) that occurs during this study, 
whether or not related to the study drug, must be reported immediately (within 24 hours of the 
study site’s knowledge of the event) by E-mail, telephone or fax to the Sponsor’s authorized 
representative at the following table. 
■■ 
■■■■■■■■■ 
■■■■■■■■■ 
■■ 
■■■■■■■■■ 
■■■■■■■■■ 
The report will contain as much available information as possible concerning the SAE to 
enable the Sponsor (or an authorized representative) to file a report, which satisfies regulatory 
reporting requirements. If SAE follow up is reported via eCRF, a completed, separate SAE 
follow up notification should be sent to Sponsor (or CRO) by fax or email within 24 hours of 
the study site’s awareness of the event. 
The information in the report of the SAE must include at least the following: 
 Name, address, and telephone number of the reporting Investigator. 
 Investigational product and study code. 
 Subject identification number, initials, sex, and date of birth or year of birth. 
 Description of the AE/SAE, measures taken, and outcome. 
 Preliminary classification of causal relationship by the Investigator. 
If SAE follow up reporting is performed using a SAE report form, its original contents should 
be appropriately reflected on the relevant page of the eCRF. 
Any SAEs reported spontaneously after the last study visit on Day 110 (or after EOS visit) will 
only be reported if the Investigator suspects a causal relationship to the study treatment. 
6.2.1.7 
Reporting of Serious Adverse Events to Regulatory Authorities and Investigators 
Investigators will be notified by the Sponsor or designee of all SAEs that require prompt 
submission to their Institutional Review Board (IRB) or Independent Ethics Committee (IEC). 
Investigators will provide written documentation of IRB/IEC notification for each report to the 
Sponsor or CRO. The Sponsor or the designee will ensure that all SAEs are reported to the 
appropriate regulatory authorities. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 58 of 91 
31 January 2018 
 
 
 
 
Any SUSAR that is fatal or life-threatening must be reported to the appropriate national 
regulatory authorities and relevant ethics committees within 7 calendar days of awareness. 
Other SUSARs must be reported within 15 calendar days of awareness. 
6.2.2 
Contraception 
The need to avoid pregnancy and a discussion concerning acceptable methods of contraception 
will be discussed with male subjects and female subjects of childbearing potential prior to the 
administration of study drug. 
Menopausal females are not considered of childbearing potential if they have experienced their 
last period more than 12 months prior to the date of informed consent. 
Both male and female subjects of childbearing potential and his/her partner will be required to 
use highly effective methods of contraception throughout the study and for 5 months after the 
administration of study drug. Highly effective methods of contraception include:  
 Oral contraceptives. 
 Other hormonal contraceptives administered as implants, percutaneous patches, or 
vaginal rings. 
 Intrauterine devices. 
 Double barrier methods, such as 
o Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository). 
o Male condom combined with a female diaphragm, either with or without a 
vaginal spermicide (foam, gel, film, cream, or suppository). 
 Sterilization 
o Tubal ligation or vasectomy. 
Male and female subjects and their partners who have been surgically sterilized for less 
than 6 months prior to the date of informed consent must agree to use a highly effective 
method of contraception during the study and for 5 months after the administration of 
study drug. 
 Abstinence from penile-vaginal intercourse, when this is the subject’s preferred and 
usual lifestyle. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 59 of 91 
31 January 2018 
 
 
 
 
6.2.3 
Pregnancy 
Females of childbearing potential will have a pregnancy test performed at screening to ensure 
the exclusion of pregnant women from the study. 
Female subjects will be instructed to inform the site if they become pregnant during the study. 
Male subjects will be instructed to inform the site if their partner becomes pregnant during the 
study. 
Female subjects of childbearing potential will have an additional test for pregnancy at the end 
of the study (Day 110). 
Any known or suspected pregnancy that occurs during the study either in subjects or female 
partners of male subjects must be reported to the Sponsor/designee within 24 hours of the time 
the Investigator becomes aware of the event. Suspected pregnancies in subjects will be 
confirmed with a pregnancy test. The subject will remain in the study and be monitored for 
safety. 
The Sponsor has a responsibility to monitor the outcome of all pregnancies reported during the 
study. The Investigator must follow up and document the course and the outcome of all 
pregnancies even if the subject withdraws consent or the study has finished. 
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study drug may 
have interfered with the effectiveness of contraceptive medications or a suspected AE is 
associated with pregnancy. 
Elective abortions without complications will not be regarded as AEs, unless they were 
therapeutic abortions (see below). Hospitalization for normal delivery of a healthy newborn 
will not be considered an SAE. 
All outcomes of pregnancy must be reported by the Investigator to the Sponsor on the 
pregnancy outcome report form within 30 days after he/she has gained knowledge of the 
normal delivery or elective abortion. The Investigator must follow up and document the course 
and the outcome of all pregnancies even if the subject was withdrawn from the study or if the 
study has finished. The baby will be followed for 1 year after the birth, provided consent is 
obtained; the Investigator must report any complications that occur even though the study has 
finished. 
Any SAE that occurs during pregnancy must be recorded on the SAE report form (e.g., 
maternal serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal 
death, congenital anomaly, birth defect) and reported within 24 hours in accordance with the 
procedure for reporting SAEs. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 60 of 91 
31 January 2018 
 
 
 
 
6.2.4 
Clinical Laboratory Evaluations 
Urine samples will be collected and blood will be drawn from each subject at screening and on 
Day 3, and Day 8, as presented in Table 1. The clinical laboratory parameters evaluated in this 
study are presented in Table 3. 
Clinical laboratory tests will be reviewed for results of potential clinical significance 
throughout the study. The Investigator will evaluate any change in laboratory values. If the 
Investigator determines a laboratory abnormality to be clinically significant, the abnormality 
will be reported as an AE (see Section 6.2.1 for definition of clinically significant laboratory 
results). Clinically significant laboratory results will be followed up to resolution or until the 
Investigator considers the abnormality chronic and/or the subject to be stable. 
Urine pregnancy testing and all laboratory assessments will be done by a local laboratory.  


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 61 of 91 
31 January 2018 
 
 
 
 
Table 3 
Clinical Laboratory Tests 
Hematology: 
White blood cell count (WBC) with differential, 
including absolute neutrophil count 
Red blood cell (RBC) count 
Hematocrit (HCT) 
Hemoglobin (Hb) 
Platelet count 
 
Urinalysis: 
Color  
pH  
Specific gravity 
Ketones 
Protein 
Glucose 
Bilirubin 
Nitrite 
Urobilinogen  
Occult blood  
Microscopic examination of sediment  
 
Additional Tests (Screening only): 
Hepatitis B surface antigen 
Hepatitis B surface antibody 
Hepatitis C virus antibody 
Human immunodeficiency virus (HIV)  
 
 
Serum Chemistry: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Blood urea nitrogen (BUN) 
Chloride 
Creatine kinase (CK) 
CK enzyme subtype*  
Troponin* 
Serum creatinine 
Creatinine clearance (estimated by weight and by 
Cockcroft-Gault formula) 
C-reactive protein 
Cholesterol 
Glucose 
Lactate dehydrogenase (LDH) 
Potassium  
Sodium  
Total bilirubin 
Direct bilirubin  
Total protein  
Uric acid 
Triglyceride 
 
Additional Tests (Screening and Day 110/EOS visit): 
Urine pregnancy (women of childbearing capacity) 
Serum pregnancy test 
Note: Urine pregnancy test will be performed before 
study drug administration in females of childbearing 
potential only. If the urine pregnancy test gives 
equivocal results, a serum pregnancy test will be 
performed to determine if the subject is pregnant. 
Pregnant women will be excluded from this study at 
screening. 
*Relevant assessment for CK enzyme subtype and Troponin will be performed only when CK result shows a 
clinical significance. 
6.2.5 
Antibody-dependent Enhancement 
Subjects will be monitored for symptoms and levels of viral shedding suggestive of suspicious 
ADE throughout the study. 
Subjects will be considered to possibly have ADE if they meet any of the following criteria: 
 Symptoms have not resolved or have worsened up to Day 8 after the administration of 
study drug in the opinion of the Investigator. 
 The subject develops a secondary influenza-like illness after Day 8. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 62 of 91 
31 January 2018 
 
 
 
 
Figure 4      Flow chart of Antibody-Dependent Enhancement (ADE) 
If a subject meets any of the criteria for suspicious ADE, virus titer will be measured using 
nasopharyngeal swab samples collected at the time of occurrence, Day 2 (24 hours [±4 hours] 
after the day of ADE occurrence), Day 3 (48 hours [±4 hours] after the day of ADE occurrence), 
Day 5 (96 hours [±4 hours] after the day of ADE occurrence) and Day 8 (168 hours [±4 hours] 
after the day of ADE occurrence). Those subjects will need to record Flu-iiQ™ (influenza 
symptoms) and body temperature in their diary twice a day (at approximately 12-hour intervals) 
from the day of ADE occurrence to Day 8 (168 hours after the day of ADE occurrence): in the 
morning [between 6 and 10 AM, approximately] and in the evening [between 6 and 10 PM, 
approximately]. If symptoms have not resolved or have worsened up to Day 8 after the day of 
ADE occurrence, same procedures will repeat. In addition, genotypic analysis on HA and NA 
genes and phenotype characterization of potential escape variants with regard to CT-P27 will 
be performed.   
If suspicious ADE occurs, DSMB will provide recommendations to continue or stop study 
after review of the case of suspicious ADE. 
 
6.2.6 
Vital Signs and Body Temperature 
At site visits, vital sign measurements (systolic blood pressure [SBP], diastolic blood pressure 
[DBP], respiratory rate, and heart rate) and body temperature will be measured at the time 
points specified in Table 1. Blood pressure (sitting) and heart rate will be measured after the 
subject has rested (sitting quietly) for at least 5 minutes. 
It should be noted that body temperature will also be recorded in on the eCRF, as discussed in 
Section 6.1.1. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 63 of 91 
31 January 2018 
 
 
 
 
6.2.7 
Hypersensitivity Reactions 
On Day 1, vital signs including blood pressure, heart rate and respiratory rate, body 
temperature, and ECG will be assessed at the following time points, and the subject will be 
monitored continuously over the period for possible immediate hypersensitivity reactions: 
 Vital sign and body temperature 
o Pre-infusion (within 15 minutes prior to the beginning of the infusion). 
o 30 minutes (±15 minutes) after the beginning of the infusion. 
o Within 15 minutes after the end of the infusion. 
o 2 hour (±15 minutes) after the end of the infusion. 
 Vital sign, body temperature and ECG 
o 1 hour (vital sign, body temperature: ±15 minutes, ECG: −30/+60 minute) 
after the end of the infusion. 
Emergency drugs and equipment suitable for assistance during anaphylactic reactions will be 
available during infusion with study drug. 
6.2.8 
Physical Findings and Other Safety Assessments 
A complete physical examination including examination of the head, neck, ears and throat, 
thorax, abdomen, extremities, neurological system, and skin and mucosae will be performed 
at screening and at Day 110/EOS visit. Evaluation of other body systems will only be 
performed when medically indicated in the opinion of the Investigator.  
In addition, at each visit, the Investigator or designee will also perform a symptom-directed 
physical assessment (which should include, at a minimum, the examination of ear, nose, throat, 
sinuses, and lungs) and evaluation for potential complications of influenza. 
Weight will be recorded at screening and at Day 110/EOS visit. Height will be recorded at 
screening, only. 
Twelve-lead ECGs will be performed at screening, on Day 8 (±4 hours), and Day 110 (±5 
days)/EOS visit. 
Electrocardiogram recordings will be obtained after the subject has been supine and at rest for 
at least 5 minutes. The Investigator or designee will review, sign, and date each ECG reading, 
noting whether or not any abnormal results are of clinical significance. The ECG will be 
repeated if any results are considered by the Investigator to be clinically significant. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 64 of 91 
31 January 2018 
 
 
 
 
Chest x-ray will be performed to assess respiratory infection at screening, and whenever 
needed during the study, as determined by the Investigator. 
All results will be recorded in the appropriate sections of the eCRF. 
6.3 
Exploratory Assessments 
A PK sub-study will only be performed on the subjects who signed additional informed consent 
to participate in a PK sub-study. Blood sampling for PK analysis will be collected from 
subjects on Day 1 at pre-infusion (within 15 minutes prior to the beginning of the infusion), 
the end of infusion (within 15 minutes after the end of the infusion), 1 hour (±15 minutes) after 
the end of the infusion, and then on Day 2 (24 hours [±4 hours] after the start of the study drug 
infusion), Day 3 (48 hours [±4 hours] after the start of the study drug infusion), Day 8 (168 
hours [±4 hours] after the start of the study drug infusion), Day 15 (±2 days), Day 29 (±5 days), 
Day 57 (±5 days), and Day 110 (±5 days)/EOS visit.  
Samples taken on Day 1 will be collected in the opposite arm from that being used for the IV 
infusion of study drug. The date and time of collection of each sample and any missing blood 
draws will be recorded in the respective eCRF. Samples will be collected, labeled, stored, and 
shipped as detailed in the Laboratory Manual. 
Bioanalysis will be carried out for the simultaneous determination of CT-P22 and CT-P23 
using a validated ligand binding assay. Bioanalysis will be carried out at the bioanalytical site. 
Contact details for the bioanalytical site are available in Table 4. 
Blood will be drawn at Day 1 (before study drug administration) and Day 110/EOS visit to 
evaluate the immunogenicity of CT-P27 components, CT-P22 and CT-P23. Samples will be 
secured at the central laboratory for immunogenicity analysis and backup samples will be 
retained. 
For the subjects with Influenza A confirmed by qPCR or cell culture, genotypic analysis on 
HA and NA genes, and phenotype characterization of potential escape variants with regard to 
CT-P27 will be evaluated using the nasopharyngeal swab samples. Samples will be secured at 
the central laboratory for analysis and backup samples will be retained. 
In addition, blood samples will be taken at Day 1 (at pre-infusion) and Day 29 (±5 days)/EOS 
visit (if a subject is early terminated from the study) to determine HI antibody in Subgroup 
(PK) Cohort. 
Primary samples will be secured at the central laboratory for PK, immunogenicity of CT-P22 
and CT-P23, and HI antibody analysis and backup samples will be retained. Back-up samples 
will be retained up to 5 years after the end of the study unless a specific authorization is 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 65 of 91 
31 January 2018 
 
 
 
 
given by the sponsor to destroy the back-up sample. Primary and back-up samples will be 
shipped to the central laboratory according to the laboratory manual, and primary samples 
should be shipped separately from the back-up samples. 
6.4 
Demographics and Medical History 
At screening, information on demographics and background characteristics will be collected. 
The demographics include age, sex (male or female), and race (Caucasian, African, Asian, or 
Other). A general medical history (e.g., previous illnesses, current conditions, and family 
history, smoking habits) will also be collected. In addition, medical history of a subject can be 
newly added on the eCRF at any time point during the AE assessment period. Medical history 
is defined as a medical event or condition that will be recorded as part of the subject’s medical 
history if the onset date of the event occurs before the ICF is signed. If a pre-existing medical 
event or condition recorded as medical history worsens after the ICF is signed, it would be 
reported as an AE, even if the onset date was prior to signing ICF. 
The information will be recorded on the eCRF. 
6.5 
Appropriateness of Measurements 
The primary and secondary efficacy endpoints are consistent with the “Guidance for Industry: 
Influenza: Developing Drugs for Treatment and/or Prophylaxis” provided by the FDA. The 
Flu-iiQ™ used in this study is a validated questionnaire developed to evaluate the influenza 
symptoms. 
The primary virology outcome, quantitative changes in viral shedding, is assessed using 
standard qPCR and cell culture methods. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 66 of 91 
31 January 2018 
 
 
 
 
7.0 QUALITY CONTROL AND QUALITY ASSURANCE 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
Investigators and appropriate study sites, review of protocol procedures with the Investigator 
and associated personnel before the study, periodic monitoring visits by the Sponsor or its 
designee, and direct transmission of clinical laboratory data from a local laboratory into the 
clinical database. The eCRF will be reviewed for accuracy and completeness by the monitor 
during on-site monitoring visits and after their return to the Sponsor or its designee; any 
discrepancies will be resolved with the Investigator or designees, as appropriate. The data will 
be entered into the study database and verified for accuracy.  
Quality assurance personnel from the Sponsor or its designee may visit the study site to carry 
out an audit of the study in compliance with regulatory guidelines and company policy. Such 
audits will require access to all study records, including source documents, for inspection and 
comparison with the eCRF. Subject privacy must, however, be respected. Sufficient prior 
notice will be provided to allow the Investigator to prepare properly for the audit.  
Similar auditing procedures may also be conducted by agents of any regulatory body reviewing 
the results of this study in support of a licensing application. The Investigator will immediately 
notify the Sponsor or its designee if they have been contacted by a regulatory agency 
concerning an upcoming inspection. 
7.1 
Data Management/Coding 
Electronic Data Capture (EDC) will be used for this study, meaning that all eCRF data will be 
entered in electronic forms at the study site. Data collection will be completed by authorized 
study site staff designated by the Investigator. Appropriate training and security measures will 
be completed with the Investigator and all authorized study site staff prior to the study being 
initiated and any data being entered into the system for any study subjects. 
All data must be entered in English. The eCRFs will always reflect the latest observations on 
the subjects participating in the study. Therefore, the eCRFs are to be completed as soon as 
possible during or after the subject’s visit. To avoid inter-observer variability, every effort will 
be made to ensure that the same individual who made the initial baseline determinations 
completes all efficacy and safety evaluations. The Investigator must verify that all data entries 
in the eCRFs are accurate and correct. If some assessments are not done, or if certain 
information is not available, not applicable, or unknown, the Investigator will indicate this in 
the eCRF. The Investigator will be required to electronically sign-off on the clinical data. 
The monitor will review the eCRFs and evaluate them for completeness and consistency. The 
eCRF will be compared with the source documents to ensure that there are no discrepancies 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 67 of 91 
31 January 2018 
 
 
 
 
between critical data. All entries, corrections, and alterations are to be made by the responsible 
Investigator or his/her designee. The monitor cannot enter data in the eCRFs. Once clinical 
data of the eCRF have been submitted to the central server, corrections to the data fields will 
be audit trailed, meaning that the reason for change, the name of the person who performed the 
change, together with time and date will be logged. Roles and rights of the site staff responsible 
for entering the clinical data into the eCRF will be determined in advance. If additional 
corrections are needed, the responsible monitor or Data Manager will raise a query in the EDC 
application. The appropriate study site staff will answer queries sent to the Investigator. This 
will be audit trailed by the EDC application meaning that the name of investigational staff and 
time and date stamp are captured. 
The eCRF is essentially considered a data entry form and will not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents used 
by the Investigator or hospital that relate to the subject’s medical history, that verify the 
existence of the subject, the inclusion and exclusion criteria, and all records covering the 
subject’s participation in the study. They include laboratory notes, ECG results, memoranda, 
pharmacy dispensing records, subject files, etc. 
The Investigator is responsible for maintaining source documents. These will be made 
available for inspection by the study monitor at each monitoring visit. The Investigator must 
submit a completed eCRF for each subject who receives study drug, regardless of duration. All 
supportive documentation submitted with the eCRF, such as laboratory or hospital records, 
will be clearly identified with the study and subject number. Any personal information, 
including subject name, will be removed or rendered illegible to preserve individual 
confidentiality. 
The eCRF records will be automatically appended with the identification of the creator, by 
means of their unique User ID. Specified records will be electronically signed by the 
Investigator to document his/her review of the data and acknowledgement that the data are 
accurate. This will be facilitated by means of the Investigator’s unique User ID and password; 
date and time stamps will be added automatically at time of electronic signature. If an entry on 
an eCRF requires change, the correction will be made in accordance with the relevant software 
procedures. All changes will be fully recorded in a protected audit trail, and a reason for the 
change will be required. 
Adverse events and medical histories will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA); concomitant medication will be coded using the World 
Health Organization (WHO) Drug Dictionary. The version numbers for both dictionaries will 
be presented in the Statistical Analysis Plan (SAP). 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 68 of 91 
31 January 2018 
 
 
 
 
7.2 
Quality Assurance Audit 
Study sites, the study database, and study documentation may be subject to Quality Assurance 
audit during the course of the study by the Sponsor or designee. In addition, inspections may 
be conducted by regulatory bodies at their discretion. 
The Investigator will promptly notify the Sponsor and designee of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports/certificates received to 
the Sponsor. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 69 of 91 
31 January 2018 
 
 
 
 
8.0 STATISTICS 
The complete version of the SAP will include all detailed statistical analysis methods, which 
will be available after the each Data Review Meeting. This statistical section presented below 
summarizes the SAP. 
The first analysis of data will occur after all subjects have completed the assessments scheduled 
for Day 15. These data will be used to determine the efficacy of treatment with CT-P27 to 
establish an effect size for subsequent clinical studies. The data will also provide information 
about the safety and PK (only Subgroup [PK] Cohort) of CT-P27 up to Day 15. An additional 
analysis will be performed when all subjects have completed the assessments scheduled for 
Day 110/EOS visit.  
8.1 
Determination of Sample Size 
Randomization will be stratified by flu vaccination history within a year (Yes vs No) and 
participation in PK sub-study (Yes vs No). 
This study is designed to obtain effect sizes of 2 different CT-P27 treatment groups and placebo 
group based on the time from the administration of study drug to resolution of influenza 
symptoms and fever. 
For this proof-of-concept dose-ranging study, assuming 90% of subjects are included in the 
eligible infected population, the total eligible sample size of 164 (63 eligible infected subjects 
per CT-P27 treatment groups and 38 subjects in placebo group) achieves 80% power to detect 
1.8 days of reduction for the primary endpoint of time to resolution with 5% two-sided 
significance level and standard deviation (SD) of 3 days using a Wilcoxon’s rank-sum test. 
Considering a dropout rate of 10%, this study will need 183 subjects to be enrolled to achieve 
164 evaluable subjects. 
For an effect size of 1.5 days of reduction in time to resolution with SD of 2.9 days, the total 
sample size could be increased to about 250 to achieve at least 80% statistical power with 5% 
two-sided significance level. 
8.2 
Study Endpoints 
8.2.1 
Primary Efficacy Endpoints 
The primary efficacy endpoint is defined as the time from the administration of study drug to 
resolution of influenza symptoms and fever.  


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 70 of 91 
31 January 2018 
 
 
 
 
Resolution of symptoms has occurred if the following influenza symptoms (as recorded on the 
Flu-iiQ™) are mild in intensity or none for at least 24 hours. 
 Respiratory symptoms (cough, sore throat, and nasal congestion). 
 Constitutional symptoms (headache, feeling feverish, body aches and pains, and 
fatigue). 
Resolution of fever is defined as: 
 Body temperature of <37.0oC for at least 24 hours.  
8.2.2 
Secondary Efficacy Endpoints 
 Time to resumption of normal activity as reported in Domain 2 of the Flu-iiQ™. 
 Time to return to normal body temperature (<37.0oC) for at least 24 hours. 
 Time to resolution of individual symptoms for at least 24 hours as recorded on the Flu-
iiQ™. 
 Severity of symptoms as recorded on the Flu-iiQ™. 
 Viral shedding in nasopharyngeal swab samples. 
 Incidence of secondary complications of influenza. 
 Quality of Life (QoL) measures as reported in Domain 3 and Domain 4 of the Flu-iiQ™. 
8.2.3 
Secondary Safety Endpoints 
The following safety parameters are secondary endpoints:  
 Treatment-emergent adverse events (TEAEs) 
 Treatment-emergent serious adverse events (TESAEs) 
 TEAEs leading to treatment discontinuation 
 Clinical laboratory analyses (hematology, biochemistry, and urinalysis laboratory tests) 
 Vital sign measurements  
 ECGs 
 Physical examination findings 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 71 of 91 
31 January 2018 
 
 
 
 
 Evaluation of ADE throughout the entire study duration. For the definition of 
suspicious ADE, please see Section 6.2.5. 
8.2.4 
Exploratory Endpoints  
Blood sampling for PK analysis will be collected from the subjects on: 
• 
Day 1 at pre-infusion (within 15 minutes prior to the beginning of the infusion), the 
end of infusion (+15 minutes), 1 hour (±15 minutes) after the end of the infusion,  
• 
Day 2 (24 hours [±4 hours] after the start of the study drug infusion),  
• 
Day 3 (48 hours [±4 hours] after the start of the study drug infusion),  
• 
Day 8 (168 hours [±4 hours] after the start of the study drug infusion), 
• 
Day 15 (±2 days), Days 29, 57 and 110 (±5 days) or at end of study visit (EOS visit).  
Blood sampling for Immunogenicity assessment will be collected on Day 1(at pre-infusion) 
and Day 110 (± 5days) or EOS visit.  
For the subjects with  Influenza A confirmed by qPCR or cell culture, genotypic analysis on 
HA and NA genes, and phenotype characterization of potential escape variants with regard to 
CT-P27 will be evaluated using the nasopharyngeal swab samples. 
Blood sampling for assessment of anti-influenza antibodies (Hemagglutination inhibition) will 
be collected on Day 1 (at pre-infusion) and Day 29 (± 5days) or EOS visit (if a subject is early 
terminated from the study) in Subgroup (PK) Cohort. 
Additional genotyping tests could be conducted if it is required from a regulatory or medical 
perspective. 
The following parameters are determined as exploratory endpoints: 
• 
PK profiles 
o AUC0-∞: Area under the concentration-time curve in serum from time zero 
extrapolated to infinite time 
o AUC0-last: Area under the concentration-time curve from time zero to the last 
quantifiable concentration 
o Cmax: Maximum observed serum concentration 
o tmax: Time of maximum concentration 
o Clast: Last observed quantifiable concentration 
o λz: Apparent terminal elimination rate constant 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 72 of 91 
31 January 2018 
 
 
 
 
o t1/2: Apparent terminal elimination half-life 
o MRT: Mean residence time 
o CL: Systemic clearance from serum after IV dosing 
o Vz: Apparent volume of distribution during the terminal elimination phase after IV 
dosing 
 
• 
Anti-drug specific antibodies for CT-P27 component antibodies (CT-P22 and CT-P23) 
• 
HI antibody. 
• 
Genotype and phenotype of isolated influenza virus 
8.3 
Statistical Methods 
The statistical analysis will be performed using ■■■■■■■■■■■■■■■■■■
■■■■. The statistical methods for this study, summarized in the following, will be 
described in a detailed SAP, which will be finalized prior to locking of the database and 
unblinding of the treatment codes. Changes from analyses planned in this protocol will be 
documented in the SAP. Any deviations from the planned analysis as described in the SAP 
will be justified and recorded in the final study report. 
The data documented and the clinical parameters measured in this study will be described using 
descriptive statistics (including number [n], mean, median, SD, minimum, and maximum) for 
quantitative variables and frequency counts and percentages for qualitative variables. Data will 
be listed in data listings.  
Baseline will be the latest available measurement prior to the start of the infusion of study drug. 
Pharmacokinetic parameters will be computed by non-compartmental methods ■■■■■■
■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■
■■■■■■■■■■■■■■■■■. 
8.4 
Analysis Populations 
8.4.1 
Intent-to-Treat Population 
The intent-to-treat (ITT) population is defined as all subjects randomized to study drug or 
placebo. All subjects will be included in the ITT as randomized even if they do not receive 
treatment. The secondary efficacy endpoint analysis and all baseline and demographic 
summaries will be performed on the ITT population. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 73 of 91 
31 January 2018 
 
 
 
 
8.4.2 
Intent-to-Treat Infected Population 
The intent-to-treat infected (ITTI) population is defined as all randomized subjects with 
confirmed influenza A by qPCR or cell culture. The primary and secondary efficacy endpoint 
analysis, the genotype and phenotype analysis will all be performed on the ITTI population.  
8.4.3 
Safety Population 
The safety population is defined as all randomized subjects receiving any amount of placebo 
or CT-P27. All safety and immunogenicity analyses will be based on the safety population. 
8.4.4 
Pharmacokinetic Population 
The PK population is defined as approximately 53 subjects (20 per CT-P27 treatment groups 
and 13 in placebo group) in Subgroup (PK) Cohort and all randomized subjects with confirmed 
influenza A by qPCR or cell culture who received a complete dose of study drug, with at least 
one post-dose PK sample. All PK analyses will be based on the PK population. 
If infusion interruptions and/or infusion rate adjustments occur during drug administration, the 
subject is still considered to have received a complete dose provided that the full calculated 
dose (45 mg/kg or 90 mg/kg) has been given at the end of the infusion. The infusion duration 
will be longer than 90 minutes (±15 minutes) in these cases and this will be documented in the 
eCRF. 
In addition, HI antibody, and the subject baseline characteristics analysis will all be performed 
on the PK population. 
8.5 
Statistical Analyses 
8.5.1 
Primary Efficacy Analysis 
The primary efficacy endpoint analysis will assess the time (in days) from the administration 
of study drug to resolution of influenza symptoms and fever. This analysis will be performed 
on the ITTI population. Data will be obtained from responses recorded on the Flu-iiQ™.  
Resolution of symptoms has occurred if the following influenza symptoms (as recorded on the 
Flu-iiQ™) are mild in intensity or none for at least 24 hours. 
 Respiratory symptoms (cough, sore throat, and nasal congestion). 
 Constitutional symptoms (headache, feeling feverish, body aches and pains, and 
fatigue). 
Resolution of fever is defined as: 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 74 of 91 
31 January 2018 
 
 
 
 
 Body temperature of <37.0oC for at least 24 hours. (The start time for resolution of 
fever is defined as the time recorded in the diary when body temperature was <37.0oC 
for at least 24 hours.) 
If the subject has received the drugs for symptom relief, the effective duration of the drugs for 
symptom relief should be considered.   
For example, the study drug was administered at 12:00 on 1st day. The first time body 
temperature recorded <37.0oC in the diary was 10:00 on 2nd day and continued more than 24 
hours. But acetaminophen/paracetamol known to be effective for 6 hours had been 
administered at 09:00 on 2nd day [1 hour prior to the time when the body temperature decreased 
<37.0oC], it will be calculated that the start time point for body temperature <37.0oC is 15:00 
on 2nd day [27 hours after the study drug administration]. Then, if the next first time body 
temperature recorded <37.0oC in the diary was 22:00 on 2nd day and body temperature was 
<37.0oC for 24 hours from then, the start time for resolution of fever is 22:00 on 2nd day [34 
hours after the study drug administration]. 
The primary efficacy endpoint will be analyzed using a Wilcoxon rank-sum test to assess 
differences between treatment groups, if every subject were followed until resolution of 
influenza symptoms and fever. The statistically significant difference of time to resolution of 
influenza symptoms and fever between placebo and CT-P27 based on Wilcoxon rank-sum test 
will be presented by p-values. If there is any censoring, the primary efficacy endpoint will be 
analyzed using Log-rank test, and Kaplan-Meier plots will be presented. 
8.5.2 
Secondary Efficacy Analyses 
The secondary efficacy endpoints will be analyzed on the ITTI and ITT populations. 
Time (in days) to resumption of normal activity, return to normal body temperature (<37.0oC), 
and resolution of individual symptoms will be analyzed using a Kaplan Meier model to assess 
differences between placebo and CT-P27.  
Individual symptoms and total symptom score will be summarized by severity, by time point, 
and by treatment group. 
Viral shedding (titers) based on qPCR and cell culture will be evaluated at the scheduled 
collection times. Changes in viral shedding will be assessed as the change from baseline in 
qPCR and log10 TCID50/mL. 
These will be summarized for each treatment group and collection time. 
The number and percentage of subjects with secondary complications of influenza will be 
summarized by treatment group. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 75 of 91 
31 January 2018 
 
 
 
 
Results for questions included in the remaining domains (3 and 4) (effect on feelings, effect on 
concerns) of the Flu-iiQ™ will be summarized by collection time and treatment group. 
Scheduled selection times are presented in Table 1. 
8.5.3 
Exploratory Analyses 
Pharmacokinetics parameters for CT-P27 components (CT-P22 and CT-P23) will be 
summarized at each dose level (45 mg/kg and 90 mg/kg) using descriptive statistics. Summary 
statistics will include the number of observations (n), mean, SD, median, minimum, maximum, 
geometric mean, and coefficient of variation (CV%). All PK analyses will be based on the PK 
population. Dose proportionality for CT-P22 and CT-P23 will be assessed. Details are 
provided below.  
Serum concentrations will be summarized by treatment group at each scheduled collection time 
as specified in Table 1. In addition to the standard summary statistics (n, mean, SD, median, 
minimum, and maximum), the geometric mean and CV% will also be presented at each time 
point. Mean serum concentration-time profiles of study drug will be plotted by treatment on 
linear and semi-logarithmic scales based on scheduled sample times. Individual concentrations 
and scheduled and actual sample times will be presented in data listings by treatment. 
Individual linear and semi-logarithmic concentration-time plots (based on scheduled sample 
times) with respective treatments presented together will also be included. For the calculation 
of PK parameters, all serum concentrations that are below the limit of quantitation (BLQ) prior 
to the first measurable concentration will be set to zero. The BLQ values after administration 
of study drug will be set equal to the lower limit of quantification. 
The following PK parameters will be calculated using non-compartmental methods for CT-P22 
and CT-P23: 
 AUC0-last calculated using the linear trapezoidal rule. This will be calculated over the 
study period. 
 Cmax obtained directly from the observed concentration versus time data. 
 AUC0-∞ calculated using the linear trapezoidal summation and extrapolated to infinity 
by addition of the last quantifiable concentration divided by the terminal rate constant: 
AUC0-last + Clast/z. 
 tmax obtained directly from the observed concentration versus time data. 
 Clast obtained from the last observed quantifiable concentration. 




CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 77 of 91 
31 January 2018 
 
 
 
 
linear regression and the line of unity slope. The 95% confidence interval (CI) or P-value for 
the slope will be presented. 
Immunogenicity will be assessed in the safety population by baseline and post-treatment serum 
measures of anti-CT-P27 component antibodies, CT-P22 and CT-P23 antibodies, using 
immunoassay. These data will be summarized by treatment groups and time point. 
Genotype and phenotype analysis will be assessed in the ITTI population by baseline and 
post-treatment virus measures. 
In addition, changes in HI antibody will be assessed in the PK population and summarized by 
treatment group and time point. 
 
8.5.4 
Safety Analyses 
The safety analysis will be performed on the safety population at the time points specified in 
Table 1 by presenting data on TEAEs, TESAEs, TEAEs leading to treatment discontinuation, 
clinical laboratory analyses, vital signs, ECG, physical examination, suspicious ADE, and 
other safety evaluations. 
8.5.4.1 
Adverse Events 
Adverse events will be graded for severity and the terminology of AEs will be described 
according to the CTCAE v4.03. All safety data will be listed and summarized by treatment 
group as appropriate. 
Adverse events will be coded to system organ class (SOC) and preferred term (PT) according 
to MedDRA. 
The following TEAE summaries will be reported by SOC, PT, and treatment group: 
 Number and percentage of subjects reporting at least one TEAE by SOC and PT 
 Number and percentage of subjects reporting at least one TESAE by SOC and PT 
 Number and percentage of subjects reporting at least one TEAE leading to treatment 
discontinuation by SOC and PT 
Treatment-emergent AEs will also be summarized by maximum severity and relationship to 
study drug with the percentage of subjects in each category. If more than one TEAE is recorded 
for a subject within any SOC or PT, the subject will only be counted once using the most severe 
assessment. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 78 of 91 
31 January 2018 
 
 
 
 
The number and percentage of subjects with suspicious TEADE will be presented by treatment 
group. 
8.5.4.2 
Clinical Laboratory Evaluations 
Clinical laboratory tests (hematology, biochemistry, and urinalysis) will be summarized, by 
treatment, at each scheduled collection time. For continuous parameters, change from baseline 
will also be summarized for all scheduled collection times after the first infusion. Clinical 
laboratory data will also be summarized using shift tables for categorical parameters. 
All laboratory results will be listed. 
8.5.4.3 
Vital Signs Measurements, Physical Findings, and Other Safety Evaluations 
Vital signs of SBP, DBP, heart rate, and respiration rate will be summarized by treatment group, 
at each scheduled collection time. Changes from baseline will also be summarized by treatment 
group. 
The number and percentage of subjects with abnormalities in vital signs or ECG during the 
infusion and immediate post-infusion period will be summarized by time point and treatment 
group. 
Physical examination results will be summarized by counts and percentages at each scheduled 
collection time. In addition, shift tables will be presented. 
Electrocardiogram parameters will be summarized by counts and percentages, at each 
scheduled collection time. In addition, shift tables will be presented. 
8.5.5 
Subject Baseline Characteristics 
Demographics (age, sex, and race) and other background characteristics such as medical 
history will be presented in summary tables for the ITT population and ITTI population. 
Qualitative data will be summarized in contingency tables, and quantitative data will be 
summarized using quantitative descriptive statistics. 
8.6 
Data to be Analyzed 
The data will be inspected for inconsistencies by performing validation checks. 
All details regarding the statistical analysis and the preparation of tables, listings, and figures 
will be described in the SAP before database lock. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 79 of 91 
31 January 2018 
 
 
 
 
8.6.1 
Missing Data 
Missing data from subjects who withdraw from the study, including AEs and any follow-up, 
will be included in the primary endpoint analysis in the ITTI population. Assuming Missing at 
Random (MAR), multiple imputation will be the primary imputation method for handling the 
missing data. Sensitivity analysis using tipping point analysis under Missing Not at Random 
(MNAR) will be also accessed for the primary endpoint analysis in the ITTI population. 
8.7 
Interim Analyses 
There is no interim analysis planned.  


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 80 of 91 
31 January 2018 
 
 
 
 
9.0 ETHICS 
9.1 
Institutional Review Board or Independent Ethics Committee 
An Ethics Committee will approve the final protocol, including the final version of the ICF 
and any other written information and/or materials to be provided to the subjects. The 
Investigator will provide the Sponsor or CRO with documentation of IRB/IEC approval of the 
protocol and informed consent before the study may begin at the study site(s). The Investigator 
will submit the written approval to the Sponsor or representative before enrollment of any 
subject into the study. 
The Sponsor or representative will approve any modifications to the ICF that are needed to 
meet local requirements. 
The Investigator will supply documentation to the Sponsor or CRO of required IRB/IEC’s 
annual renewal of the protocol and any approvals of revisions to the informed consent 
document or amendments to the protocol. 
The Investigator will report promptly to the IRB/IEC any new information that may adversely 
affect the safety of subjects or the conduct of the study. Similarly, the Investigator will submit 
written summaries of the study status to the IRB/IEC annually, or more frequently if requested 
by the IRB/IEC. Upon completion of the study, the Investigator will provide the ethics 
committee with a brief report of the outcome of the study, if required. 
The Sponsor or representative will provide Regulatory Authorities, Ethics Committees, and 
Investigators with safety updates/reports according to local requirements, including SUSARs, 
where relevant. 
9.2 
Ethical Conduct of the Study 
This study will be conducted and the informed consent will be obtained according to the ethical 
principles stated in the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, 
Brazil, October 2013)7, the applicable guidelines for GCP (CPMP/ICH/135/95), or the 
applicable drug and data protection laws and regulations of the countries where the study will 
be conducted. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
The study will be conducted in compliance with GCP and the applicable national regulations 
so as to assure that the rights, safety, and well-being of the participating study subjects are 
protected consistent with the ethical principles that have their origin in the Declaration of 
Helsinki. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 81 of 91 
31 January 2018 
 
 
 
 
9.3 
Subject Information and Informed Consent 
The ICF will be used to explain the risks and benefits of study participation to the subject in 
simple terms before the subject will be entered into the study. The ICF contains a statement 
that the consent is freely given, that the subject is aware of the risks and benefits of entering 
the study, and that the subject is free to withdraw from the study at any time. Written consent 
must be given by the subject and/or legal representative, after the receipt of detailed 
information on the study. 
The Investigator is responsible for ensuring that informed consent is obtained from each 
subject or legal representative and for obtaining the appropriate signatures and dates on the 
informed consent document prior to the performance of any protocol procedures and prior to 
the administration of study drug. The Investigator will provide each subject with a copy of the 
signed and dated consent form. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 82 of 91 
31 January 2018 
 
 
 
 
10.0 STUDY ADMINISTRATION 
10.1 Administrative Structure 
Table 4 
Administrative Structure 
■■■■■■ 
■■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■■■■■■■■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■■■■■■■■■■■■■ 
■■■■■■■■■■■■ 
■■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■■■■■■■■■■■■■ 
■■■■■■■■■■■■ 
■■■■■■■■■■■■ 
■■■■■■■■■■■■■■■■■■ 
■■■■■■■■■■■■ 
 
10.2 Data Handling and Record Keeping 
It is the Investigator’s responsibility to maintain essential study documents (protocol and 
protocol amendments, completed eCRFs, signed ICFs, relevant correspondence, and all other 
supporting documentation). The study site will plan on retaining such documents for 
approximately 15 years after study completion. The study site will retain such documents until 
at least 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or at least 2 
years after the formal discontinuation of clinical development of the investigational product. 
These documents will be retained for a longer period if required by the applicable regulatory 
requirements or the hospital, institution, or private practice in which the study is being 
conducted. Subject identification codes (subject names and corresponding study numbers) will 
be retained for this same period of time. These documents may be transferred to another 
responsible party, acceptable to the Sponsor, who agrees to abide by the retention policies. 
Written notification of transfer must be submitted to the Sponsor. The Investigator must 
contact the Sponsor prior to disposing of any study records. 
For studies conducted outside the US under a US Investigational New Drug Application 
(IND), the Principal Investigator must comply with US FDA IND regulations and with those 
of the relevant national and local health authorities. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 83 of 91 
31 January 2018 
 
 
 
 
10.3 Direct Access to Source Data/Documents 
The Investigator will prepare and maintain adequate and accurate source documents to record 
all observations and other pertinent data for each subject randomized into the study. 
The Investigator will allow the Sponsor, the CRO, and authorized regulatory authorities to 
have direct access to all documents pertaining to the study, including individual subject 
medical records, as appropriate. 
10.4 Investigator Information 
10.4.1 
Investigator Obligations 
This study will be conducted in accordance with the ICH Harmonized Tripartite Guideline for 
GCP (GCP, 1996 8); the US CFR Title 21 parts 50, 54, 56, and 312; and European Legislation; 
and the ethical principles that have their origin in the Declaration of Helsinki. 
The Investigator agrees to conduct the study in compliance with this protocol after the approval 
of the protocol by the IEC/IRB in compliance with local regulatory requirements. The 
Investigator and the Sponsor will sign the protocol to confirm this agreement. 
10.4.2 
Protocol Signatures 
After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative (Appendix 1). By signing the protocol, 
the Investigator confirms in writing that he/she has read, understands, and will strictly adhere 
to the study protocol and will conduct the study in accordance with ICH Tripartite Guidelines 
for Good Clinical Practice 8 and applicable regulatory requirements. The study will not be able 
to start at any site where the Investigator has not signed the protocol. 
10.4.3 
Publication Policy  
The data generated by this study are confidential information of the Sponsor. The Sponsor will 
make the results of the study publicly available. 
Independent analysis and/or publication of these data by the Investigator or any member of 
his/her staff are not permitted without prior written consent of the Sponsor. Written permission 
to the Investigator will be contingent on the review by the Sponsor of the statistical analysis 
and manuscript and will provide for nondisclosure of the Sponsor’s confidential or proprietary 
information. In all cases, the parties agree to submit all manuscripts or abstracts to all other 
parties 60 days prior to submission. This will enable all parties to protect proprietary 
information and to provide comments based on information that may not yet be available to 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 84 of 91 
31 January 2018 
 
 
 
 
other parties. The publication policy with respect to the Investigator and study site will be set 
forth in details in the Clinical Trial Agreement. 
10.5 Financing and Insurance  
The Sponsor will obtain liability insurance, which covers this study as required by local law 
and/or national regulations and/or ICH guidelines, whichever is applicable. The terms of the 
insurance will be kept in the study files. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 85 of 91 
31 January 2018 
 
 
 
 
11.0 STUDY MANAGEMENT 
11.1 Monitoring 
11.1.1 Data Safety Monitoring Board 
This study will be monitored by an independent DSMB consisting of a PK specialist, 
statistician, chairing physician, and an independent physician. Further details will be 
provided in a DSMB charter. 
11.1.2 Monitoring of the Study 
The Sponsor has engaged the services of a CRO to perform all monitoring functions within 
this study. Study monitors will work in accordance with the CRO’s SOPs and have the same 
rights and responsibilities as monitors from the Sponsor organization. Monitors will establish 
and maintain regular contact between the Investigator and the Sponsor. 
Monitors will evaluate the competence of each study site, informing the Sponsor about any 
problems relating to facilities, technical equipment, or medical staff. During the study, 
monitors will check that written informed consent has been obtained from all subjects correctly 
and that data are recorded correctly and completely. Monitors are also entitled to compare 
entries in eCRFs with corresponding source data and to inform the Investigator of any errors 
or omissions. Monitors will also control adherence to the protocol at the study site. They will 
arrange for the supply of investigational product and ensure appropriate storage conditions are 
maintained. 
Monitoring visits will be conducted according to all applicable regulatory requirements and 
standards. Regular monitoring visits will be made to each site while subjects are enrolled in 
the study. The monitor will make written reports to the Sponsor on each occasion that contact 
with the Investigator is made, regardless of whether it is by phone or in person. 
During monitoring visits, entries in the eCRFs will be compared with the original source 
documents (source data verification). For all entries, 100% of the data will be checked.  
11.1.3 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the investigator agrees to allow the sponsor, representatives 
of the sponsor, or other regulatory agency access to all study records. 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 86 of 91 
31 January 2018 
 
 
 
 
The principal investigator or sub-investigator should promptly notify the sponsor and its 
designee of any audits scheduled by any regulatory authorities and promptly forward copies 
of any audit reports or certificate received to the sponsor. 
The investigator should promptly notify the sponsor and CRO of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
11.2 Management of Protocol Amendments and Deviations 
11.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the subject, must be reviewed and approved by the sponsor or its 
designee. Amendments to the protocol must be submitted to the investigator’s IRB/IEC for 
approval before subjects can be enrolled into an amended protocol. 
11.2.2 Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review and approval, to the sponsor for agreement, 
and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by the 
subject or investigator that results in a significant, additional risk to the subject. Significant 
deviations can include nonadherence to inclusion or exclusion criteria, or nonadherence to 
regulatory regulations or ICH GCP guidelines, and will lead to the subject being withdrawn 
from the study. 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Deviations from the protocol, including deviations of inclusion/exclusion 
criteria, will be assessed as “minor” or “major” in agreement with the sponsor. Deviations 
will be defined prior to unblinding. Principal investigators will be notified in writing by the 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 87 of 91 
31 January 2018 
 
 
 
 
monitor of deviations. The IRB/IEC should be notified of all protocol deviations in a timely 
manner.  
11.3 Study Termination 
Although CELLTRION, Inc. has every intention of completing the study, CELLTRION, Inc. 
reserves the right to discontinue the study at any time for clinical or administrative reasons. 
Study termination is defined as the date on which the last subject completes the last visit (if 
the study is not discontinued by CELLTRION, Inc.). 
11.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies) as required by 
the applicable regulatory requirement(s). The sponsor will also ensure that the clinical study 
reports in marketing applications meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and Content of Clinical Study Reports. 
It is planned that 2 clinical study reports will be written. 
 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 88 of 91 
31 January 2018 
 
 
 
 
12.0 REFERENCES 
1. Centers for Disease Control and Prevention. Seasonal Influenza Q & A. 
http://www.cdc.gov/flu/about/qa/disease.htm. 
2. Hsu J, Santesso N, Mustafa R, Brozek J, Chen YL, Hopkins JP, Cheung A, et al. 
Antivirals for treatment of influenza: a systematic review and meta-analysis of 
observational studies. Ann Intern Med 2012; 156(7):512-24. 
3. Pizzorno A, Abed Y, Boivin G. Influenza drug resistance. Semin Respir Crit Care Med 
2011; 32(4):409-22. 
4. Smith SM, Gums JG. Antivirals for influenza: strategies for use in pediatrics. Paediatr 
Drugs. 2010; 12(5):285-99. 
5. Smith JR, Rayner CR, Donner B, Wollenhaupt M, Klumpp K, Dutkowski R. 
Oseltamivir in seasonal, pandemic, and avian influenza: a comprehensive review of 10-
years clinical experience. Adv Ther. 2011; 28(11):927-59. 
6. U.S. Department of Health and Human Services Food and Drug Administration Center 
for Drug Evaluation and Research (CDER) April 2011 Clinical Antimicrobial 
Guidance for Industry Influenza: Developing Drugs for Treatment and/or Prophylaxis  
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guid
ances/ucm091219.pdf 
7. World Medical Association Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Subjects. (Oct 2013) 
http://www.up.ac.za/media/shared/Legacy/sitefiles/file/45/2875/declarationofhelsinki
_fortaleza_brazil2013.pdf 
8. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human use ICH Harmonised Tripartite Guideline, 
Guideline for Good Clinical Practice E6(R1) 10 June 1996. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
6/E6_R1_Guideline.pdf 
 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 89 of 91 
31 January 2018 
 
 
 
 
13.0 APPENDICES 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 90 of 91 
31 January 2018 
 
 
 
 
13.1 Appendix 1: Signature of Investigator 
PROTOCOL TITLE: A Phase IIb, Randomized, Double-blind, Multicenter, Placebo-
controlled Study Evaluating the Efficacy and Safety of CT-P27 in Subjects with Acute 
Uncomplicated Influenza A Infection 
PROTOCOL NO: 
CT-P27 2.2 
This protocol is a confidential communication of CELLTRION. I confirm that I have read this 
protocol, I understand it, and I will work according to this protocol. I will also work 
consistently with the ethical principles that have their origin in the Declaration of Helsinki and 
that are consistent with good clinical practices and the applicable laws and regulations. 
Acceptance of this document constitutes my agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval from 
CELLTRION. 
I will not make changes to the protocol before consulting with CELLTRION, Inc. or implement 
protocol changes without independent ethics committee approval except to eliminate an 
immediate risk to subjects. I agree to administer the investigational medicinal product only to 
subjects under my personal supervision or the supervision of a Coordinating Investigator.  
I will not supply the investigational medicinal product to any person not authorised to receive 
it. Confidentiality will be protected. Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the 
name of the site in which the study will be conducted. Return the signed copy to CELLTRION. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
Signature of Investigator:      
__________________________            Date:  ________ 
Printed Name:                                ___________________________ 
Investigator Title:                           ___________________________ 
 
Name/Address of Site:               
___________________________ 
 
___________________________ 
 
___________________________ 


CELLTRION, Inc. 
CT-P27 2.2 
Clinical Study Protocol 
CONFIDENTIAL 
 
5.0  
Page 91 of 91 
31 January 2018 
 
 
 
 
13.2 Appendix 2: Flu-iiQ™ 
[Note: It is the Sponsor's responsibility to obtain copyright permissions for any scales or 
questionnaires]  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
1/62 page 
 
 
Effective Date: 01-Aug-2018 
 
STATISTICAL ANALYSIS PLAN 
 
Study Title 
A Phase IIb, Randomized, Double-blind, Multicenter, Placebo-controlled  
Study Evaluating the Efficacy and Safety of CT-P27 in Subjects with Acute 
Uncomplicated Influenza A Infection 
 
Protocol No./ Version 
CT-P27 2.2/ V5.0 
Sponsor 
Celltrion, Inc. 
Version No. 
V3.1  
 
 
■■■■■■ 
 
 
 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
2/62 page 
 
 
Effective Date: 01-Aug-2018 
 
Signature page 
 
 
Prepared by: 
 
 
 
 
 
 
 
 
 
Date (DD-MMM-YYYY) 
 
Name/Position 
 
Signature 
 
 
Reviewed by: (■■■■■■) 
 
 
 
 
 
 
 
Date (DD-MMM-YYYY) 
 
Name/Position 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
3/62 page 
 
 
Effective Date: 01-Aug-2018 
 
 
Approved by Sponsor 
 
 
 
 
 
 
 
 
 
 
Date (DD-MMM-YYYY) 
 
Name/Position 
 
Signature 
 
 
 
 
 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
4/62 page 
 
 
Effective Date: 01-Aug-2018 
 
Version Information (Document revision history) 
Version 
Effective Date 
Prepared by 
Details 
1.0 
14FEB2018 
■■■■■■ 
First Version 
2.0 
21MAY2018 
■■■■■■ 
Updated after data review meeting 
3.0 
06AUG2018 
■■■■■■ 
Update for the Follow-Up CSR 
3.1 
31OCT2018 
■■■■■■ 
Updated after data review meeting for 
the Follow-Up CSR 
 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
5/62 page 
 
 
Effective Date: 01-Aug-2018 
 
Abbreviation 
Term 
Definition 
ADE 
Antibody-Dependent Enhancement 
AEs 
Adverse Events 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the Curve 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EOS 
End-of-Study 
Flu-iiQTM 
Influenza Intensity and Impact Questionnaire 
GMFR 
Geometric Mean Fold Rise 
GMT 
Geometric Mean Titer 
HA 
Hemagglutinin 
HI 
Hemagglutination Inhibition 
ICF 
Informed Consent Form 
ICH  
International Council for Harmonization 
IP 
Investigational Product 
ITT 
Intent-to-Treat 
ITTI 
Intent-to-Treat Infected 
LLoQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Neuraminidase 
NCS 
Not Clinically Significant 
PK 
Pharmacokinetics 
PT  
Preferred Term 
QoL 
Quality of Life  
qPCR 
quantitative Polymerase Chain Reaction  
SAE 
Serious Adverse Event 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
6/62 page 
 
 
Effective Date: 01-Aug-2018 
 
Term 
Definition 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TCID50 
Median Tissue Culture Infected Dose 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
ULoQ 
Upper Limit of Quantification 
WHODD 
World Health Organization Drug Dictionary 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
7/62 page 
 
 
Effective Date: 01-Aug-2018 
 
Contents 
 
Signature page ................................................................................................................................................. 2 
Version Information (Document revision history) ........................................................................................... 4 
Abbreviation .................................................................................................................................................... 5 
1. 
Introduction ............................................................................................................................................. 9 
1.1 
Study Design and Plan ................................................................................................................ 9 
2. 
Objectives .............................................................................................................................................. 11 
2.1 
Primary Objective..................................................................................................................... 11 
2.2 
Secondary Objectives ............................................................................................................... 11 
2.3 
Exploratory Objectives ............................................................................................................. 11 
3. 
Endpoints ............................................................................................................................................... 11 
3.1 
Efficacy Endpoints .................................................................................................................... 11 
3.2 
Safety Endpoints ...................................................................................................................... 12 
3.3 
Exploratory Endpoints .............................................................................................................. 12 
4. 
Randomization, Stratification and Blinding ........................................................................................... 12 
5. 
General Statistical Considerations ......................................................................................................... 13 
5.1 
General Analysis Considerations .............................................................................................. 13 
5.2 
Determination of Sample Size .................................................................................................. 13 
5.3 
Analysis Populations ................................................................................................................ 13 
5.4 
External Data Handling............................................................................................................. 14 
6. 
Protocol Deviation ................................................................................................................................. 15 
7. 
Subject Disposition ................................................................................................................................ 15 
8. 
Demographics and Baseline Characteristics .......................................................................................... 15 
8.1 
Demographics and Subject Characteristics .............................................................................. 15 
8.2 
Clinical Characteristics.............................................................................................................. 16 
8.3 
Viral Serology ........................................................................................................................... 16 
8.4 
Medical History ........................................................................................................................ 16 
9. 
Treatments and Medications ................................................................................................................. 16 
9.1 
Prior and Concomitant Medications ........................................................................................ 16 
9.2 
Study Drug Exposure ................................................................................................................ 17 
9.3 
Use of Drugs for Symptom Relief ............................................................................................. 17 
10. Efficacy Analysis ..................................................................................................................................... 17 
10.1 
Primary Efficacy Analysis .......................................................................................................... 17 
10.2 
Secondary Efficacy Analyses ..................................................................................................... 19 
10.3 
Missing Data Handling ............................................................................................................. 21 
10.3.1 Missing Data Handling for Primary Efficacy Analysis .......................................................... 21 
10.3.2 Missing Data Handling for Secondary Efficacy Analyses ..................................................... 22 
11. Exploratory Analysis .............................................................................................................................. 23 
11.1 
Pharmacokinetic Analysis ......................................................................................................... 23 
11.1.1 Serum Concentration .......................................................................................................... 23 
11.1.2 Serum Pharmacokinetic Parameters .................................................................................. 24 
11.2 
Immunogenicity Analysis ......................................................................................................... 25 
11.3 
Other Exploratory Analysis ....................................................................................................... 26 
11.3.1 HI Antibody ......................................................................................................................... 26 
11.3.2 Genotype ............................................................................................................................ 26 
11.3.3 Phenotype .......................................................................................................................... 26 
12. Safety Analysis ....................................................................................................................................... 27 
12.1 
Adverse Events ......................................................................................................................... 27 
12.1.1 Treatment-Emergent Adverse Event ................................................................................... 28 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
8/62 page 
 
 
Effective Date: 01-Aug-2018 
 
12.1.2 Treatment-Emergent Serious Adverse Event ...................................................................... 29 
12.2 
Clinical Laboratory Analyses ..................................................................................................... 29 
12.2.1 Hematology ........................................................................................................................ 29 
12.2.2 Biochemistry ....................................................................................................................... 30 
12.2.3 Urinalysis ............................................................................................................................ 30 
12.3 
Vital Signs ................................................................................................................................. 30 
12.4 
Immediate Hypersensitivity ..................................................................................................... 30 
12.5 
Electrocardiogram .................................................................................................................... 31 
12.6 
Physical Examination and Weight ............................................................................................ 31 
12.7 
Pregnancy Test ......................................................................................................................... 31 
12.8 
Chest X-ray ............................................................................................................................... 32 
12.9 
Suspicious ADE ......................................................................................................................... 32 
13. Changes to Protocol-Specified Analysis ................................................................................................. 32 
14. Appendices ............................................................................................................................................ 34 
14.1 
Schedule of Assessments ......................................................................................................... 34 
14.2 
CTCAE Grades ........................................................................................................................... 39 
14.2.1 Laboratory Grades .............................................................................................................. 40 
14.3 
Date Imputation ....................................................................................................................... 44 
14.3.1 Prior and Concomitant Medication .................................................................................... 44 
14.3.2 Symptom Relief Medication ............................................................................................... 45 
14.4 
Use of Antibiotics/Antifungal/Antiviral for Subjects with Secondary Complications ............... 46 
14.4.1 Algorithm for Capture Rule for Antibiotics/Antifungal/Antiviral ........................................ 46 
14.4.2 ATC Code List for Antibiotics/Antifungal/Antiviral .............................................................. 46 
14.5 
Drugs for Symptom Relief and Effective Duration .................................................................... 48 
14.6 
Coding of Categories and Signs and Symptoms for TEAEs due to IRR ...................................... 49 
14.7 
List of Tables, Listings, Figures .................................................................................................. 50 
15. Role & Responsibilities .......................................................................................................................... 62 
16. Applied SOPs .......................................................................................................................................... 62 
17. Applied SDs ............................................................................................................................................ 62 
 
 
 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
9/62 page 
 
 
Effective Date: 01-Aug-2018 
 
1. 
Introduction 
1.1 Study Design and Plan 
The Statistical Analysis Plan (SAP) is based on the final study protocol CT-P27 2.2 (A Phase IIb, Randomized, 
Double-blind, Multicenter, Placebo-controlled Study Evaluating the Efficacy and Safety of CT-P27 in Subjects 
with Acute Uncomplicated Influenza A Infection) Version 5.0 dated 31 January 2018 and electronic Case 
Report Form (eCRF) Version 4.1 dated 28 September 2017 and covers full study analysis and data presentation. 
This is a phase IIb, multicenter, placebo-controlled, randomized, double-blind, parallel-arm study to evaluate 
the efficacy and safety of two doses of CT-P27 (45 mg/kg and 90 mg/kg) in subjects with acute uncomplicated 
influenza A infection. This proof-of-concept study will provide dose-ranging information for the subsequent 
clinical development of the drug. 
No study procedures will be performed prior to informing the subject about the study and obtaining written 
informed consent. However, any test result which was obtained within the allowed screening period can be 
used as screening data for subject’s convenience. It is critical that subjects receive treatment with study drug 
no more than 48 hours after the onset of symptoms (window of +12 hours is allowed). The time of onset of 
illness is defined as the earlier of either (a) the time when the body temperature was first measured as ≥
38.0oC (≥100.4oF) or (b) the time when the subject experienced the presence of at least two symptoms that 
are respiratory and/or constitutional (moderate to severe in intensity). For most subjects, obtainment of the 
Informed Consent Form (ICF), screening for eligibility, randomization and treatment will occur on the same 
day. Though obtainment of the ICF may occur on the day prior to screening, randomization or treatment, it 
must be within 24 hours before the administration of study drug. 
To be eligible for enrollment, subjects must have a positive test result for influenza A by a rapid influenza 
diagnostic test. At screening, nasopharyngeal swab samples will be collected for two times to be used for 
rapid influenza diagnostic test and virology assessment. The enrollment process is presented in Figure 1. 
Figure 1 Enrollment Process 
 
 
Approximately 183 subjects with influenza A to be enrolled in the study will be randomly assigned to 1 of 3 
groups, CT-P27 45 mg/kg, CT-P27 90 mg/kg, or placebo (approximately 70 subjects per CT-P27 treatment 
groups and 43 subjects in placebo group). Randomization will be stratified by flu vaccination history within a 
year (Yes vs No) and participation in Pharmacokinetic (PK) sub-study (Yes vs No). A schematic diagram of 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
10/62 page 
 
 
Effective Date: 01-Aug-2018 
 
subject assignment is presented in Figure 2. 
Figure 2 Schematic diagram of Subject Assignment 
 
All enrolled subjects will be given a single dose of CT-P27 45 mg/kg, CT-P27 90 mg/kg, or placebo 
intravenously over 90 minutes (±15 minutes) on Day 1 and then followed by Day 110.  
A PK sub-study will be performed on the subjects who signed informed consent to participate in a PK sub-
study. Of total number of subjects to be enrolled, approximately 53 subjects (20 subjects per CT-P27 
treatment groups and 13 subjects in placebo group) will be included in the Subgroup (PK) Cohort, and 
additional PK samples from the subjects in this cohort will be collected according to the schedule of 
assessments. A schematic diagram for the study cohorts is presented in Figure 3.  
Figure 3 Schematic Diagram for the Study Cohorts 
 
 
Subjects may be admitted to a hospital from Day 1 (before study drug administration) to Day 3 (after 
completion of the 48 hours assessments) if deemed necessary by the investigator’s judgement. 
The first analysis of data will occur after all subjects have completed the assessments scheduled for Day 15. 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
11/62 page 
 
 
Effective Date: 01-Aug-2018 
 
As study recruitment was conducted through 2 influenza seasons to reach the expected sample size, 
approximately 1-year gap has been made between the subjects who enrolled during first season (randomized 
before 30Apr2017) and second season (randomized from 01May2017). To include as much available data as 
possible in the 1st Clinical Study Report (CSR), the whole data up to Day 110/EOS visit for the first season 
subjects, and the data up to Day 15 for the second season subjects will be summarized in the 1st CSR. In the 
Follow-Up CSR, the whole data up to study close will be included and summarized.  
These data will be used to determine the efficacy of treatment with CT-P27 to establish an effect size of CT-
P27 in comparison to placebo based on time to resolution of influenza symptoms and fever. Information on 
effect size, as well as the safety and PK will be used in the selection of doses for subsequent clinical studies. 
2. 
Objectives 
2.1 Primary Objective 
To evaluate efficacy as determined according to the time to resolution of respiratory and constitutional 
symptoms of influenza and fever 
 
2.2 Secondary Objectives 
To evaluate the additional efficacy and safety of CT-P27, including potential effects on the incidence of 
Antibody-Dependent Enhancement (ADE) 
 
2.3 Exploratory Objectives 
 
To assess the PK of CT-P27 components (CT-P22 and CT-P23) 
 
To assess immunogenicity 
 
To assess Hemagglutination Inhibition (HI) antibody 
 
To assess the characterization of isolated influenza viruses 
 
3. 
Endpoints 
3.1 Efficacy Endpoints 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is defined as the time from the administration of study drug to resolution of 
influenza symptoms and fever as recorded in the diary. 
Resolution of symptoms has occurred if the following influenza symptoms recorded on the Influenza Intensity 
and Impact Questionnaire (Flu-iiQTM) in the diary are mild in intensity or none for at least 24 hours. 
 
Respiratory symptoms (cough, sore throat, and nasal congestion) 
 
Constitutional symptoms (headache, feeling feverish, body aches and pains, and fatigue) 
Resolution of fever is defined as: 
 
Body temperature of <37.0°C for at least 24 hours  
 
Secondary Efficacy Endpoints: 
 
Time to resumption of normal activity as reported in Domain 2 of the Flu-iiQTM 
 
Time to return to normal body temperature (<37.0°C) for at least 24 hours  
 
Time to resolution of individual symptoms for at least 24 hours as reported in Domain 1 of the Flu-
iiQTM 
 
Severity of symptoms as reported in Domain 1 of the Flu-iiQTM 
 
Viral shedding in nasopharyngeal swab samples 
 
Incidence of secondary complications of influenza 
 
Quality of Life (QoL) measures as reported in Domain 3 and Domain 4 of the Flu-iiQTM 
 
Physician assessment 
 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
12/62 page 
 
 
Effective Date: 01-Aug-2018 
 
3.2 Safety Endpoints 
The following safety parameters are secondary endpoints: 
 
Treatment-emergent adverse events (TEAEs) 
 
Treatment-emergent serious adverse events (TESAEs) 
 
Clinical laboratory analyses (hematology, biochemistry, and urinalysis laboratory tests) 
 
Vital sign measurements 
 
Immediate hypersensitivity monitoring 
 
Electrocardiograms (ECGs) 
 
Physical examination findings 
 
Weight assessment 
 
Pregnancy test 
 
Chest X-ray 
 
Evaluation of ADE throughout the entire study duration 
 
3.3 Exploratory Endpoints 
 
PK profiles: 
o 
AUC0-∞: Area under the concentration-time curve in serum from time zero extrapolated to 
infinite time 
o 
AUC0-last: Area under the concentration-time curve from time zero to the last quantifiable 
concentration 
o 
Cmax: Maximum observed serum concentration 
o 
tmax: Time of maximum concentration 
o 
Clast: Last observed quantifiable concentration 
o 
λz: Apparent terminal elimination rate constant 
o 
t1/2: Apparent terminal elimination half-life 
o 
MRT : Mean residence time 
o 
CL : Systemic clearance from serum after IV dosing 
o 
Vz : Apparent volume of distribution during the terminal elimination phase after IV dosing 
 
Immunogenicity analysis: 
o 
Anti-drug specific antibodies and neutralizing antibodies for CT-P27 component antibodies 
(CT-P22 and CT-P23) 
 
HI antibody 
 
Genotype and phenotype of isolated influenza virus 
 
4. 
Randomization, Stratification and Blinding 
Subjects will be randomly assigned to a treatment group after they provide an ICF and meet all the inclusion 
criteria and none of the exclusion criteria by using Interactive Web Response System (IWRS). The 
randomization will be stratified by flu vaccination history within a year (Yes vs No) and participation in PK 
sub-study (Yes vs No). 
This study will be double-blinded. The study blind will not be broken except in a medical emergency (where 
knowledge of the investigational medicinal product administered would affect the treatment of the 
emergency) or regulatory requirement (e.g., for Serious Adverse Event (SAE) or death). If the blind is broken, 
the date, time, and reason must be recorded in the subject’s eCRF and any associated AE report. 
The database will be unblinded to unblind person predefined by the sponsor ■■■■■■. However, the 
study will remain blinded to the investigators and subjects until study termination. 
 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
13/62 page 
 
 
Effective Date: 01-Aug-2018 
 
5. 
General Statistical Considerations 
5.1 General Analysis Considerations 
The statistical analysis will be performed using ■■■■■■) ■■■■■■■■■■■■■■■■■■■■
■■■■. Any deviations from the planned analysis as described in this SAP will be justified and recorded in 
the CSR. 
The data documented and the clinical parameters measured in this study will be described using descriptive 
statistics (including number [n], mean, median, Standard Deviation (SD), minimum, and maximum) for 
continuous variables: minimum and maximum will be presented to the same number of decimal places as 
the raw data, mean and median will be presented to one more decimal place than the raw data, and SD will 
be presented to two more decimal places than the raw data. If the geometric mean is to be presented, it will 
be set to the same precision as the mean. However, geometric mean will not be calculated when minimum 
value from the data is zero. Percent Coefficient of Variation (CV%) will be presented to two decimal places. 
P-values will be rounded to three decimal places. If a p-value is less than 0.001 it will be reported as “<0.001”. 
If a p-value is greater than 0.999 it will be reported as “>0.999”.  
Categorical data will be summarized using count and percentage in each category. Percentages will be 
presented to one decimal place. The percentage will be suppressed when the count is zero in order to draw 
attention to the non-zero counts. “Not done” and “Missing” category will be included to account for cases 
of no assessment and missing respectively even if they are not recorded in eCRF. The denominator for all 
percentages will be the number of subjects within the treatment group for the population of interest, unless 
otherwise indicated. 
All data will be displayed in listings. Unless otherwise specified, listings will be sorted by the treatment group, 
subject number, and assessment date or visit date, if applicable. In cases where more ordering is required, 
other variables will be included in the sort order as applicable. 
Baseline will be the latest available measurement prior to the start of the infusion of study drug.  
When summarizing End-of-Study (EOS) visit, the early termination cases are excluded from the summary for 
EOS visit, but will be presented in data listings. Unscheduled results will not be included in the summary 
tables except for determining baseline or if unscheduled results are necessary to interpret data, but they will 
be presented in data listings. 
 
5.2 Determination of Sample Size 
This study is designed to obtain effect sizes of 2 different CT-P27 treatment groups and placebo group based 
on the time from the administration of study drug to resolution of influenza symptoms and fever. 
For this proof-of-concept dose-ranging study, assuming 90% of subjects are included in the eligible infected 
population, the total eligible sample size of 164 (63 eligible infected subjects per CT-P27 treatment groups 
and 38 subjects in placebo group) achieves 80% power to detect 1.8 days of reduction for the primary 
endpoint of time to resolution with 5% two-sided significance level and SD of 3 days using a Wilcoxon’s rank-
sum test.  
Considering a dropout rate of 10%, this study will need 183 subjects to be enrolled to achieve 164 evaluable 
subjects. 
For an effect size of 1.5 days of reduction in time to resolution with SD of 2.9 days, the total sample size could 
be increased to about 250 to achieve at least 80% statistical power with 5% two-sided significance level. 
 
5.3 Analysis Populations 
ITT and ITTI populations will be analyzed according to the randomized treatment groups and safety and PK 
populations will be analyzed according to the actual treatment groups. 
 
 
Intent-to-Treat (ITT) Population: defined as all subjects randomized to study drug.  
All subjects will be included in the ITT as randomized even if they do not receive treatment, except 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
14/62 page 
 
 
Effective Date: 01-Aug-2018 
 
for the following situation: 
Subjects who are screening failures but are randomized in the IWRS by accident and do not 
receive any study drug will not be included in the ITT population. 
 
Intent-to-Treat Infected (ITTI) Population: defined as all randomized subjects with confirmed 
influenza A by quantitative Polymerase Chain Reaction (qPCR) or cell culture. 
 
Safety Population: defined as all randomized subjects receiving any amount (full or partial dose) of 
study drug, except for the following situation: 
Subjects who do not receive study drug but receive normal saline solution will be included in 
the safety population and they will be analyzed in the placebo group. 
 
PK Population: defined as all randomized subjects with confirmed influenza A by qPCR or cell 
culture who received a complete dose of study drug, with at least one post-dose PK sample.  
If infusion interruptions and/or infusion rate adjustments occur during the drug administration, the subject 
is still considered to have received a complete dose provided that the full calculated dose (45 mg/kg or 90 
mg/kg) has been given at the end of the infusion. 
The analysis populations will be used for the analyses as follows: 
 
ITT Population: 
o 
Demographic and baseline characteristics 
o 
Use of drugs for symptom relief 
o 
Secondary efficacy endpoints 
 
ITTI Population: 
o 
Demographic and baseline characteristics 
o 
Primary efficacy endpoint 
o 
Secondary efficacy endpoints 
o 
Genotype  
o 
Phenotype 
 
Safety Population: 
o 
Viral serology 
o 
Prior and concomitant medications 
o 
Study drug exposure 
o 
Safety endpoints 
o 
Immunogenicity 
 
PK Population: 
o 
Demographic and baseline characteristics 
o 
PK analysis 
o 
HI antibody 
HI antibody, genotype and phenotype will be analyzed in the Follow-Up CSR only.  
 
5.4 External Data Handling 
When combining data from eCRF and that of analytical facilities such as ■■■■■■■■■■■■, 
discrepancy will be handled as follows:  
1) Recorded as collecting sample in eCRF but no corresponding results from analytical facility – listing will 
display only sample collection visit/date/time from eCRF; 
2) No corresponding records in eCRF for results from analytical facility – listing will display only specimen 
collection visit/date and results from analytical facility; 
3) Discrepancy in sample collection date from eCRF and analytical facility – listing will display results from 
analytical facility and visit/date/time from eCRF if not missing; if sample collection date/time is missing in 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
15/62 page 
 
 
Effective Date: 01-Aug-2018 
 
eCRF then use specimen collection visit/date from analytical facility. 
 
6. 
Protocol Deviation 
Subject data will be reviewed for major protocol deviations by a qualified clinical reviewer prior to the blinded 
Data Review Meeting (DRM). In the DRM, all analysis populations will be also reviewed and documented 
prior to unblinding the study. The protocol deviations will be classified as 7 types: 
o 
Inclusion/Exclusion criteria & Consent procedure 
o 
Investigational Product (IP) dosing error, IP usage error 
o 
IP dispensing error 
o 
Use of unauthorized treatment (e.g., prohibited drug, restricted drug) 
o 
Visit window deviation 
o 
Failure to perform required study procedure 
o 
Other 
Protocol deviation listing with classified type and description of deviation will be presented for the ITT 
population. 
 
7. 
Subject Disposition 
The number of subjects who are screened, randomized, and treated with study drug will be summarized in 
the ITT population. Reason of screening failure will be summarized overall and the number of administered 
subjects who have completed or discontinued study will be summarized with reason of discontinuation by 
treatment group and overall. 
A subject will be considered to have been randomized if the subject is allocated to a randomization number 
as recorded on the ‘Randomization Requirements’ page of the eCRF. A subject will be considered to have 
administered treatment in the study if “Yes” was recorded for the question, ‘Was the Study Drug 
Administration performed?’ in ‘Study Drug Administration' page of the eCRF. A subject will be considered to 
have completed the study if “Yes” was recorded for the question, ‘Did the subject complete the study?’ in 
‘End of Study’ page of the eCRF. Likewise, a subject is considered to have discontinued the study if “No” was 
recorded for the same question. A subject will be considered to be ongoing the study if they have been 
randomized and no information has been yet recorded in the ‘End of Study’ page of the eCRF. 
  
8. 
Demographics and Baseline Characteristics 
Demographics and other baseline characteristics recorded at screening visit will be presented in summary 
tables and listings for populations of interest.  
   
8.1 Demographics and Subject Characteristics 
The following continuous variables will be summarized using descriptive statistics by treatment group: 
o 
Age (years) 
o 
Height (cm) 
o 
Weight (kg) 
o 
Body Mass Index, BMI (kg/m2) 
Age will be automatically calculated in the eCRF system based on the date of the informed consent visit and 
the year of birth considering whether birth date has passed the informed consent date or not. BMI will be 
automatically calculated in the eCRF system as: Weight (kg) / [Height (m)]2 using weight and height from 
‘Weight’ and ‘Subject Characteristics’ pages of the eCRF. 
The following categorical variables will be summarized in contingency tables: 
o 
Sex (Male, Female) 
o 
Fertility status (if female – Childbearing potential, Sterility, Menopause) 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
16/62 page 
 
 
Effective Date: 01-Aug-2018 
 
o 
Ethnicity (Hispanic or Latino, not Hispanic or Latino, Not reported, Unknown) 
o 
Race (Caucasian, African, Asian, Other) 
o 
Smoking status (Never smokers, Former smokers, Current smokers, Unknown) 
o 
Flu vaccination history within a year (Yes, No) 
Summary tables will be presented for ITT, ITTI, and PK populations. Also data will be listed for the ITT 
population. 
 
8.2 Clinical Characteristics 
The following continuous variables will be summarized using descriptive statistics by treatment group: 
o 
Duration from onset of illness to study drug administration (hours): [Start date/time of study drug 
administration] – [Date/time of onset of illness] 
o 
Influenza symptoms score at screening: Average scores of respiratory, constitutional, systemic and 
total symptoms 
o 
Body temperature (°C)  at screening 
The following categorical variables will be summarized in contingency tables: 
o 
Influenza subtype (Influenza A/H1, Influenza A/H3, Influenza A/H1 and H3, Unknown, NA) 
o 
Influenza confirmed (by cell culture, qPCR, both, no) 
o 
Rapid kit test results (positive, negative) 
When influenza A virus load from qPCR has quantitative value or less than Lower Limit of Quantification 
(LLoQ), then influenza is confirmed. However, when influenza A virus load from cell culture has only 
quantitative value, then influenza is confirmed by cell culture. 
Summary tables will be presented for ITT, ITTI, and PK populations. Also data will be listed for the ITT 
population. 
 
8.3 Viral Serology 
At screening, the following viral serology assessments will be performed: Hepatitis B Surface Antibody 
(HBsAb), Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus Antibody, Human Immunodeficiency Virus 
(HIV). The results of HBsAb, HBsAg, and Hepatitis C Virus Antibody will be classified as “Negative”, “Gray zone”, 
“Positive” or “Not done” with specification. Also, the results of HIV will be classified as “Negative”, “Positive” 
or “Not done” with specification. A listing and table will be produced for the safety population. 
 
8.4 Medical History 
Medical history is defined as a medical event or condition that will be recorded as part of the subject’s 
medical history if the onset of the event occurs before the ICF is signed.  
Medical history will be summarized by treatment group with number and percentage and displayed by 
System Organ Class (SOC) and Preferred Term (PT). SOCs will be presented in alphabetical order and within 
each SOC, the PTs will also be presented in alphabetical order in the ITT, ITTI and PK populations. Subjects 
that have more than one prevalence per PT within each SOC will be counted only once. Medical history will 
also be listed for the ITT population. 
Medical histories will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.1 
or later, and the version number will be shown as a footnote on the corresponding tables and a listing. 
 
9. 
Treatments and Medications 
9.1 Prior and Concomitant Medications 
Use of all medications (drugs taken from 30 days prior to randomization until Day 110 or EOS visit) will be 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
17/62 page 
 
 
Effective Date: 01-Aug-2018 
 
recorded in the subject’s eCRF.  
A prior medication is defined as any medication with end date prior to the exposure to study drug.  
A concomitant medication is defined as any medication that is ongoing, or has an end date that is on or after 
the date of study drug infusion. The start date of a concomitant medication can be before or after the date 
of first infusion. If the last taken time of medication and study drug infusion are available, then the time will 
be considered with date in determining the prior/concomitant medication. 
If a subject takes specific medication several times within specific period of observation (i.e. prior or 
concomitant), then that medication is only counted once within the period where it is taken. 
Prior and concomitant medications will be summarized by treatment group for safety population with 
number and percentage and displayed by Drug Class (Level 2) and PT. Drug Class will be presented in 
alphabetical order and within each Drug Class, the PTs will also be presented in alphabetical order. At each 
level of subject summarization, a subject is counted only once if a subject reported one or more medication 
at that level. When Anatomical Therapeutic Chemical (ATC) Level 2 for Drug Class is not available, Level 1 will 
be used instead.  
Prior and concomitant medications will be identified in a listing for the ITT and safety population. 
For the purpose of inclusion in prior or concomitant medication tables, incomplete medication start and end 
dates will be imputed as described in Appendix 14.3.1. A listing will display actually recorded (no imputed) 
dates in eCRF.  
Prior and concomitant medications will be coded using the ATC classification of World Health Organization 
Drug Dictionary (WHODD) version September 2017 or later, and the version number will be shown as a 
footnote on the corresponding tables and listings. 
 
9.2 Study Drug Exposure 
Study drug exposure will be summarized by treatment group with number and percentage of the subjects 
who received full dose, partial dose, or are not administered study drug. The planned and administered dose 
(mg) of study drug will be also summarized using descriptive statistics.  
A listing will be provided by treatment group showing the details of study drug exposure including actual 
administered dose for each subject. The actual administered dose will be calculated as Dose (45mg/kg or 
90mg/kg for CT-P27 groups and 90mg/kg for Placebo group)*Weight at screening if a subject was 
administered planned dose. In case, the recorded weight is not correct, the actual administered dose will be 
calculated using weight recorded on the deviation list. This analysis will be performed on the safety 
population. 
 
9.3 Use of Drugs for Symptom Relief 
Drugs for symptom relief will be confirmed based on the recorded medications with “Yes” for the question, 
‘Is this drug used for symptom relief?’ of the ‘Prior and Concomitant Medications’ page of eCRF.  
Drugs for symptom relief will be summarized in a table in a similar manner to the table of concomitant 
medication described in section 9.1 for the ITT population. 
Incomplete start date/time or end date/time of drugs for symptom relief will be imputed as described in 
Appendix 14.3.2. 
 
10. Efficacy Analysis 
10.1 Primary Efficacy Analysis 
The primary efficacy endpoint analysis will assess the time from the administration of study drug to resolution 
of influenza symptoms and fever. The Flu-iiQTM and body temperature recorded in diary including records as 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
18/62 page 
 
 
Effective Date: 01-Aug-2018 
 
a part of suspicious ADE assessment will be used for the analysis. The Flu-iiQ™ is a validated questionnaire 
with four domains. This includes the Domain 1; intensity of influenza symptoms, Domain 2; impact on 
activities, Domain 3; effects on feelings and Domain 4; concerns due to influenza. Subjects are offered four 
choices, ranging from the most positive response (e.g., none or not at all) to the most negative choice (e.g., 
severe or great difficulty). This analysis will be performed on the ITTI population. 
The definitions of resolution of influenza symptoms and fever are described below. 
Resolution of symptoms has occurred if all of the following influenza symptoms (as recorded on the Flu-iiQTM 
of Domain 1) are mild in intensity or none for at least 24 hours. (4-point scale - 0: None, 1: Mild, 2: Moderate, 
3: Severe). 
 
Respiratory symptoms (cough, sore throat, and nasal congestion) 
 
Constitutional symptoms (headache, feeling feverish, body aches and pains, and fatigue) 
Resolution of fever is defined as: 
 
Body temperature (as recorded in the diary) of <37.0°C for at least 24 hours.  
The start time for resolution of influenza symptom and fever is defined as the start time when symptoms and 
fever are resolved, whichever occurred latest.  
The time (in days) from the administration of study drug to resolution of influenza symptoms and fever will 
be calculated as follows: [Start date/time of resolution of influenza symptoms and fever] – [Start date/time 
of study drug administration]. If time of completion of diary for Flu-iiQTM and body temperature is missing 
then the time will be assumed to be 10:00 AM and 10:00 PM for Morning and Evening, respectively. 
If the subject has received the drugs for symptom relief, the effective duration of the drugs for symptom relief 
should be considered in determining the start time for resolution of symptom and fever. 
For example, the study drug was administered at 12:00 on 1st day. The first time body temperature recorded 
<37.0°C  in the diary was 10:00 on 2nd day and continued more than 24 hours. But acetaminophen/ 
paracetamol known to be effective for 6 hours had been administered at 09:00 on 2nd day [1 hour prior to 
the time when the body temperature decreased <37.0°C ], it will be calculated that the start time point for 
body temperature <37.0°C  is 15:00 on 2nd day [27 hours after the study drug administration]. Then, if the 
next time body temperature recorded <37.0°C  in the diary since 15:00 was 22:00 on 2nd day and body 
temperature was <37.0°C  for 24 hours from then, the start time for resolution of fever is 22:00 on 2nd  day 
[34 hours after the study drug administration].  
Drugs for symptom relief will be discussed during blinded DRM (14.5). Only drugs for symptom relief with an 
effective duration overlapping the primary endpoint duration (from a day of resolution start to resolution 
end) will be considered as drugs that affect the result of primary efficacy analysis. Effective durations of each 
drug will be discussed during blinded DRM too.  
The primary efficacy endpoint will be analyzed using a Wilcoxon rank-sum test to assess differences between 
treatment groups (CT-P27 45 mg/kg vs placebo, CT-P27 90 mg/kg vs placebo), if every subject is followed 
until resolution of influenza symptoms and fever. The Wilcoxon rank-sum test will be used to test for a 
statistical significant difference of time to resolution between placebo and CT-P27. The results of the analysis 
will be summarized using p-values. The significant level will be set to 5%. If p-value is lower than 5%, it is 
considered that there is a significant difference between placebo and CT-P27. For subjects who withdrew 
from the study before the symptoms have resolved or if the symptoms did not resolve until the data cut-off, 
data will be censored at the latest date/time recorded on the diary or start date/time of study drug 
administration when there are no recorded data on the diary after study drug administration. If there is any 
censoring, the primary efficacy endpoint will be analyzed using Log-rank test and Gehans Wilcoxon test, and 
the result will be presented by p-values from the two tests. Also the table will present count of censoring 
reasons and 25th percentile, median, 75th percentile of time from administration of study drug to resolution. 
Kaplan-Meier plots will be presented. 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
19/62 page 
 
 
Effective Date: 01-Aug-2018 
 
If there are no censoring data, sensitivity analysis using tipping point analysis under Missing Not at Random 
(MNAR) will be also performed to explain varying cases about average unobserved outcomes dropouts on 
two treatment groups. 
Sensitivity Analyses which alter resolution conditions of primary efficacy analysis will be performed on the 
ITTI population. Following two endpoints will be assessed as described for the primary efficacy endpoint.  
 
Time (in days) to resolution of influenza symptom (respiratory and constitutional symptoms) 
In the analysis, fever is not considered and the definition of resolution of symptom is the same as those of 
primary efficacy analysis.  
 
Time (in days) to resolution of influenza symptom and fever 
In the analysis, threshold of resolution of fever is changed to 37.8°C and the definition o f resolution of 
symptom is the same as those of primary efficacy analysis. 
 
10.2 Secondary Efficacy Analyses 
The secondary efficacy endpoints will be analyzed on the ITTI and ITT populations. For time-to-event analyses 
of secondary efficacy endpoints, records on diary for suspicious ADE assessment and unscheduled 
assessment of site body temperature will be used together with data from regular scheduled assessment. 
 
The following secondary efficacy endpoints will be analyzed using a Kaplan Meier model to assess 
differences between placebo and CT-P27. Missing time of completion of diary will be considered as 
described in the section for the primary efficacy endpoint: 
o 
Time (in days) to resumption of normal activity as reported in Domain 2 of the Flu-iiQTM: [Start 
date/time of resumption of normal activity] – [Start date/time of study drug administration] 
The resumption of normal activity has occurred if the degree of difficulty of all of the Domain 
2 items are of no difficulty or some difficulty for at least 24 hours. 
o 
Time (in days) to return to normal body temperature (<37.0°C) for at least 24 hours : [Start 
date/time of resolution of fever] – [Start date/time of study drug administration] 
Data of body temperature recorded on the diary as well as the ones measured from the sites 
will be used to determine the return time to normal body temperature for at least 24 hours. 
However, assessments which exceeds 24 hours measurement interval will be excluded 
because of lack of consecutiveness in determining the resolution.  
If time of measurement of body temperature from site is missing, then the time will be 
imputed based on time of study drug administration such that missing body temperature 
assessment time on Day 3 will be imputed as: Infusion time + 48 hours. Missing times on other 
days will be imputed in the same manner. 
o 
Time to resolution of individual symptoms for at least 24 hours as reported in Domain 1 of the 
Flu-iiQTM: [Start date/time of resolution of individual influenza symptoms] – [Start date/time 
of study drug administration] 
The resolution of individual influenza symptoms will be determined as described for the 
primary efficacy endpoint. 
 
Severity of symptoms as recorded on the Domain 1 of the Flu-iiQTM 
o 
Impact of influenza symptoms consist of 4 scales of the items in Domain 1 (respiratory 
symptoms, constitutional symptoms, systemic symptoms, total symptoms) 
- 
Respiratory symptoms: cough, sore throat, and nasal congestion 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
20/62 page 
 
 
Effective Date: 01-Aug-2018 
 
- 
Constitutional symptoms: headache, feeling feverish, body aches and pains, and fatigue 
- 
Systemic symptoms: headache, feeling feverish, body aches and pains, fatigue, neck pain, 
interrupted sleep, and loss of appetite 
- 
Total score: all items in Domain 1 
Descriptive statistics of actual value and change from baseline for average score in each scale 
will be presented by treatment group at each visit. 
If there are missing values in items in Domain 1, missing data will be handled according to 
section 10.3.  
o 
Descriptive analysis for AUC of average symptom score from date of baseline assessment to 
last measurable value of subjects who have at least one post-baseline result. 
If there are missing values in average symptom scores between observed ones, the missing 
values are assumed to fall linearly between observed values.  
o 
Mean daily symptom score on the Domain 1 of the Flu- iiQTM  
Average of total symptom score for each time point will be plotted with the SD of mean score.  
o 
Incidence of symptoms on the Domain 1 with Grade 2 or Higher 
The proportion of subjects who developed any of the 7 individual influenza symptoms (cough, 
sore throat, nasal congestion, headache, feeling feverish, body aches and pains, and fatigue 
from Flu-iiQTM Domain 1) with moderately or severe in intensity (Grade 2 or higher) will be 
calculated from baseline to Day 8. Most severe score will be counted per each day. Subjects 
with incomplete data and no recorded symptoms will not be counted (i.e. did not experience 
symptoms Grade 2 or higher). 
All item scores of Flu-iiQTM will be listed by each domain and time point. Additional listing for Flu-
iiQTM will be provided including average score of Domain 1 (respiratory, constitutional, systemic, 
total symptom score), Domain 3, Domain 4 and AUC of Domain 1. 
 
Viral shedding in nasopharyngeal swab samples 
Viral shedding (titers) of swab samples based on qPCR and cell culture will be evaluated at the 
scheduled collection times. The listing will include titer results, whether the influenza A is confirmed 
and Area under the Curve (AUC) of viral loads. However, since cell culture results have information 
of both influenza A and B, the listing and tables for cell culture will present analysis results 
regardless of influenza type. Changes in viral shedding will be assessed as the change from baseline 
in log10vp/mL and log10TCID50/mL for qPCR and cell culture respectively. If viral loads are lower than 
LLoQ (2.18 for qPCR), they will be treated as value without inequality sign. Whereas viral load lower 
than LLoQ for cell culture (0.75) will be considered as negative value and a negative value will be 
treated as 0. If the subtype of influenza A is “H1”, “NA” or “Unknown”, the virus titer from HA assay 
will be used for cell culture analysis. Otherwise, if the subtype is “H3”, the virus titer from NP ELISA 
will be used.  
These will be summarized for each treatment group and collection time.  
The following analyses will also be performed: 
o 
Summary of viral shedding results; percentage of subjects with positive/negative viral 
shedding at each visit (baseline, day 2, 3, 5, 8) 
o 
Duration (in days) of viral shedding; from date/time of baseline assessment to last positive 
sample. Subjects with at least one positive sample after baseline will be included in the 
summary. 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
21/62 page 
 
 
Effective Date: 01-Aug-2018 
 
o 
AUC of viral levels; from date of baseline assessment to last measurable value of subjects who 
have at least one post-baseline result (including BLQ (Below the Limit of Quantification) and 
negative values). If there are BLQ or missing values between measurable values, they are 
assumed to fall linearly between measurable values. 
o 
Change from baseline in descriptive statistics of viral shedding of Swab Samples; descriptive 
statistics of actual value and change from baseline for viral shedding of swab samples will be 
presented by treatment group at each visit. 
o 
Mean viral load titer (log values) 
Mean viral load titer for each scheduled time point will be plotted with the SD of mean value. 
 
Incidence of secondary complications of influenza 
The presence of secondary complications of influenza A infection will be determined by the 
Investigator’s assessment of the subject’s clinical condition. An Adverse Event (AE) will be 
considered as secondary complication if “Yes” is checked for the question, ‘Is this Adverse event 
Secondary Complications of Influenza?’ of the ‘Adverse Event’ page of eCRF. 
The number and percentage of subjects with secondary complications of influenza will be 
summarized by treatment group and PT. Secondary complications of Influenza will be summarized 
by SOC and PT, displaying the number and percentage of subjects with at least one secondary 
complications of Influenza. Secondary complications of influenza A will be listed including following 
variables: SOC, PT and reported term; Start date/time; End date/time; Duration of AE in days; 
Frequency; Outcome; Intensity; Relationship to study drug. 
The number and percentage of subjects with secondary complications of influenza who had used 
or never used antibiotics/antifungal/antiviral will be summarized by treatment group and overall 
for each PT of secondary complication AE. The summary of secondary complication AE will be 
presented in alphabetical order of PTs. The antibiotics/antifungal/antiviral for subjects with 
secondary complications will be discussed at the blind DRM. Algorithms for capture rule of the 
antibiotics/antifungal/antiviral is presented in Appendix 14.4.1 and ATC code list is presented in 
Appendix 14.4.2. 
 
QoL measures as reported in Domain 3 and Domain 4 of the Flu-iiQTM (effect on feelings, concerns 
due to influenza) 
Each item will be scored with a 4-point scale (0: Not at all, 1: Somewhat, 2: Moderately, 3: 
Extremely), and the QoL will be presented as the average score of each domain, and will be 
summarized with descriptive statistics by collection time and treatment group. 
 
Physician Assessment 
Physician assessment including ears, nose, throat, sinuses, lungs, potential complications of 
Influenza will be performed at each scheduled time (Screening, Day 2, Day 3, Day 5, Day 8, Day 
110/EOS). The results will be classified as “Normal”, “Abnormal, NCS”, “Abnormal, CS” or “Not done” 
with specification. The number and percentage of subjects regarding the result of physician 
assessment will be summarized by treatment group and system in the form of a shift table to detect 
changes from baseline in the ITT population. All physician assessment data will be listed for each 
subject by treatment group, visit, system and interpretation in the ITT population. 
 
10.3 Missing Data Handling 
10.3.1 Missing Data Handling for Primary Efficacy Analysis 
When the Flu-iiQTM has missing values (unanswered questions), two different approaches to handle the 
missing data will be taken to evaluate the impact of missing data on the primary efficacy results.  
1) Missing data will not be imputed and only recorded Flu-iiQTM will be used for the analysis.  


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
22/62 page 
 
 
Effective Date: 01-Aug-2018 
 
2) On the other hand, missing data will be replaced by 0 or imputed using multiple imputation when 
at least one score on respiratory or constitutional symptoms in Domain 1 had been recorded.  
Primary efficacy results from two different approaches will be compared to assess impact of missing 
imputation.  
Prior to missing imputation, the number of missing values on a particular scale (respiratory or constitutional 
symptoms in Domain 1) will be considered in determining of way of imputation as follows: 
2-1) If the number of missing items is less than half of the total number of items on a scale, missing 
values will be replaced by 0. 
a. 
Respiratory symptom scale: if one of three items is missing, the other two recorded items will 
be used assuming a missing item has 0 value.   
b. 
Constitutional symptom scale: if one of four items is missing, the other three recorded items 
will be used assuming a missing item has 0 value.  
2-2) If the number of missing items is greater than or equal to half of the total number of items on 
a scale, multiple imputation will be conducted unless there is evidence that missing values would 
have 0 value.  
2-2-1) 
Missing items are replaced by zero: when Flu-iiQTM is not complete, then reason of not 
done recorded in eCRF will be manually reviewed. If subjects had indicated that they 
had ceased to complete the questionnaire because their symptom had disappeared or 
completed the questionnaire only on days when they experienced symptoms, missing 
items since then will be replaced by zero.  
2-2-2) 
Multiple imputation: for any other cases, missing data will be imputed using multiple 
imputation method assuming Missing at Random (MAR). Several imputed datasets 
created by multiple imputations will be pooled. 
Missing body temperature from diary will not be imputed, but when 3 subsequent time points have only 
missing value for middle of the time points and subject data indicates resolution of fever at the other two 
time points, then it can be considered that fever has resolved. The following examples should be used for 
reference: 
a. Example 1: Resolution of fever is considered to be maintained for 24 hours 
Day 1 morning (10NOV16, 9:00 AM) Resolved 
Day 1 evening (10NOV16, 9:00 PM) Missing 
Day 2 morning (11NOV16, 9:00 AM) Resolved 
b. Example 2: Resolution of fever is not considered to be maintained for 24 hours 
Day 1 morning (10NOV16, 9:00 AM) Resolved 
Day 1 evening (10NOV16, 9:00 PM) Missing 
Day 2 morning (11NOV16, 9:00 AM) Missing 
Day 2 evening (11NOV16, 9:00 PM) Resolved  
 
10.3.2 Missing Data Handling for Secondary Efficacy Analyses 
10.3.2.1 Time to Resumption of Normal Activity as Reported in Domain 2 of the Flu-iiQ™ 
If the number of missing items on Domain 2 is less than half of the total number of items on the domain, 
missing values will be replaced by 0 (same rule as 2-1 in section 10.3.1). Otherwise, it cannot be considered 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
23/62 page 
 
 
Effective Date: 01-Aug-2018 
 
that normal activity is resumed. 
 
10.3.2.2 Time to Return to Normal Body Temperature (<37.0℃) for at Least 24 hours 
Missing body temperature from diary or sites will not be imputed. However when there are missing values 
between two time-points with interval 24 hours at which normal body temperature are reported, it can be 
considered that fever is resolved for 24 hours. 
 
10.3.2.3 Time to Resolution of Individual Symptoms for at Least 24 hours as Recorded on the Flu-iiQ™ 
The same rule for missing body temperature described in section 10.3.1 will be applied.   
 
10.3.2.4 Severity of Symptoms as Recorded on the Flu-iiQ™ 
If the number of missing items on each scale of Domain 1 is less than half of the total number of items on 
the scale, only the recorded items are used for the analysis. Otherwise, data of that visit will be excluded 
from the analysis. 
 
10.3.2.5 Quality of Life Measures as Reported in Domain 3 and Domain 4 of the Flu-iiQ™ 
The same rule as described in section 10.3.2.4 will be applied.  
 
11. Exploratory Analysis 
11.1 Pharmacokinetic Analysis 
11.1.1 Serum Concentration 
Blood samples will be collected from each subject during this study for the determination of the PK of CT-
P27 components (CT-P22 and CT-P23) administered as 45 mg/kg and 90 mg/kg. Blood samples for PK analysis 
will be drawn according to the following schedule.  
 
Day of study period 
Time point 
Window 
Day 1 
Pre-infusion 
Within 15 minutes prior to the 
beginning of the infusion 
End of infusion 
+15 minutes 
1 hour after EOI 
± 15 minutes 
Day 2 
24 hours after SOI 
± 4 hours 
Day 3 
48 hours after SOI 
Day 8 
168 hours after SOI 
Day 15 
336 hours after SOI 
± 2 days 
Day 29 
672 hours after SOI 
± 5 days 
Day 57 
1344 hours after SOI 
Day 110 or EOS visit 
2616 hours after SOI or EOS visit 
Abbreviations: EOI, end of infusion; SOI, start of infusion; EOS, end of study 
Serum samples will be analyzed to determine the concentrations of CT-P27 components (CT-P22 and CT-P23) 
using a validated immunoassay. 
Serum concentrations of CT-P27 components (CT-P22 and CT-P23) will be summarized for PK population by 
treatment group at each scheduled collection time using descriptive statistics; n, mean, SD, geometric mean, 
CV%, minimum, median, and maximum values. Mean serum concentration-time profiles of study drug will 
be plotted by treatment on linear and semi-logarithmic scales based on scheduled sample times. Individual 
concentrations, scheduled timepoints/actual sample collection times and deviations from scheduled 
collection times will be presented in data listing by treatment in PK population. Individual linear and semi-
logarithmic concentration-time plots (based on scheduled sample times) with respective treatments will also 
be presented together. Since the placebo group has BLQ values for serum concentration, it will not be 






 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
26/62 page 
 
 
Effective Date: 01-Aug-2018 
 
assay will follow a three-tiered approach consisting of (i) screening assay, (ii) specificity/confirmatory assay, 
and (iii) titration. The test outcome for the screening assay will be: {“Potential Positive” or “Negative”}. 
Samples that are “Potential Positive” in the screening assay will be undergone further testing in the 
specificity/confirmatory assay to determine if subjects are a true positive. The test outcome for the 
specificity/confirmatory assay will be: {“Reactive”, “Negative”, and “Not applicable (N/A)”}. “Reactive” 
indicates a true positive test outcome, “Negative” is considered negative and “N/A” indicates the assay was 
negative at the screening phase of the process. Subjects with a “Negative” test outcome for either screening 
or specificity/confirmatory assays will be considered negative for the overall ADA assessment. For further 
characterization, quantitative antibody level will be assessed by titration in confirmed positive samples. The 
ADA value of the CT-P22 and CT-P23 tagged assay will be transformed using a log transformation. 
Transformed ADA value can be obtained using [log2(X/20)] + 1 transformation. 
Samples that are positive in the assessment will be analyzed further to conduct a NAb assessment. The same 
three-tiered approach of ADA assay will be applied to NAb assay. Transformed NAb value can be obtained 
using [log2(X/10)] + 1 transformation. If ADA or NAb titer values in the data are in inequality forms, the sign 
of inequality will be removed and then the values will be transformed. 
Immunogenicity result for CT-P22 and CT-P23 are listed and summarized separately. The number and 
percentage of subject will be presented by treatment group and test at each scheduled time point for the 
safety population. 
  
11.3 Other Exploratory Analysis 
Blood sampling for assessment of anti-influenza antibodies (Hemagglutination inhibition) will be collected 
on Day 1 (at pre-infusion) and Day 29 (± 5days) or EOS visit (if a subject is early terminated from the study) 
in Subgroup (PK) Cohort. 
Genotypic analysis on Hemagglutinin (HA) and Neuraminidase (NA) genes, and phenotype characterization 
of potential escape variants with regard to CT-P27 will be assessed using the nasopharyngeal swab samples. 
 
11.3.1 HI Antibody  
Individual HI antibody will be assessed repeatedly in each collection time (Baseline, Day 29) and the 
geometric mean value of those duplicated HI antibody results will be used in the analyses. The Geometric 
Mean Titer (GMT) and sample collection times will be presented in data listing by treatment group in PK 
population. 
HI antibody will be summarized using geometric mean, minimum, median, and maximum of GMT values and 
Geometric Mean Fold Rise (GMFR; fold increase in GMT for Day 29 vs Baseline) by actual treatment group 
and each scheduled collection time. Also proportion of subjects with the titer values of Baseline <10 and Day 
29≥40, Baseline>40, Day 29 >40, GMFR≥4, and Baseline≥10 and GMFR≥4 will be summarized. 
The values below the LLoQ (10) will be imputed as 5 and the imputed values will be used for summary table. 
 
11.3.2 Genotype 
Genotype results will be presented in data listing by treatment group and subtype (H1N1 HA, H1N1 NA, H3N2 
HA, H3N2, NA) in ITTI population. 
Screening (influenza A positive sample regardless of titer value) and the last influenza A positive sample in 
time with > 4 log10vp/ml will be analysed. 
 
11.3.3 Phenotype 
Potential CT-P27 resistant variants will be selected by phenotypic virus titration assay. The result of this assay 
will be generated as a separate report. 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
27/62 page 
 
 
Effective Date: 01-Aug-2018 
 
Among potential variants, the samples for CT-P27 susceptibility and neuraminidase enzyme phenotyping 
assay will be selected in accordance with the central laboratory protocol. For potential variants, CT-P27 
susceptibility assay and neuraminidase enzyme phenotyping assay will be performed to determine the half 
maximal effective concentration (EC50) value for CT-P27 and the half maximal inhibitory concentration (IC50) 
value for neuraminidase inhibitor (Oseltamivir), respectively. These values will be used to assess the 
resistance against CT-P27 and neuraminidase inhibitor. The fold resistance change which is the ratio of two 
resistance values will be presented with resistance values in data listing by treatment group in ITTI population. 
If one of values, EC50 or IC50, has the Upper Limit of Quantification (ULoQ) the value will be treated as limit of 
quantification for the calculation of fold resistance change. All of results in the listing will be presented with 
3 decimal places. 
 
12. Safety Analysis 
All safety analyses will be performed in the safety population by actual treatment group presenting data on 
AEs, Clinical laboratory results (Hematology, Biochemistry, Urinalysis), Vital signs, Immediate Hypersensitivity, 
ECG, Physical examination, Weight, Pregnancy test, Chest X-ray, Suspicious ADE.  
 
12.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject enrolled (i.e., when the ICF is signed) 
into this study regardless to its causal relationship to study drug. An AE can, therefore, be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease. 
All AEs will be classified by SOC and PT according to the MedDRA version 20.1 or later and the version number 
will be shown as a footnote on the corresponding tables and listings. AEs will be graded for intensity according 
to the Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 (Appendix 14.2). 
Listings for AEs occurring during the study will be provided by actual treatment received. The listing will 
include the following information from the eCRF: SOC, PT and reported term; Start date/time; End date/time; 
Whether the event is classified as TEAE or TEAE due to Infusion Related/Anaphylactic Reaction (IRR) (Yes, No); 
Duration of AE in days (Duration= [End date-Start date] +1); Frequency (continuous, intermittent, transient, 
other with specified frequency); Outcome (recovered, recovered with sequelae, recovering, not recovered, 
fatal, unknown); Intensity (Grade 1(mild), Grade 2(moderate) Grade 3(severe), Grade 4(life-threatening), 
Grade 5(death)); Relationship to study drug (Definite, Possible, Probable, Unrelated, Not assessable); Action 
taken with study treatment (No action taken, Dose reduce, IP interrupted, IP withdrawn, Other with specified 
action); Other treatment (No treatment, Medication treatment, Non-medication treatment with specified 
treatment, Both medication and non-medication treatment with specified treatment); Whether a subject 
terminated from study due to this AE (Yes, No); Whether the event is serious (Yes, No); Whether the event is 
classified as secondary complication (Yes, No). 
Events will be considered to be related if relationship is definite, possible, probable or not assessable for the 
study drug. 
A summary table of overall AEs will be presented by actual treatment group, including the following: 
 
Total number of AEs, SAEs 
 
Number and percentage of subjects with at least one AE, SAE, TEAE, TESAE, TEAE leading to study 
discontinuation, TEAE due to IRR, TEAE leading to death. 
A SAE is defined as any AE occurring at any dose that results in any of the following outcomes; death, life-
threatening, in subject hospitalization or prolongation of existing hospitalization, disability/incapacity, 
congenital anomaly in the offspring of a subject who received drug, other SAEs; important medical events 
that may not result in death, be life-threatening, or require hospitalization may be considered SAEs when, 
based upon appropriate medical judgment, they may jeopardize the subject or require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
28/62 page 
 
 
Effective Date: 01-Aug-2018 
 
All SAEs will be listed including the variables detailed in the listing for AEs above except whether the event is 
serious (Yes, No). 
Furthermore, additional information of SAEs will be listed in a separate listing including following variables: 
SOC, PT and reported term; Start date/time; End date/time; Whether the event is classified as TEAE or TEAE 
due to IRR; Serious criteria (hospitalization initial, hospitalization prolonged, life-threatening, results in death, 
persistent or significant/incapacity, congenital anomaly or birth defect, other medically important serious 
event); Admission date/Discharge date for hospitalized subjects; Death date; Autopsy performance (Yes, No); 
Death certificate completion (Yes, No) for subjects resulted death; SAE abating after stopping the study drug 
(Yes, No, NA); SAE description; SAE reoccurring after reintroduction of the study drug (Yes, No, NA). 
  
12.1.1 Treatment-Emergent Adverse Event 
A TEAE is defined as 1) a new event that occurs during or after treatment with study drug or 2) any event 
present at baseline that worsens in either intensity or frequency after exposure to study drug. If laboratory 
test abnormalities occur after the start of the administration of study drug, only clinically significant results 
will be considered to be TEAEs. Clinically significant cases are defined in section 6.2.1 of the protocol.  
AEs that are checked “Post Dose” to the question ‘Is this AE occurred before first administration?’ in ‘Adverse 
Event’ page of the eCRF will be considered as TEAEs.  
Total Number of TEAEs will be presented by actual treatment group. The number and percentage of subjects 
with at least one TEAE will be presented in total and by SOC, PT, relationship, intensity, and actual treatment 
group. The summary of TEAEs will be presented in alphabetical order of SOCs. Within each SOC, the PTs will 
also be presented in alphabetical order. At each level of summarization for the number of subjects with an 
event, a subject is counted only once if they reported one or more events and only the worst intensity will 
be counted. The following TEAE summaries will also be reported in separate tables. 
 
TEAEs considered to be related to study drug.  
 
TEAEs for at least 1% of subjects within PT among total treatment group.  
 
TEAEs with the intensity ≥Grade 3. 
TEAEs considered to be related to study drug and TEAEs for at least 1% of subjects will be presented without 
relationship and intensity in summary tables. 
 
12.1.1.1 Treatment-Emergent Adverse Events Leading to Study Discontinuation 
TEAEs that are checked “Yes” to the question ‘Did the adverse event cause the subject to be discontinued 
from the study?’ in the ‘Adverse Event’ page of the eCRF will be considered as TEAEs leading to study 
discontinuation. 
TEAEs leading to study discontinuation will be presented in a table in a similar manner to the tables of TEAEs 
described in section 12.1.1. Also, TEAEs leading to study discontinuation will be listed including the variables 
detailed in section 12.1 except whether a subject terminated from study due to this AE (Yes, No). 
 
12.1.1.2 Treatment-Emergent Adverse Events due to Infusion Related/Anaphylactic Reaction 
TEAEs that are checked “Yes” in ‘Is this Adverse event classified as an infusion related/anaphylactic reaction 
(IRR)?’ in the ‘Adverse Event’ page of the eCRF will be considered for this summary.  
Table of TEAEs due to IRR will be presented in a similar manner to the tables of TEAEs described in section 
12.1.1. TEAEs due to IRR will be listed including the variables detailed in section 12.1 with date/time of Blood 
Pressure (BP) assessment, Systolic Blood Pressure (SBP) (mmHg), Diastolic Blood Pressure (DBP) (mmHg) and 
comments except whether the event is classified as a secondary complication (Yes, No).  
Also signs and symptoms of IRR will be presented in separate table and listing. The number and percentage 
of subjects with TEAE due to IRR and the number of events will be presented by actual treatment group and 
sign and symptom within category. A subject is counted only once if they reported one or more events. The 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
29/62 page 
 
 
Effective Date: 01-Aug-2018 
 
number of events at each level of summarization will be presented as well. Sign and symptom of IRR 
information will be listed including the following information from the eCRF: SOC, PT and reported term; Start 
date/time, End date/time, Category, Signs and Symptoms, and Intensity (Grade 1 (mild), Grade 2 (moderate), 
Grade 3 (severe), Grade 4 (life-threatening), Grade 5 (death)). In case of ‘Other’ in eCRF, specified terms of 
signs and symptoms will be coded according to MedDRA, and SOC and PT will be listed as categories and 
signs and symptoms, respectively, instead of recorded ones in eCRF. Coded categories and symptoms in 
Appendix 14.6 will be confirmed during blind DRM. 
 
12.1.2 Treatment-Emergent Serious Adverse Event 
TESAEs will be presented in a table in a similar manner to the tables of TEAEs described in section 12.1.1.  
 
12.2 Clinical Laboratory Analyses 
Clinical laboratory (hematology, biochemistry, urinalysis) tests will be performed in local laboratories and 
results will be converted to standard units that are defined as in the sections 12.2.1, and 12.2.2.  
Hematology, biochemistry and urinalysis parameters will be labeled with a CTCAE term and grading will be 
applied to post-baseline values for the parameters where possible according to CTCAE v 4.03. When CTCAE 
grade is upon clinical input only, the grading will not be applied, but grade require numeric and partial clinical 
input, grade will be assigned based on the numeric portion only. The CTCAE terms and grades for applicable 
parameters are listed in Appendix 14.2.1. The CTCAE grades for this analysis will be Grade 1 (Mild), Grade 2 
(Moderate), Grade 3 (Severe) and Grade 4 (Life-threatening). The CTCAE Grade 5 (Death) will not be applied 
in this analysis since death cannot be determined from a numeric laboratory result. If the post-baseline result 
for a subject does not satisfy any CTCAE grade, it will be classified as “No Grade”. If a laboratory parameter 
value falls within the local normal range, the grade will be classified as “No grade” even if the value has the 
numeric grade according to CTCAE v 4.03. 
If the laboratory parameter value falls in outside the normal range: ‘low’ or ‘high’, they will be flagged in each 
visit. All hematology, biochemistry and numeric urinalysis data will be listed with high and low flags to show 
if a value is outside the normal range. 
The results for all hematology, biochemistry and categorical urinalysis parameters will be categorized into 
Normal, Abnormal/Not Clinically Significant (NCS) or Abnormal/Clinically Significant (CS) using the local 
laboratory normal ranges used by study site and provided by local laboratory prior to analysis.  
The number and percentage of subjects with a result for each grade will be summarized by CTCAE term, 
CTCAE grade and actual treatment group. The summary includes only the most severe case during the overall 
visits. 
For the purpose of summarization, numeric laboratory parameters with inequality signs (‘<’ or ‘>’) will be 
converted to numeric by removing the inequality sign and keeping only the numeric component of the result 
(e.g., result of ‘<2.6’ would be converted to numeric ‘2.6’). The values which are converted to SI unit will be 
used in the analyses. If the maximum of decimal place for converted parameter is greater than or equal to 3, 
then the result is presented with 3 decimal places in the listing (but Eosinophil result is presented with 4 
decimal places). The decimal places for descriptive statistics are presented based on the presented results in 
the listings. 
 
12.2.1 Hematology 
The following hematology laboratory tests will be included: White blood cells (WBC) (109/L), Red blood cells 
(RBC) (1012/L), Hemoglobin (g/dL), Hematocrit (Proportion of 1.0), Platelet (109/L), Neutrophil (Proportion of 
1.0), Lymphocyte (Proportion of 1.0), Monocyte (Proportion of 1.0), Eosinophil (Proportion of 1.0), Basophil 
(Proportion of 1.0), Absolute Neutrophil Count (ANC) (109/L). In addition, Absolute Lymphocyte Count (ALC) 
(109/L) will be calculated as follows: [WBC (109/L) * Lymphocytes (Proportion of 1.0)]. It will be presented in 
the listing with CTCAE grading and summarized in the CTCAE grading table, but will not be included in the 
hematology summary tables. 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
30/62 page 
 
 
Effective Date: 01-Aug-2018 
 
All hematology parameters will be summarized by parameter and actual treatment group for all scheduled 
collection times (Baseline, Day 3, Day 8) using descriptive statistics. Also, the additional shift table regarding 
the results of normality (Normal, Abnormal/NCS, and Abnormal/CS) will be summarized for all scheduled 
collection visit. All hematology test result data will be listed for each subject by actual treatment group, visit 
and individual test results. 
 
12.2.2 Biochemistry 
The following chemistry laboratory tests will be included: Albumin (g/L), Alkaline phosphatase (U/L), Alanine 
Aminotransferase (ALT) (U/L), Aspartate Aminotransferase (AST) (U/L), Blood Urea Nitrogen (BUN) (mmol/L), 
Chloride (mmol/L), Creatine Kinase (CK) (U/L), CK enzyme subtype (μg/L), Troponin (μg/L), Serum creatinine 
(μmol/L), Creatinine clearance (mL/min), C-reactive protein (nmol/L), Cholesterol (mmol/L), Glucose 
(mmol/L), Lactate Dehydrogenase (LDH) (IU/L), Potassium (mmol/L), Sodium (mmoI/L), Total bilirubin 
(μmol/L), Direct bilirubin (μmol/L), Total protein (g/L), Uric acid (mmol/L), Triglyceride (mmol/L). 
Biochemistry results will be presented in tables and listing in a similar manner to the tables and listing of 
hematology in section 12.2.1. Since relevant assessment for CK enzyme subtype and Troponin are performed 
only when CK result shows a clinical significance, they will not be summarized in visit based summary tables. 
Creatinine Clearance will be calculated using Cockcroft-Gault formula: [(140-Age)*Weight (in kilograms) * 
[0.85 if Female]] / [72*Serum Creatinine (in mg/dL)]. The Weight assessed at screening and calculated age 
using birth date and date of serum creatinine assessed at each visit will be used in the formula. Since the 
creatinine clearance was calculated using value of serum creatinine, additional normality for the creatinine 
clearance is not collected, therefore, the information will not be listed and summarized in a shift table. 
 
12.2.3 Urinalysis 
Numeric urinalysis parameters (pH, specific gravity) will be summarized by descriptive statistics for all 
scheduled collection times (Baseline, Day 3, Day 8). Categorical urinalysis parameters (Ketones, Protein, 
Glucose, Bilirubin, Nitrite, Urobilinogen, Occult Blood, Color) will be summarized in the form of shift table. 
Results of normality (Normal, Abnormal/NCS, and Abnormal/CS) will be summarized for all scheduled 
collection times. 
Numeric and categorical parameters will be listed in separate listings. Both test result will be listed for each 
subject by actual treatment group, visit and individual test results. 
If microscopic examination of sediment performed, the results will be listed. 
 
12.3 Vital Signs 
Vital signs of SBP, DBP, heart rate, respiratory rate, and body temperature will be summarized by actual 
treatment group, at each scheduled collection time (Baseline, Day 2, Day 3, Day 5, Day 8, and Day 110/EOS) 
using descriptive statistics. Changes from baseline will also be summarized by actual treatment group. Vital 
sign parameters with body temperature will be listed for each subject by actual treatment group, visit and 
individual test results. 
 
12.4 Immediate Hypersensitivity 
Vital sign parameters (SBP, DBP, respiratory rate, heart rate), body temperature and ECG measured for 
immediate hypersensitivity on Day 1 will be summarized by treatment group, at each scheduled collection 
time: 
 
Vital sign 
o 
Pre-infusion (within 15 minutes prior to the beginning of the infusion) 
o 
30 minutes (±15 minutes) after the beginning of the infusion 
o 
Within 15 minutes after the end of the infusion 
o 
1 hour (±15 minutes) after the end of the infusion 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
31/62 page 
 
 
Effective Date: 01-Aug-2018 
 
o 
2 hours (±15 minutes) after the end of the infusion 
 
ECG 
o 
1 hour (±15 minutes) after the end of the infusion 
Immediate hypersensitivity findings will be classified as “Normal”, “Abnormal, NCS”, and “Abnormal, CS”. The 
results will be summarized by time point and actual treatment group with the number and percentage of 
subjects in each classification. The number and percentage of subjects who have a clinically notable vital sign 
and body temperature will be presented by actual treatment group, time point and parameter. The criteria 
for clinically notable results are defined as follows: 
Parameter: 
 
SBP (mmHg): Low ≤90, High ≥160 
 
DBP (mmHg): Low ≤50, High ≥90  
 
Respiratory rate (breaths per minute): Low ≤12, High ≥20 
 
Heart rate (beats per minute): Low ≤50, High ≥100 
 
Body temperature (°C): Low ≤35.0, High ≥38.0 
Data collected on monitoring for immediate hypersensitivity; vital sign, body temperature and ECG data will 
be listed by actual treatment group and time point. 
 
12.5 Electrocardiogram 
12-Lead ECG will be performed at screening, on Day 8, and Day 110/EOS. ECG findings will be classified as 
“Normal”, “Abnormal, NCS”, “Abnormal, CS”. The number and percentage of subjects will be summarized by 
actual treatment group and visit, in the form of a shift table to detect changes from baseline. All 12-Lead ECG 
data will be listed for each subject by actual treatment group and visit. 
 
12.6 Physical Examination and Weight 
Physical examination findings will be classified as “Normal”, “Abnormal, NCS”, “Abnormal, CS” or “Not done” 
with specification. The number and percentage of subjects will be provided by actual treatment group and 
body system, in the form of a shift table to detect changes from baseline. The following body systems will be 
examined; 
 
Head 
 
Neck 
 
Ear and Throat 
 
Thorax 
 
Abdomen 
 
Extremities 
 
Neurological System 
 
Skin and Mucosae 
All Physical examination data will be listed for each subject by actual treatment group, visit and body system. 
Weight will be summarized in the form of change from baseline table by actual treatment group, at each 
scheduled collection time (Baseline, Day 110/EOS) using descriptive statistics. Weight will be listed with 
physical examination for each subject by actual treatment group and visit. 
 
12.7 Pregnancy Test 
Females of childbearing potential will have urine pregnancy test performed at screening by a local laboratory 
and will have an additional test for pregnancy at the end of the study (Day 110). If the urine pregnancy test 
gives equivocal results, a serum pregnancy test will be performed prior to study drug administration. Subjects 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
32/62 page 
 
 
Effective Date: 01-Aug-2018 
 
with a positive test result will be excluded from the study.  
Urine pregnancy results will be classified as “Positive”, “Negative” or “Equivocal” and Serum pregnancy 
results will be “Positive” or “Negative”. 
The pregnancy test by urine and serum pregnancy results will be summarized in a table by actual treatment 
group and visit showing the number and percentage of subjects. Percentages are calculated by using the 
number of female of child-bearing potential in the Safety population as the denominator. All pregnancy test 
result will be listed for each subject by actual treatment group, visit and individual test results. 
 
12.8 Chest X-ray 
Chest X-ray assessment will be performed at screening. If symptoms have not relieved up to Day 3, chest X-
ray will be performed to determine presence of secondary complications of influenza A infection. Moreover, 
if the investigator considers chest X-ray is necessary, then it will be performed during the study to evaluate 
the lower respiratory tract. Findings will be classified as “Normal”, “Abnormal, NCS” or “Abnormal, CS”. The 
number and percentage of subjects regarding the result of chest X-ray assessment will be summarized by 
actual treatment group and visit in the form of a shift table to detect changes from baseline.  
All chest X-ray result will be listed for each subject by actual treatment group and visit.  
 
12.9 Suspicious ADE 
Subjects will be considered to possibly have ADE if they meet any of the following criteria: 
 
Symptoms have not resolved or have worsened up to Day 8 after the administration of study drug 
in the opinion of the investigator 
 
The subject develops a secondary influenza-like illness after Day 8 
Subjects with suspicious ADE will be required to assess virus titer using the nasopharyngeal swab sample, 
Flu-iiQTM and body temperature up to Day 8 after the day of ADE occurrence. If symptoms have not resolved 
or have worsened up to Day 8 after the day of ADE occurrence, same procedures will repeat. 
The number and percentage of subjects who meet the criteria for suspicious ADE will be presented by actual 
treatment group. 
Data recorded in ‘Suspicious ADE’ page of eCRF will be listed in listings for Flu-iiQTM, body temperature and 
virus titer of nasopharyngeal swab samples which are collected in scheduled visits. 
 
13. Changes to Protocol-Specified Analysis 
 
The analysis scope for the 1st CSR is extended up to Day 110/EOS for subjects who enrolled in the 
first season to obtain sufficient data. (currently specified in 8.0 section of the protocol, but updated 
in 1.1 section of SAP) 
 
The definition of ITT population is changed to exclude subjects who are screening failures but 
randomized by accident. (currently specified in 8.4.1 section of the protocol, but updated in 5.3 
section of the SAP) 
 
The definition of safety population is changed to include all subjects who receive any amount of 
study drug even if it’s only the normal saline solution but to analyze such subjects as the placebo 
group. (currently specified in 8.4.3 section of the protocol, but updated in 5.3 section of the SAP) 
 
The sensitivity analysis using tipping point analysis will be performed only when there is no 
censoring case. (currently specified in 8.6.1 section of the protocol, but updated in 10.1 section of 
the SAP) 
 
Handling of BLQ values after administration of study drug is updated. (currently specified in 8.5.3 
section of the protocol, but updated in 11.1.1 section of the SAP) 
 
Description of %AUCex is updated according to the European Medicines Agency’s guidance in 
“GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCE”. (CPMP/QWP/EWP/1401/98 Rev. 1) 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
33/62 page 
 
 
Effective Date: 01-Aug-2018 
 
(CHMP 2010). (currently specified in 8.5.3 section of the protocol, but updated in 11.1.2 section of 
the SAP) 
 
Senitivity analyses of primary efficacy analysis are added.  
 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
34/62 page 
 
 
Effective Date: 01-Aug-2018 
 
14. Appendices 
14.1 Schedule of Assessments 
Evaluation 
Screening 1 
Treatment  
Post-Treatment  
Day 1 
Day 2  
Day 3 
Day 5 
Day 8 
Day 15 
(±2 days) 
Day 29 
(±5 days) 
Day 57 
(±5 days) 
Day 110 / EOS 
visit22 
(±5 days) 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
Demographic, medical history, and height 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
 
 
 
 
 
 
 
 
 
Physical examination and weight 
X 
 
 
 
 
 
 
 
 
X 
Hepatitis B/C and HIV tests (local)  
X 2 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (local) 3 
X 4 
 
 
 
 
 
 
 
 
X  
Clinical laboratory analyses 5 (local) 
X 6 
 
 
X  
 
X 
 
 
 
 
Vital Signs (blood pressure, heart rate, respiratory rate) 7 
X 
X 
X 
X 
X 
X 
 
 
 
X 
12-Lead ECG 8 
X 
 
 
 
 
X 
 
 
 
X 
Chest x-ray 9 
X 
 
 
(X)10 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Infusion of CT-P27 or placebo 11 
 
X 
 
 
 
 
 
 
 
 
Blood sampling for PK (only Subgroup [PK] Cohort) 12 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Blood sampling for immunogenicity  
 
X13 
 
 
 
 
 
 
 
X 
Blood sampling for HI antibody (only Subgroup [PK] 
Cohort) 
 
X13 
 
 
 
 
 
X 
 
 
Monitoring for immediate hypersensitivity 14 
 
X 
 
 
 
 
 
 
 
 
Collection of a nasopharyngeal swab 15 
X 
 
X 
X 
X 
X 
 
 
 
 
 
Rapid influenza diagnostic test 16 
x 
 
 
 
 
 
 
 
 
 
 
Virus titer (qPCR and Cell culture) 
x 
 
x 
x 
x 
x 
 
 
 
 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
35/62 page 
 
 
Effective Date: 01-Aug-2018 
 
Evaluation 
Screening 1 
Treatment  
Post-Treatment  
Day 1 
Day 2  
Day 3 
Day 5 
Day 8 
Day 15 
(±2 days) 
Day 29 
(±5 days) 
Day 57 
(±5 days) 
Day 110 / EOS 
visit22 
(±5 days) 
 
The characterization of isolated 
influenza viruses  
x 
 
(x) 
 
 
 
 
Physician assessment 17 
X 
 
X 
X 
X 
X 
 
 
 
X 
Flu-iiQ™ 18 
X 
X 
 
 
 
 
Body Temperature 19 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Concomitant medication 20 
X 
X (continuously throughout the study) 
Adverse events 21 
X 
X (continuously throughout the study) 
ADE=antibody-dependent enhancement; AE=adverse event; ECG=electrocardiogram; eCRF=electronic case report form; EOS=End of Study; Flu-iiQ™=Influenza Intensity and Impact 
Questionnaire; HI=hemagglutination inhibition; HIV=Human immunodeficiency virus; PK=pharmacokinetic 
Note: The assessments designated with an (X) will only be performed in selected subjects under the conditions explained in the footnotes. 
1. 
For most subjects, obtainment of the informed consent form (ICF), screening for eligibility, randomization and treatment will occur on the same day. 
Though obtainment of the ICF may occur on the day prior to screening, randomization or treatment, it must be within 24 hours before the administration 
of study drug.  
2. 
Hepatitis B surface antigen, Hepatitis B surface antibody, Hepatitis C virus antibody, and HIV will be assessed at screening in all subjects (mandatory). The 
results of these tests are not intended as eligibility assessments, but collected to provide baseline information. 
3. 
For females of child-bearing potential only. 
4. 
Urine pregnancy test will be performed at screening. If the urine pregnancy test gives equivocal results, a serum pregnancy test will be performed prior to 
study drug administration. Subjects with a positive test result will be excluded from the study. 
5. 
Clinical laboratory analysis will be performed at screening and on Day 3, Day 8. All clinical laboratory analysis will be performed at the local laboratory. The 
laboratory tests to be performed are presented in Table 3 of CT-P27 2.2 protocol v5.0. 
6. 
Clinical laboratory results will not be used for assessment of eligibility, but to establish baseline values. 
7. 
Vital sign will be performed at screening, Day 1 (prior to infusion), Day 2 (±4 hours), Day 3 (±4 hours), Day 5 (±4 hours), Day 8 (±4 hours) and Day 110 (±5 
days) after the start of the study drug infusion. Blood pressure (sitting) and heart rate will be measured after the subject has rested (sitting quietly) for at 
least 5 minutes. 
8. 
12-Lead ECGs will be performed at screening, on Day 8 (±4 hours), and Day 110 (±5 days) (or EOS visit in early termination case).  


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
36/62 page 
 
 
Effective Date: 01-Aug-2018 
 
9. 
Chest x-rays to evaluate the lower respiratory tract will be performed at screening and if the Investigator considers it is clinically appropriate, chest x-rays to 
evaluate the lower respiratory tract will be performed during the study. 
10. If symptoms have not relieved up to Day 3, chest x-ray will be performed to determine presence of secondary complications of influenza A infection. 
11. Treatment with study drug must occur no more than 48 hours after the onset of symptoms. If the adjustments of visit schedule is required, additional 12 
hours can be allowed (Maximum onset of illness: 60 hours).  
12. PK blood sampling at: 
• Day 1: pre-infusion (within 15 minutes prior to the beginning of study drug infusion), at the end of infusion (within 15 minutes after the end of study 
drug infusion), and 1 hour (±15 minutes) after the end of the study drug infusion. 
• Day 2: 24 hours (±4 hours) after the start of the study drug infusion. 
• Day 3: 48 hours (±4 hours) after the start of the study drug infusion. 
• Day 8: 168 hours (±4 hours) after the start of the study drug infusion. 
• Day 15 (±2 days), Day 29 (±5 days), Day 57 (±5 days), and Day 110 (±5 days)/EOS visit. 
13. Day 1: prior to the study drug infusion. 
14. On Day 1, vital signs (including blood pressure and heart rate, respiratory rate), body temperature and ECG will be assessed at the time points listed below, 
and the subject will be monitored continuously over the period for possible immediate hypersensitivity reactions. 
• Vital sign and body temperature 
o 
Pre-infusion (within 15 minutes prior to the beginning of the infusion). 
o 
30 minutes (±15 minutes) after the beginning of the infusion. 
o 
Within 15 minutes after the end of the infusion. 
o 
2 hour (±15 minutes) after the end of the infusion. 
• Vital sign, body temperature and ECG 
o 
1 hour (vital sign, body temperature: ±15 minutes, ECG: −30/+60 minutes) after the end of the infusion. 
Emergency drugs and equipment suitable for assistance during anaphylactic reactions will be available during infusion with study drug. 
15. When collecting the nasopharyngeal swabs, nasopharyngeal swabbing will be performed by trained site personnel. A nasopharyngeal swab sample will be 
obtained from all subjects up to Day 8 on the following schedule:  
 Screening (Nasopharyngeal swab samples will be collected for two times to be used for rapid influenza diagnostic test and virology assessment.) 
 Day 2: 24 hours (±4 hours) after the start of the study drug infusion. 
 Day 3: 48 hours (±4 hours) after the start of the study drug infusion. 
 Day 5: 96 hours (±4 hours) after the start of the study drug infusion. 
 Day 8: 168 hours (±4 hours) after the start of the study drug infusion. 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
37/62 page 
 
 
Effective Date: 01-Aug-2018 
 
16. Sponsor-supplied or agreed in advance rapid influenza diagnostic test material will be used. And if there is available test result confirmed as influenza A 
prior to obtaining written informed consent and that result was from the influenza diagnostic test which is agreed with Sponsor in advance, that test result 
can be allowed. At screening, testing must be performed within 24 hours before study drug administration. Subjects with a negative test result by rapid 
diagnostic test, who have onset of symptoms within 48 hours (window of +12 hours is allowed) before study drug administration, can be rescreened only 
once. 
17. The Investigator or designee will perform a symptom-directed physical examination (which should include, at a minimum, the examination of ear, nose, 
throat, sinuses, and lungs) and assessment for potential complications of influenza. 
18. The subject will record the results of the Flu-iiQTM in the diary. 
 Flu-iiQTM will be recorded once by the subject at the screening visit and will be recorded twice a day (at approximately 12-hour intervals) from Day 1 to 
Day 8 (in the morning [between 6 and 10 AM, approximately] and in the evening [between 6 and 10 PM, approximately]). 
19. Body temperature which a subject experiences in prior to screening will be collected and body temperature taken with any type of thermometer will be 
acceptable. However, from the screening period, Sponsor-supplied thermometer will be used. 
 Temperature will be measured by subject; It will be recorded twice a day (at approximately 12-hour intervals) from Day 1 to Day 8 (in the morning 
[between 6 and 10 AM, approximately] and in the evening [between 6 and 10 PM, approximately]). 
 Temperature will be measured by site personnel at site: at screening, Day 1 (prior to infusion), Day 2 (±4 hours), Day 3 (±4 hours), Day 5 (±4 hours) and 
Day 8 (±4 hours). 
 These will be used for assessment of endpoint.  
20. Use of all medications, from 30 days prior to randomization and up until Day 110/EOS visit, will be recorded in the subject’s eCRF. 
21. AEs will be collected from the date the informed consent form is signed until Day 110/EOS visit. 
22. EOS visit will be done at Day 110. But if a subject is early terminated from the study, EOS visit will be done to assess safety parameters at any time. 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
38/62 page 
 
 
Effective Date: 01-Aug-2018 
 
Schedule of Assessments (Unscheduled Visits Subjects with Suspicious ADE) 
Evaluation 
Suspicious ADE Assessment 
Day of occurrence1 
Day 2  
Day 3 
Day 5 
Day 8 5 
Collection of a nasopharyngeal swab 
X 
X 
X 
X 
X 
 
Virus titer (qPCR and Cell 
culture) 2 
x 
x 
x 
x 
x 
 
The characterization of 
isolated influenza viruses  
x 
(x) 
Flu-iiQTM3 
X 
Body Temperature4 
X 
1. 
The day of suspicious ADE occurrence. 
 Symptoms have not resolved or have worsened up to Day 8 (168 hours) after the administration of study drug in the opinion of the Investigator. 
 The subject develops a secondary influenza-like illness after Day 8 (168 hours). 
2. 
Nasopharyngeal swab will be collected once a day up to Day 8 on the following schedule:  
• 
Day of occurrence 
• 
Day 2: 24 hours (±4 hours) 
• 
Day 3: 48 hours (±4 hours) 
• 
Day 5: 96 hours (±4 hours) 
• 
Day 8: 168 hours (±4 hours) 
3. 
Flu-iiQ™ and the body temperature in the diary twice a day up to Day 8 (168 hours) from Day 1 to Day 8 (in the morning [between 6 and 10 AM, 
approximately] and in the evening [between 6 and 10 PM, approximately]). 
4. 
Body temperature will be assessed by Sponsor-supplied thermometer. 
5. 
If symptoms have not resolved or have worsened up to Day 8 after the day of ADE occurrence, same procedure will repeat. 
 
 
 
 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
39/62 page 
 
 
Effective Date: 01-Aug-2018 
 
14.2 CTCAE Grades 
Grade 1 
Mild; asymptomatic or mild symptoms; 
clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental Activities of Daily Living (ADL1) 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL2 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated. 
Grade 5 
Death related to AE. 
Note: Activities of Daily Living (ADL) 
1. Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
2. Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
40/62 page 
 
 
Effective Date: 01-Aug-2018 
 
14.2.1 Laboratory Grades 
CTCAE Term 
Laboratory Parameter 
 
Level 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Anemia 
Hemoglobin  
Low 
<LLN - 10.0 g/dL 
<10.0 - 8.0 g/dL 
<8.0 g/dL 
- 
Alanine 
aminotransferase 
increased 
Alanine 
Aminotransferase 
(ALT) 
High 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Alkaline phosphatase 
increased 
Alkaline phosphatase 
High 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Aspartate 
aminotransferase 
increased 
Aspartate 
Aminotransferase 
(AST) 
High 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Blood bilirubin 
increased 
Total Bilirubin 
High 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
Cholesterol high 
Cholesterol 
High 
 >ULN - 7.75 
mmol/L 
>7.75 - 10.34 mmol/L 
>10.34 - 12.92 mmol/L 
>12.92 mmol/L 
CPK increased 
Creatine 
Phosphokinase (CPK) 
High 
>ULN - 2.5 x ULN 
>2.5 x ULN - 5 x ULN 
>5 x ULN - 10 x ULN 
>10 x ULN 
Creatinine increased 
Creatinine 
High 
>1 - 1.5 x baseline; 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x baseline; 
>1.5 - 3.0 x ULN 
>3.0 baseline; 
>3.0 - 6.0 x ULN 
>6.0 x ULN 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
41/62 page 
 
 
Effective Date: 01-Aug-2018 
 
CTCAE Term 
Laboratory Parameter 
 
Level 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
increased 
Hemoglobin 
High 
Increase in >0 - 2 
gm/dL above ULN 
or above baseline if 
baseline is above 
ULN 
Increase in >2 - 4 
gm/dL above ULN or 
above baseline if 
baseline is above 
ULN 
Increase in >4 gm/dL 
above ULN or above 
baseline if baseline is 
above ULN 
- 
Hyperglycemia 
Glucose 
High 
Fasting glucose 
value >ULN - 8.9 
mmol/L 
Fasting glucose value 
>8.9 - 13.9 mmol/L 
>13.9 - 27.8 mmol/L; 
>27.8 mmol/L; 
Hyperkalemia 
Potassium 
High 
>ULN - 5.5 mmol/L 
>5.5 - 6.0 mmol/L 
>6.0 - 7.0 mmol/L 
>7.0 mmol/L 
Hypernatremia 
Sodium 
High 
>ULN - 150 mmol/L 
>150 - 155 mmol/L 
>155 - 160 mmol/L; 
>160 mmol/L 
Hypertriglyceridemia 
Triglyceride 
High 
1.71 mmol/L - 3.42 
mmol/L 
>3.42 mmol/L - 5.7 
mmol/L 
>5.7 mmol/L - 11.4 
mmol/L 
>11.4 mmol/L; 
Hyperuricemia 
Uric acid 
High 
>ULN - 10 mg/dL 
(0.59 mmol/L) 
- 
- 
>0.59 mmol/L; 
Hypoalbuminemia 
Albumin 
Low 
<LLN - 30 g/L 
<30 - 20 g/L 
<20 g/L; 
- 
Hypoglycemia 
Glucose 
Low 
<LLN - 3.0 mmol/L 
<3.0 - 2.2 mmol/L 
<2.2 - 1.7 mmol/L 
<1.7 mmol/L 
Hypokalemia 
Potassium 
Low 
<LLN - 3.0 mmol/L 
- 
<3.0 - 2.5 mmol/L 
<2.5 mmol/L 
Hyponatremia 
Sodium 
Low 
<LLN - 130 mmol/L 
- 
<130 - 120 mmol/L 
<120 mmol/L 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
42/62 page 
 
 
Effective Date: 01-Aug-2018 
 
CTCAE Term 
Laboratory Parameter 
 
Level 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Leukocytosis 
White blood cell (WBC) 
High 
- 
- 
>100,000/mm3 ; 
(>100x10e9 /L) 
- 
Lymphocyte count 
decreased 
Lymphocyte 
Low 
<LLN - 800/mm3; 
<LLN - 0.8 x 10e9 /L 
<800 - 500/mm3; 
<0.8 - 0.5 x 10e9 /L 
<500 - 200/mm3; 
 <0.5 - 0.2 x 10e9 /L 
<200/mm3;  
<0.2 x 10e9 /L 
Lymphocyte count 
increased 
Lymphocyte 
High 
- 
>4000/mm3 - 
20,000/mm3; 
(>4 - 20x10e9 /L) 
>20,000/mm3; 
(>20x10e9 /L) 
- 
Neutrophil count 
decreased 
Absolute Neutrophil 
Count (ANC) 
Low 
<LLN - 1.5 x 10e9 /L 
<1.5 - 1.0 x 10e9 /L 
<1.0 - 0.5 x 10e9 /L 
<0.5 x 10e9 /L 
Platelet count 
decreased 
Platelet  
Low 
<LLN - 75.0 x 10e9 /L 
<75.0 - 50.0 x 10e9 /L 
<50.0 - 25.0 x 10e9 /L 
<25.0 x 10e9 /L 
Proteinuria 
Protein 
High 
1+ proteinuria; 
urinary protein 
Adults: 2+ 
proteinuria 
- 
- 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
43/62 page 
 
 
Effective Date: 01-Aug-2018 
 
CTCAE Term 
Laboratory Parameter 
 
Level 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
White blood cell 
decreased 
White blood cell (WBC) 
Low 
<LLN - 3.0 x 10e9 /L 
<3.0 - 2.0 x 10e9 /L 
<2.0 - 1.0 x 10e9 /L 
<1.0 x 10e9 /L 
Note: LLN= Lower Limit of Normal, ULN= Upper Limit of Normal 
[1] Hyperglycemia was graded according to CTCAE which includes fasting glucose value although blood sample was taken regardless of fasting state. 
[2] If suggested unit for CTCAE grading is not applicable to SI unit, it was converted to SI unit and applied. 
[3] In case of numeric value for grading is identical such as Hypokalemia and Hyperuricemia, CTCAE grade which include numeric value only was applied, because 
abnormal laboratory value with clinical input was reported as an adverse event and graded accordingly.


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
44/62 page 
 
 
Effective Date: 01-Aug-2018 
 
 
14.3 Date Imputation 
14.3.1 Prior and Concomitant Medication 
Prior and concomitant medications will be coded using the WHO Drug Dictionary version Sep2017 or later. 
For the purpose of inclusion in prior and/or concomitant medication tables, incomplete medication start and 
end dates will be imputed as follows: 
If the start date is incomplete, the following rules will be applied: 
 
If the day is missing (e.g. XXFEB2017), the month and year of the partial date will be compared to 
the date of illness onset. 
o 
If the month and the year are equal for both dates, the start date will be imputed as the earlier 
date of: (i) the date of illness onset, or (ii) the recorded end date of the medication. If the 
recorded end date is missing, the start date will be imputed as the date of illness onset. 
o 
If the month or year is not equal for both dates, the start date will be imputed as the first day 
of the month (e.g. 01FEB2017). 
 
If the day and month are missing (e.g. XXXXX2017), the year of the partial date will be compared 
to the date of illness onset. 
o 
If the years are equal for both dates, the start date will be imputed as the earlier date of: (i) 
the date of illness onset, or (ii) the recorded end date of the medication. If the recorded end 
date is missing, the start date will be imputed as the date of illness onset. 
o 
If the years are not equal for both dates, the start date will be imputed as the first day of 
January of the year (e.g. 01JAN2017). 
If the end date is incomplete the following rules will be applied: 
 
If the day is missing (e.g. XXFEB2017), the month and year of the partial date will be compared to 
the date of End of Study (EOS). 
o 
If the month and the year are equal for both dates, the end date will be imputed as the later 
date of: (i) EOS, or (ii) the recorded/imputed start date of the medication. 
o 
If the month or year is not equal for both dates, the end date will be imputed as the last day 
of the month (e.g. 28FEB2017). 
 
If the day and month are missing (e.g. XXXXX2017), the year of the partial date will be compared 
to the date of End of Study (EOS). 
o 
If the years are equal for both dates, the end date will be imputed as the later date of: (i) EOS, 
or (ii) the recorded/imputed start date of the medication. 
o 
If the years are not equal for both dates, the end date will be imputed as the last day of the 
year (e.g. 31DEC2017). 
 
In the case of the death of a subject, if the imputed end date is after the date of death, the end 
date will be imputed as the date of death. 
For the missing day imputation, the following examples should be used for reference: 
 
Example 1: 
Medication start: UNJUN2017 
Medication end: 20OCT2017 
Date of illness onset: 16OCT2017 
Medication start imputed: 01JUN2017 
 
Example 2: 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
45/62 page 
 
 
Effective Date: 01-Aug-2018 
 
Medication start: UNOCT2017 
Medication end: 20OCT2017 
Date of illness onset: 16OCT2017 
Medication start imputed: 16OCT2017 
 
Example 3: 
Medication start: UNOCT2017 
Medication end: 20OCT2017 
Date of illness onset: 24OCT2017 
Medication start imputed: 20OCT2017 
 
14.3.2 Symptom Relief Medication 
The start date imputation will follow the same rules applied for the prior and concomitant start dates. 
The end date imputation will also follow the same rules applied for the prior and concomitant end dates, 
except that the partial dates will be compared to the dates of Day 8 instead of EOS. For subjects with 
suspicious ADE, the same rules will be applied, but last date of suspicious ADE assessment will be used instead 
of Day 8. 
To determine the start time for resolution of symptom and fever in primary efficacy analysis, incomplete first 
and last taken time of symptom relief drug will be imputed as follows: 
 
Route 
Frequency 
Time of first taken 
Time of last taken 
Oral 
Respiratory(Inhalation) 
Intramuscular 
Ophthalmic 
Once, Daily 
08:00 
08:00 
BID 
08:00 
20:00 
TID 
08:00 
20:00 
Intravenous 
Once, Daily 
08:00 
23:59 
BID 
08:00 
23:59 
TID 
08:00 
23:59 
※ If a symptom relief drug was administered once intravenously and single dose is 2g then missing last taken 
time will be imputed as the first taken time. 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
46/62 page 
 
 
Effective Date: 01-Aug-2018 
 
14.4 Use of Antibiotics/Antifungal/Antiviral for Subjects with Secondary Complications 
14.4.1 Algorithm for Capture Rule for Antibiotics/Antifungal/Antiviral 
For summary of antibiotics (including antifungal and antiviral) use for subjects with secondary complication 
of influenza A infection, 4 steps are applied as follows: 
Step 1. Capture the secondary complications. 
Step 2. Capture medication use. 
In the ‘Adverse Event’ page of the eCRF, “Medication treatment” or “Both medication and non-medication 
Treatment, specify” is selected for the question, ‘Other Treatment’.  
Step 3. Capture the medication related with secondary complications. 
Medication start date recorded in the ‘Prior and Concomitant Medications’ page of the eCRF is between AE 
start and end date. (AE Start Date ≤ Medication Start Date ≤ AE End date)  
Plus, indication of medication is the same as the term of AE.  
Step 4. Capture the antibiotics/antifungal/antiviral. 
The ATC codes listed in the Appendix 14.4.2 will be used to capture the antibiotics/antifungal/antiviral. 
 
14.4.2 ATC Code List for Antibiotics/Antifungal/Antiviral 
Following ATC Codes (WHODD version September 2017) list for antibiotics will be confirmed at the blind DRM.  
 
Level 2 
WHODD code (Level 4) 
J01 Bacterials for systemic use 
J01AA Tetracyclines 
J01 Bacterials for systemic use 
J01BA Amphenicols 
J01 Bacterials for systemic use 
J01CA Penicillins with extended spectrum 
J01 Bacterials for systemic use 
J01CE Beta-lactamase sensitive penicillins 
J01 Bacterials for systemic use 
J01CF Beta-lactamase resistant penicillins 
J01 Bacterials for systemic use 
J01CG Beta-lactamase inhibitors 
J01 Bacterials for systemic use 
J01CR Combinations of penicillins, inc. beta-lactamase inhibitors 
J01 Bacterials for systemic use 
J01DB First-generation cephalosporins 
J01 Bacterials for systemic use 
J01DC Second-generation cephalosporins 
J01 Bacterials for systemic use 
J01DD Third-generation cephalosporins 
J01 Bacterials for systemic use 
J01DE Fourth-generation cephalosporins 
J01 Bacterials for systemic use 
J01DF Monobactams 
J01 Bacterials for systemic use 
J01DH Carbapenems 
J01 Bacterials for systemic use 
J01DI Other cephalosporins and penems 
J01 Bacterials for systemic use 
J01EA Trimethoprim and derivatives 
J01 Bacterials for systemic use 
J01EB Short-acting sulfonamides 
J01 Bacterials for systemic use 
J01EC Intermediate-acting sulfonamides 
J01 Bacterials for systemic use 
J01ED Long-acting sulfonamides 
J01 Bacterials for systemic use 
J01EE Combinations of sulfonamides and trimethoprim, incl. 
derivatives 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
47/62 page 
 
 
Effective Date: 01-Aug-2018 
 
J01 Bacterials for systemic use 
J01FA Macrolides 
J01 Bacterials for systemic use 
J01FF Lincosamides 
J01 Bacterials for systemic use 
J01FG Streptogramins 
J01 Bacterials for systemic use 
J01GA Streptomycins 
J01 Bacterials for systemic use 
J01GB Other aminoglycosides 
J01 Bacterials for systemic use 
J01MA Fluoroquinolones 
J01 Bacterials for systemic use 
J01MB Other quinolones 
J01 Bacterials for systemic use 
J01RA Combinations of antibacterials 
J01 Bacterials for systemic use 
J01WA Herbal antibacterials for systemic use 
J01 Bacterials for systemic use 
J01WB Herbal urinary antiseptics and antiinfectives 
J01 Bacterials for systemic use 
J01XA Glycopeptide antibacterials 
J01 Bacterials for systemic use 
J01XB Polymyxins 
J01 Bacterials for systemic use 
J01XC Steroid antibacterials 
J01 Bacterials for systemic use 
J01XD Imidazole derivatives 
J01 Bacterials for systemic use 
J01XE Nitrofuran derivatives 
J01 Bacterials for systemic use 
J01XX Other antibacterials 
J02 Antimycotics for systemic use 
J02AA Antibiotics 
J02 Antimycotics for systemic use 
J02AB Imidazole derivatives 
J02 Antimycotics for systemic use 
J02AC Triazole derivatives 
J02 Antimycotics for systemic use 
J02AW Herbal antimycotics for systemic use 
J02 Antimycotics for systemic use 
J02AX Other antimycotics for systemic use 
J04 Antimycobactierals 
J04AB Antibiotics 
J05 Antivirals for systemic use 
J05AA Thiosemicarbazones 
J05 Antivirals for systemic use 
J05AB Nucleosides and nucleotides excl. reverse transcriptase 
inhibitors 
J05 Antivirals for systemic use 
J05AC Cyclic amines 
J05 Antivirals for systemic use 
J05AD Phosphonic acid derivatives 
J05 Antivirals for systemic use 
J05AE Protease inhibitors 
J05 Antivirals for systemic use 
J05AF Nucleoside and nucleotide reverse transcriptase inhibitors 
J05 Antivirals for systemic use 
J05AG Non-nucleoside reverse transcriptase inhibitors 
J05 Antivirals for systemic use 
J05AH Neuraminidase inhibitors 
J05 Antivirals for systemic use 
J05AR Antivirals for treatment of HIV infections, combinations 
J05 Antivirals for systemic use 
J05AX Other antivirals 
J05 Antivirals for systemic use 
J05WA Herbal antivirals for systemic use 
N04 Anti-parkinson drugs 
N04BB Adamantane derivatives 
R02 Throat preparations 
R02AB Antibiotics 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
48/62 page 
 
 
Effective Date: 01-Aug-2018 
 
S02 Otologicals 
S02AA Antiinfectives 
S02 Otologicals 
S02AW Herbal antiinfectives 
S02 Otologicals 
S02CA Corticosteroids and antiinfectives in combination 
S03 Ophthalmological and otological 
preparations 
S03AA Antiinfectives 
S03 Ophthalmological and otological 
preparations 
S03CA Corticosteroids and antiinfectives in combination 
 
14.5 Drugs for Symptom Relief and Effective Duration 
Drug (PT) 
Effective Duration (Hours) 
ACETYLCYSTEINE 
12 
ACTIFED /00005601/ 
12 
BENZYDAMINE HYDROCHLORIDE 
12 
CEFDITOREN PIVOXIL 
8 
CEFRADINE 
12 
CHLORPHENAMINE 
6 
CHLORPHENAMINE MALEATE 
6 
CODENA-S 
8 
DESLORATADINE 
24 
DEXIBUPROFEN 
12 
DICLOFENAC 
24 
ELECTROLYTES NOS W/GLUCOSE 
0 
ERDOSTEINE 
12 
FLUOROMETHOLONE ACETATE 
6 
FLUTICASONE FUROATE 
24 
GLUCOSE 
0 
LEVOCETIRIZINE 
DIHYDROCHLORIDE 
32 
LEVODROPROPIZINE 
6 
LEVOFLOXACIN 
8 
MONTELUKAST 
24 
PARACETAMOL 
6  ( Single dose : 100 mg, 300 mg, 500 mg, 1000 mg) 
8  (Single dose : 650 mg, 1300 mg) 
PETHIDINE 
8 
PHENIRAMINE 
24 
PREDNISOLONE 
24 
PROPACETAMOL HYDROCHLORIDE 
12 
PSEUDOEPHEDRINE 
12 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
49/62 page 
 
 
Effective Date: 01-Aug-2018 
 
HYDROCHLORIDE 
SODIUM CHLORIDE 
0 
THEOBROMINE 
12 
TRAMADOL 
6 
TRAMADOL HYDROCHLORIDE 
6 
TROPHAMINE /02659801/ 
0 
ZIPEPROL DIHYDROCHLORIDE 
12 
 
14.6 Coding of Categories and Signs and Symptoms for TEAEs due to IRR 
The following table includes the mapping for re-coding of category “Other” based on MedDRA ver 20.1. 
 
Previous Category 
Previous Sign and 
Symptom 
New Category 
New Sign and Symptom 
Other 
Diarrhea 
Gastrointestinal disorders 
Diarrhoea 
Other 
Hiccup 
Respiratory, 
thoracic 
and 
mediastinal disorders 
Hiccups 
 
 
 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
50/62 page 
 
 
Effective Date: 01-Aug-2018 
 
14.7 List of Tables, Listings, Figures 
 
List of Tables 
Table 
Number 
Population 
Table Description 
Source Listing 
14.1.1 
ITT 
Summary of Analysis Populations 
Listing 16.2.1.1 Analysis Population 
14.1.2 
ITT 
Summary of Subject Disposition 
Listing 16.2.1.2 Screening Failure,  
Listing 16.2.4.1 Subject Disposition,  
Listing 16.2.1.3 End of Study 
14.1.3.1 
ITT 
Summary of Demographics and Subject Characteristics 
Listing 16.2.4.2 Demographic and Subject 
Characteristics 
14.1.3.2 
ITTI 
Summary of Demographics and Subject Characteristics 
Listing 16.2.4.2 Demographic and Subject 
Characteristics 
14.1.3.3 
PK 
Summary of Demographics and Subject Characteristics 
Listing 16.2.4.2 Demographic and Subject 
Characteristics 
14.1.4.1 
ITT 
Summary of Clinical Characteristics 
Listing 16.2.4.3 Clinical Characteristics, 
Listing 16.2.6.1.1 Flu-iiQ: Average score 
and AUC 
14.1.4.2 
ITTI 
Summary of Clinical Characteristics 
Listing 16.2.4.3 Clinical Characteristics, 
Listing 16.2.6.1.1 Flu-iiQ: Average score 
and AUC 
14.1.4.3 
PK 
Summary of Clinical Characteristics 
Listing 16.2.4.3 Clinical Characteristics, 
Listing 16.2.6.1.1 Flu-iiQ: Average score 
and AUC 
14.1.5 
Safety 
Summary of Hepatitis B/C and HIV Test 
Listing 16.2.4.5 Hepatitis B/C and HIV Test 
14.1.6.1 
ITT  
Summary of Medical History 
Listing 16.2.4.6 Medical History 
14.1.6.2 
ITTI 
Summary of Medical History 
Listing 16.2.4.6 Medical History 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
51/62 page 
 
 
Effective Date: 01-Aug-2018 
 
14.1.6.3 
PK 
Summary of Medical History 
Listing 16.2.4.6 Medical History 
14.1.7 
Safety 
Summary of Prior Medications 
Listing 16.2.4.8.2 Prior and Concomitant 
Medications 
14.1.8 
Safety 
Summary of Concomitant Medications 
Listing 16.2.4.8.2 Prior and Concomitant 
Medications 
14.1.9 
Safety 
Summary of Study Drug Exposure 
Listing 16.2.5.1 Study Drug Administration 
14.1.10 
ITT 
Use of Drugs for Symptom Relief 
Listing 16.2.4.8.1 Prior and Concomitant 
Medications 
14.2.1.1 
ITTI 
Summary of Time to Resolution of Influenza Symptom and Fever - Wilcoxon 
Rank-Sum Test 
Listing 16.2.5.1 Study Drug Administration, 
Listing 16.2.6.1 Flu-iiQ, Listing 16.2.6.2 
Body Temperature from Diary 
14.2.1.2 
ITTI 
Summary of Time to Resolution of Influenza Symptom and Fever - Wilcoxon 
Rank-Sum Test (Imputation) 
Listing 16.2.5.1 Study Drug Administration, 
Listing 16.2.6.1 Flu-iiQ, Listing 16.2.6.2 
Body Temperature from Diary 
14.2.1.1 
ITTI 
Summary of Time to Resolution of Influenza Symptom and Fever  
Listing 16.2.1.3 End of Study, Listing 
16.2.5.1 Study Drug Administration, Listing 
16.2.6.1 Flu-iiQ, Listing 16.2.6.2 Body 
Temperature from Diary 
14.2.1.2 
ITTI 
Summary of Time to Resolution of Influenza Symptom and Fever (Imputation) 
Listing 16.2.1.3 End of Study, Listing 
16.2.5.1 Study Drug Administration, Listing 
16.2.6.1 Flu-iiQ, Listing 16.2.6.2 Body 
Temperature from Diary 
14.2.1.3 
ITTI 
Summary of Time to Resolution of Influenza Symptom and Fever - Sensitivity 
Analysis (Tipping Point Analysis) 
Listing 16.2.5.1 Study Drug Administration, 
Listing 16.2.6.1 Flu-iiQ, Listing 16.2.6.2 
Body Temperature from Diary 
14.2.1.4 
ITTI 
Summary of Time to Resolution of Influenza Symptom - Sensitivity Analysis 
Listing 16.2.1.3 End of Study, Listing 
16.2.5.1 Study Drug Administration, Listing 
16.2.6.1 Flu-iiQ 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
52/62 page 
 
 
Effective Date: 01-Aug-2018 
 
14.2.1.5 
ITTI 
Summary of Time to Resolution of Influenza Symptom and Fever (<37.8℃) - 
Sensitivity Analysis 
Listing 16.2.1.3 End of Study, Listing 
16.2.5.1 Study Drug Administration, Listing 
16.2.6.1 Flu-iiQ, Listing 16.2.6.2 Body 
Temperature from Diary 
14.2.2.1 
ITT 
Summary of Time to Resumption of Normal Activity - Kaplan-Meier Model 
Listing 16.2.1.3 End of Study, Listing 
16.2.5.1 Study Drug Administration, Listing 
16.2.6.1 Flu-iiQ 
14.2.2.2 
ITTI 
Summary of Time to Resumption of Normal Activity - Kaplan-Meier Model 
Listing 16.2.1.3 End of Study, Listing 
16.2.5.1 Study Drug Administration, Listing 
16.2.6.1 Flu-iiQ 
14.2.3.1 
ITT 
Summary of Time to Resolution of Fever - Kaplan-Meier Model  
Listing 16.2.1.3 End of Study, Listing 
16.2.5.1 Study Drug Administration, Listing 
16.2.6.2 Body Temperature from Diary, 
Listing 16.2.9.1 Vital Signs and Body 
Temperature 
14.2.3.2 
ITTI 
Summary of Time to Resolution of Fever - Kaplan-Meier Model 
Listing 16.2.1.3 End of Study, Listing 
16.2.5.1 Study Drug Administration, Listing 
16.2.6.2 Body Temperature from Diary, 
Listing 16.2.9.1 Vital Signs and Body 
Temperature 
14.2.4.1 
ITT 
Summary of Time to Resolution of Individual Influenza Symptom - Kaplan-
Meier Model 
Listing 16.2.1.3 End of Study, Listing 
16.2.5.1 Study Drug Administration, Listing 
16.2.6.1 Flu-iiQ 
14.2.4.2 
ITTI 
Summary of Time to Resolution of Individual Influenza Symptom - Kaplan-
Meier Model 
Listing 16.2.1.3 End of Study, Listing 
16.2.5.1 Study Drug Administration, Listing 
16.2.6.1 Flu-iiQ 
14.2.5.1 
ITT 
Change from Baseline in Descriptive Statistics of Influenza Symptoms (Flu-iiQ 
Domain 1) - Respiratory Symptoms 
Listing 16.2.6.1.1 Flu-iiQ : Average Score 
and AUC 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
53/62 page 
 
 
Effective Date: 01-Aug-2018 
 
14.2.5.2 
ITTI 
Change from Baseline in Descriptive Statistics of Influenza Symptoms (Flu-iiQ 
Domain 1) - Respiratory Symptoms 
Listing 16.2.6.1.1 Flu-iiQ: Average Score 
and AUC 
14.2.6.1 
ITT 
Change from Baseline in Descriptive Statistics of Influenza Symptoms (Flu-iiQ 
Domain 1) - Constitutional Symptoms 
Listing 16.2.6.1.1 Flu-iiQ: Average Score 
and AUC 
14.2.6.2 
ITTI 
Change from Baseline in Descriptive Statistics of Influenza Symptoms (Flu-iiQ 
Domain 1) - Constitutional Symptoms 
Listing 16.2.6.1.1 Flu-iiQ: Average Score 
and AUC 
14.2.7.1 
ITT 
Change from Baseline in Descriptive Statistics of Influenza Symptoms (Flu-iiQ 
Domain 1) - Systemic Symptoms 
Listing 16.2.6.1.1 Flu-iiQ: Average Score 
and AUC 
14.2.7.2 
ITTI 
Change from Baseline in Descriptive Statistics of Influenza Symptoms (Flu-iiQ 
Domain 1) - Systemic Symptoms 
Listing 16.2.6.1.1 Flu-iiQ: Average Score 
and AUC 
14.2.8.1 
ITT 
Change from Baseline in Descriptive Statistics of Influenza Symptoms (Flu-iiQ 
Domain 1) - Total 
Listing 16.2.6.1.1 Flu-iiQ: Average Score 
and AUC 
14.2.8.2 
ITTI 
Change from Baseline in Descriptive Statistics of Influenza Symptoms (Flu-iiQ 
Domain 1) - Total 
Listing 16.2.6.1.1 Flu-iiQ: Average Score 
and AUC 
14.2.9.1 
ITT 
Descriptive Statistics for AUC of Symptom Score 
Listing 16.2.6.1.1 Flu-iiQ : Average Score 
and AUC 
14.2.9.2 
ITTI 
Descriptive Statistics for AUC of Symptom Score 
Listing 16.2.6.1.1 Flu-iiQ : Average Score 
and AUC 
14.2.10.1.1 
ITT 
Summary of Viral Shedding Results from qPCR 
Listing 16.2.6.3.1 Virus Titer Results from 
qPCR 
14.2.10.1.2 
ITTI 
Summary of Viral Shedding Results from qPCR 
Listing 16.2.6.3.1 Virus Titer Results from 
qPCR 
14.2.10.2.1 
ITT 
Summary of Viral Shedding Results from Cell Culture 
Listing 16.2.6.3.2 Virus Titer Results from 
Cell Culture 
14.2.10.2.2 
ITTI 
Summary of Viral Shedding Results from Cell Culture 
Listing 16.2.6.3.2 Virus Titer Results from 
Cell Culture 
14.2.11.1.1 
ITT 
Descriptive Statistics of Duration of Viral Sheddings from qPCR 
Listing 16.2.6.3.1 Virus Titer Results from 
qPCR 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
54/62 page 
 
 
Effective Date: 01-Aug-2018 
 
14.2.11.1.2 
ITTI 
Descriptive Statistics of Duration of Viral Sheddings from qPCR 
Listing 16.2.6.3.1 Virus Titer Results from 
qPCR 
14.2.11.2.1 
ITT 
Descriptive Statistics of Duration of Viral Sheddings from Cell Culture 
Listing 16.2.6.3.2 Virus Titer Results from 
Cell Culture 
14.2.11.2.2 
ITTI 
Descriptive Statistics of Duration of Viral Sheddings from Cell Culture 
Listing 16.2.6.3.2 Virus Titer Results from 
Cell Culture 
14.2.12.1.1 
ITT 
Descriptive Statistics of AUC of Viral Loads from qPCR 
Listing 16.2.6.3.1 Virus Titer Results from 
qPCR 
14.2.12.1.2 
ITTI 
Descriptive Statistics of AUC of Viral Loads from qPCR 
Listing 16.2.6.3.1 Virus Titer Results from 
qPCR 
14.2.12.2.1 
ITT 
Descriptive Statistics of AUC of Viral Loads from Cell Culture 
Listing 16.2.6.3.2 Virus Titer Results from 
Cell Culture 
14.2.12.2.2 
ITTI 
Descriptive Statistics of AUC of Viral Loads from Cell Culture 
Listing 16.2.6.3.2 Virus Titer Results from 
Cell Culture 
14.2.13.1.1 
ITT 
Change from Baseline in Descriptive Statistics of Viral Sheddings of Swab 
Samples from qPCR 
Listing 16.2.6.3.1 Virus Titer Results from 
qPCR 
14.2.13.1.2 
ITTI 
Change from Baseline in Descriptive Statistics of Viral Sheddings of Swab 
Samples from qPCR 
Listing 16.2.6.3.1 Virus Titer Results from 
qPCR 
14.2.13.2.1 
ITT 
Change from Baseline in Descriptive Statistics of Viral Sheddings of Swab 
Samples from Cell Culture 
Listing 16.2.6.3.2 Virus Titer Results from 
Cell Culture 
14.2.13.2.2 
ITTI 
Change from Baseline in Descriptive Statistics of Viral Sheddings of Swab 
Samples from Cell Culture 
Listing 16.2.6.3.2 Virus Titer Results from 
Cell Culture 
14.2.14.1 
ITT 
Summary of Presence of Secondary Complications of Influenza A 
Listing 16.2.6.4 Secondary Complications 
of Influenza A 
14.2.14.2 
ITTI 
Summary of Presence of Secondary Complications of Influenza A 
Listing 16.2.6.4 Secondary Complications 
of Influenza A 
14.2.15.1 
ITT 
Use of Antibiotics for Subjects with Secondary Complications 
Listing 16.2.4.8.1 Prior and Concomitant 
Medications, Listing 16.2.6.4 Secondary 
Complication of Influenza A 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
55/62 page 
 
 
Effective Date: 01-Aug-2018 
 
14.2.15.2 
ITTI 
Use of Antibiotics for Subjects with Secondary Complications 
Listing 16.2.4.8.1 Prior and Concomitant 
Medications, Listing 16.2.6.4 Secondary 
Complication of Influenza A 
14.2.16.1 
ITT 
Change from Baseline in Descriptive Statistics of Effect on Feelings (Flu-iiQ 
Domain 3) - Total 
Listing 16.2.6.1.1 Flu-iiQ: Average Score 
and AUC 
14.2.16.2 
ITTI 
Change from Baseline in Descriptive Statistics of Effect on Feelings (Flu-iiQ 
Domain 3) - Total 
Listing 16.2.6.1.1 Flu-iiQ: Average Score 
and AUC 
14.2.17.1 
ITT 
Change from Baseline in Descriptive Statistics of Concerns due to Influenza 
(Flu-iiQ Domain 4) - Total 
Listing 16.2.6.1.1 Flu-iiQ: Average Score 
and AUC 
14.2.17.2 
ITTI 
Change from Baseline in Descriptive Statistics of Concerns due to Influenza 
(Flu-iiQ Domain 4) - Total 
Listing 16.2.6.1.1 Flu-iiQ: Average Score 
and AUC 
14.2.18 
ITT 
Shift Table of Physician Assessment 
Listing 16.2.6.5 Physician Assessment 
14.2.19.1 
PK 
Descriptive Statistics of Serum Concentration (μg /mL) of CT-P22 
Listing 16.2.6.6.1 Individual Serum 
Concentration (μg /mL) of CT-P22 
14.2.19.2 
PK 
Descriptive Statistics of Serum Concentration (μg /mL) of CT-P23 
Listing 16.2.6.6.2 Individual Serum 
Concentration (μg /mL) of CT-P23 
14.2.20.1 
PK 
Descriptive Statistics of Pharmacokinetic Parameters of CT-P22 
Listing 16.2.6.7.1 Individual 
Pharmacokinetic Parameters of CT-P22 
14.2.20.2 
PK 
Descriptive Statistics of Pharmacokinetic Parameters of CT-P23 
Listing 16.2.6.7.2 Individual 
Pharmacokinetic Parameters of CT-P23 
14.2.21.1 
PK 
Statistical Analysis to Assess Dose Proportionality of CT-P22 
Listing 16.2.6.7.1 Individual 
Pharmacokinetic Parameters of CT-P22 
14.2.21.2 
PK 
Statistical Analysis to Assess Dose Proportionality of CT-P23 
Listing 16.2.6.7.2 Individual 
Pharmacokinetic Parameters of CT-P23 
14.2.22 
Safety 
Summary of Immunogenicity Results 
Listing 16.2.6.8.1 Immunogenicity Testing 
of CT-P22, Listing 16.2.6.8.2 
Immunogenicity Testing of CT-P23 
14.2.23 
PK 
Summary of HI Response Results 
Listing 16.2.4.3 Clinical Characteristics, 
Listing 16.2.6.9 Individual HI Antibody 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
56/62 page 
 
 
Effective Date: 01-Aug-2018 
 
14.3.1.1 
Safety 
Summary of Overall Adverse Events 
Listing 16.2.7.1 Adverse Events 
14.3.1.2 
Safety 
Summary of Treatment-Emergent Adverse Events 
Listing 16.2.7.1 Adverse Events 
14.3.1.3 
Safety 
Summary of Related Treatment-Emergent Adverse Events 
Listing 16.2.7.1 Adverse Events 
14.3.1.4 
Safety 
Summary of Treatment-Emergent Adverse Events for at least 1% of Subjects 
Listing 16.2.7.1 Adverse Events 
14.3.1.5 
Safety 
Summary of Treatment-Emergent Adverse Events with the Intensity ≥Grade 3 
Listing 16.2.7.1 Adverse Events 
14.3.1.6 
Safety 
Summary of Treatment-Emergent Adverse Events Leading to Study 
Discontinuation 
Listing 14.3.2.3 TEAE Leading to Study 
Discontinuation 
14.3.1.7 
Safety 
Summary of Treatment-Emergent Adverse Events due to Infusion 
Related/Anaphylactic Reactions 
Listing 14.3.2.4 TEAE due to Infusion 
Related/Anaphylactic Reactions 
14.3.1.8 
Safety 
Summary of Treatment-Emergent Adverse Events due to Infusion 
Related/Anaphylactic Reactions (Signs & Symptoms) 
Listing 14.3.2.5 TEAE due to Infusion 
Related/Anaphylactic Reactions: 
Additional Information (Signs & 
Symptoms) 
14.3.2.1 
Safety 
Summary of Treatment-Emergent Serious Adverse Events 
Listing 14.3.2.1 Serious Adverse Events 
14.3.4.1 
Safety 
Summary of CTCAE grading 
Listing 16.2.8.1 Hematology, Listing 
16.2.8.2 Biochemistry, Listing 16.2.8.4 
Urinalysis - Categorical Parameters 
14.3.4.2 
Safety 
Change from Baseline in Descriptive Statistics of Hematology 
Listing 16.2.8.1 Hematology 
14.3.4.3 
Safety 
Shift Table of Hematology Results 
Listing 16.2.8.1 Hematology 
14.3.4.4 
Safety 
Change from Baseline in Descriptive Statistics of Biochemistry 
Listing 16.2.8.2 Biochemistry 
14.3.4.5 
Safety 
Shift Table of Biochemistry Results 
Listing 16.2.8.2 Biochemistry 
14.3.4.6 
Safety 
Change from Baseline in Descriptive Statistics of Urinalysis 
Listing 16.2.8.3 Urinalysis - Numeric 
Parameters 
14.3.4.7 
Safety 
Shift Table of Urinalysis Results 
Listing 16.2.8.4 Urinalysis - Categorical 
Parameters 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
57/62 page 
 
 
Effective Date: 01-Aug-2018 
 
14.3.5.1 
Safety 
Change from Baseline in Descriptive Statistics of Vital Signs and Body 
Temperature 
Listing 16.2.9.1 Vital Signs and Body 
Temperature 
14.3.5.2 
Safety 
Summary of Immediate Hypersensitivity Monitoring Interpretation 
Listing 16.2.9.2 Immediate 
Hypersensitivity - Vital Signs and Body 
Temperature, Listing 16.2.9.3 Immediate 
Hypersensitivity - Electrocardiograms 
14.3.5.3 
Safety 
Summary of Clinically Notable Vital Signs and Body Temperature Results during 
Hypersensitivity Monitoring 
Listing 16.2.9.2 Immediate 
Hypersensitivity - Vital Signs and Body 
Temperature 
14.3.5.4 
Safety 
Shift Table of Electrocardiogram Findings 
Listing 16.2.9.4 12-Lead 
Electrocardiograms 
14.3.5.5 
Safety 
Shift Table of Physical Examination Findings 
Listing 16.2.9.5 Physical Examination and 
Weight 
14.3.5.6 
Safety  
Change from Baseline in Descriptive Statistics of Weight 
Listing 16.2.9.5 Physical Examination and 
Weight 
14.3.5.7 
Safety 
Summary of Pregnancy Test Results 
Listing 16.2.9.6 Pregnancy Test 
14.3.5.8 
Safety 
Shift Table of Chest X-ray 
Listing 16.2.9.7 Chest X-ray 
14.3.6 
Safety 
Summary of Suspicious Antibody-Dependent Enhancement 
Listing 16.2.6.1 Flu-iiQ, Listing 16.2.6.2 
Body Temperature from Diary, Listing 
16.2.6.3.1 Virus Titer Results from qPCR, 
Listing 16.2.6.3.2 Virus Titer Results from 
Cell Culture 
 
 
List of Data Listings 
Listing Number 
Population 
Listing Description 
16.2.1.1 
ITT 
Analysis Population  


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
58/62 page 
 
 
Effective Date: 01-Aug-2018 
 
16.2.1.2 
All subjects 
Screening Failure  
16.2.1.3 
ITT 
End of Study 
16.2.2.1 
ITT 
Major Protocol Deviation 
16.2.4.1 
ITT 
Subject Disposition  
16.2.4.2 
ITT 
Demographic and Subject Characteristics  
16.2.4.3 
ITT 
Clinical Characteristics 
16.2.4.4 
ITT 
Rapid Influenza Diagnostic Test of Nasopharyngeal Swab Samples 
16.2.4.5 
Safety 
Hepatitis B/C and HIV Test 
16.2.4.6 
ITT 
Medical History  
16.2.4.7 
ITT 
Inclusion/Exclusion Criteria 
16.2.4.8.1 
ITT 
Prior and Concomitant Medications 
16.2.4.8.2 
Safety 
Prior and Concomitant Medications 
16.2.5.1 
Safety 
Study Drug Administration 
16.2.6.1 
ITT 
Flu-iiQ 
16.2.6.1.1 
ITT 
Flu-iiQ: Average Score and AUC 
16.2.6.2 
ITT 
Body Temperature from Diary 
16.2.6.3.1 
ITT 
Virus Titer Results from qPCR 
16.2.6.3.2 
ITT 
Virus Titer Results from Cell Culture 
16.2.6.4 
ITT 
Secondary Complication of Influenza A 
16.2.6.5 
ITT 
Physician Assessment 
16.2.6.6.1 
PK 
Individual Serum Concentration (μg /mL) of CT-P22 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
59/62 page 
 
 
Effective Date: 01-Aug-2018 
 
16.2.6.6.2 
PK 
Individual Serum Concentration (μg /mL) of CT-P23 
16.2.6.7.1 
PK 
Individual Pharmacokinetic Parameters of CT-P22 
16.2.6.7.2 
PK 
Individual Pharmacokinetic Parameters of CT-P23 
16.2.6.8.1 
Safety 
Immunogenicity Testing of CT-P22 
16.2.6.8.2 
Safety 
Immunogenicity Testing of CT-P23 
16.2.6.9 
PK 
Individual HI Antibody 
16.2.6.10.1 
ITTI 
Genotype - H1N1 Hemagglutinin (HA) 
16.2.6.10.2 
ITTI 
Genotype - H1N1 Neuraminidase (NA) 
16.2.6.10.3 
ITTI 
Genotype - H3N2 Hemagglutinin (HA) 
16.2.6.10.4 
ITTI 
Genotype - H3N2 Neuraminidase (NA) 
16.2.6.11.1 
ITTI 
Phenotype - CT-P27 Susceptibility 
16.2.6.11.2 
ITTI 
Phenotype - Oseltamivir 
16.2.7.1 
Safety 
Adverse Events  
14.3.2.1 
Safety 
Serious Adverse Events 
14.3.2.2 
Safety 
Serious Adverse Events: Additional Information  
14.3.2.3 
Safety 
TEAE Leading to Study Discontinuation 
14.3.2.4 
Safety 
TEAE due to Infusion Related/Anaphylactic Reactions  
14.3.2.5 
Safety 
TEAE due to Infusion Related/Anaphylactic Reactions: Additional Information (Signs & Symptoms) 
16.2.8.1 
Safety 
Hematology  
16.2.8.2 
Safety 
Biochemistry  
16.2.8.3 
Safety 
Urinalysis - Numeric Parameters 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
60/62 page 
 
 
Effective Date: 01-Aug-2018 
 
16.2.8.4 
Safety 
Urinalysis - Categorical Parameters 
16.2.8.5 
Safety 
Urinalysis - Microscopic Examination 
16.2.9.1 
Safety 
Vital Signs and Body Temperature 
16.2.9.2 
Safety 
Immediate Hypersensitivity - Vital Signs and Body Temperature 
16.2.9.3 
Safety 
Immediate Hypersensitivity - Electrocardiograms 
16.2.9.4 
Safety 
12-Lead Electrocardiograms 
16.2.9.5 
Safety 
Physical Examination and Weight 
16.2.9.6 
Safety 
Pregnancy Test 
16.2.9.7 
Safety 
Chest X-ray 
16.2.10.1 
ITT 
General Comments 
 
 
List of Figures 
Figure Number 
Population Figure Description 
Source Listing 
14.2.1 
ITTI 
Summary of Time to Resolution of Influenza Symptom and Fever (Kaplan-Meier 
Plot) 
Listing 16.2.5.1 Study Drug 
Administration, Listing 16.2.6.1 Flu-iiQ, 
Listing 16.2.6.2 Body Temperature from 
Diary  
14.2.8.1.1 
ITT 
Mean (+/-SD) Daily Total Symptoms Score 
Listing 16.2.6.1.1 Flu-iiQ: Average Score 
and AUC 
14.2.8.1.2 
ITTI 
Mean (+/-SD) Daily Total Symptoms Score 
Listing 16.2.6.1.1 Flu-iiQ: Average Score 
and AUC 
14.2.8.2.1 
ITT 
Incidence of Symptoms Grade 2 or Higher from Baseline to Day 8 
Listing 16.2.6.1 Flu-iiQ  
14.2.8.2.2 
ITTI 
Incidence of Symptoms Grade 2 or Higher from Baseline to Day 8 
Listing 16.2.6.1 Flu-iiQ 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
61/62 page 
 
 
Effective Date: 01-Aug-2018 
 
14.2.13.1.1 
ITT 
Mean (+/-SD) Viral Load Titer (log values) from qPCR 
Listing 16.2.6.3.1 Virus Titer Results 
from qPCR 
14.2.13.1.2 
ITTI 
Mean (+/-SD) Viral Load Titer (log values) from qPCR 
Listing 16.2.6.3.1 Virus Titer Results 
from qPCR 
14.2.13.2.1 
ITT 
Mean (+/-SD) Viral Load Titre (log values) from Cell Culture 
Listing 16.2.6.3.2 Virus Titer Results 
from Cell Culture 
14.2.13.2.2 
ITTI 
Mean (+/-SD) Viral Load Titre (log values) from Cell Culture 
Listing 16.2.6.3.2 Virus Titer Results 
from Cell Culture 
14.2.18.1 
PK 
Mean (+/-SD) Serum Concentrations-Time Profiles of CT-P22 
Listing 16.2.6.6.1 Individual Serum 
Concentration (μg/mL) of CT-P22  
14.2.18.2 
PK 
Mean (+/-SD) Serum Concentrations-Time Profiles of CT-P23 
Listing 16.2.6.6.2 Individual Serum 
Concentration (μg /mL) of CT-P23  
14.2.19.1 
PK 
Individual Serum Concentration-Time Profiles of CT-P22 
Listing 16.2.6.6.1 Individual Serum 
Concentration (μg /mL) of CT-P22  
14.2.19.2 
PK 
Individual Serum Concentration-Time Profiles of CT-P23 
Listing 16.2.6.6.2 Individual Serum 
Concentration (μg /mL) of CT-P23  
14.2.20.1 
PK 
Plot of Log-Transformed Cmax and AUC0-last (for CT-P22) versus Log-Transformed 
Dose 
Listing 16.2.6.7.1 Individual 
Pharmacokinetic Parameters of CT-P22 
14.2.21.1 
PK 
Plot of Log-Transformed Cmax and AUC0-last (for CT-P23) versus Log-Transformed 
Dose 
Listing 16.2.6.7.2 Individual 
Pharmacokinetic Parameters of CT-P23 
 
 
 


 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
■■■■■■ 
Statistical Analysis Plan 
62/62 page 
 
 
Effective Date: 01-Aug-2018 
 
15. Role & Responsibilities 
Role 
Name 
Responsibilities 
Biostatistician 
■■■■■■ 
Responsible for conducting statistical analysis and managing all the 
relevant tasks 
QC Biostatistician 
■■■■■■ 
Responsible for reviewing the statistical analysis results conducted by the 
Project Biostatistician 
 
16. Applied SOPs 
SOP No. 
SOP Version_Effective date 
SOP Name 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
 
 
17. Applied SDs 
SD No. 
SD Version_Effective date 
SD Name 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■ 
■■■■■■