Clinical trial NCT03083990
Conditions: Healthy
Sponsor: Innovent Biologics (Suzhou) Co. Ltd.
Start date: 2017-03-09; Completion date: 2017-08-17
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To confirm the PK similarity of IBI305 and bevacizumab in healthy volunteers .

Detailed description:

Arms: arm 1: IBI 305 ,3mg/kg, infusion in 90 minutes arm 2: Bevacizumab (Avastin) 3mg/kg, infusion in 90 minutes
Interventions: intervention 1: IBI305(Bevacizumab Biosimilar) intervention 2: Avastin(Bevacizumab)
Intervention descriptions: intervention 1: 3mg/kg, infusion in 90minutes intervention 2: 3mg/kg, infusion in 90minutes

Protocol documents:
Prot_000.pdf: 
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Product Name: IBI305
Protocol Number: CIBI305A201
Version: v 1.0
Version Date: Aug. 3, 2016
Clinical Trial Approval Number: 2016L04809
Protocol Title: A RANDOMIZED, DOUBLE-BLIND, CONTROLLED
SINGLE-DOSE PHASE I CLINICAL STUDY OF IBI305 VERSUS
BEVACIZUMAB TO ASSESS PHARMACOKINETICS, SAFETY,
TOLERABILITY, AND IMMUNOGENICITY IN HEALTHY MALE
SUBJECTS
Protocol Number: CIBI305A201
Version: v 1.0
Version Date: Aug. 3, 2016
Sponsor: Innovent Biologics (Suzhou) Co., Ltd.
Study Center: Phase I Clinical Trial Laboratory, The First Hospital of Jilin University
Principal Investigator (PI): Ding Yanhua
NCT Number：NCT03083990
CONFIDENTIALITY STATEMENT
This document contains confidential and propriety information of Innovent Biologics (Suzhou) Co., Ltd., only for
purpose of review by the investigators of this clinical trial, the Ethics Committee, CRO, regulatory authorities, and
relevant medical institutions. Disclosure of confidential information, whether in oral, written or electronic form, to
any third party unrelated to this trial without the prior written consent of Innovent Biologics (Suzhou) Co., Ltd., is
strictly prohibited. Unless required by applicable laws or regulations, confidential information may not be disclosed.
In any case, all recipients of this dossier shall be informed of such requirement for confidentiality and these
individuals may no longer disclose such information. Likewise, this restriction on disclosure applies to all the


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Product Name: IBI305
Protocol Number: CIBI305A201
Version: v 1.0
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documents to be provided in future and indicated to be confidential in nature.


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Product Name: IBI305
Protocol Number: CIBI305A201
Version: v 1.0
Version Date: Aug. 3, 2016
PROTOCOL SIGNATURE PAGE
I hereby agree to
•
endeavor to conduct this study in strict accordance with this protocol, Good Clinical
Practice (GCP), and applicable laws and regulations.
•
keep all data information provided by the sponsor pursuant to the requirement for
confidentiality, and that such information has to be indicated to be confidential before being
submitted to the Ethics Committee.
I have read this protocol and agree all the information therein.
Sponsor’s Medical Director: Zhou Hui
Sponsor: Innovent Biologics (Suzhou) Co., Ltd.
Signature:
Date:
Principal Investigator: Ding Yanhua
Institution: The First Hospital of Jilin University
Signature:
Date:
Sponsor's Statistician: Wei Zhaohui
Organization: Innovent Biologics (Suzhou) Co., Ltd.
Signature:
Date:


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Product Name: IBI305
Protocol Number: CIBI305A201
Version: v 1.0
Version Date: Aug. 3, 2016
Sponsor
Company name
Innovent Biologics (Suzhou) Co., Ltd.
Study Director
Zhou Hui
Address
No. 168 Dongping Street, Suzhou Industrial Park,
Suzhou, Jiangsu, China
Postal Code
215123
Tel.
021-31652896
Mobile Phone
18036091799
Fax
021-31652800
E-mail
hui.zhou@innoventbio.com
Principal Investigator
Institution
The First Hospital of Jilin University
Study Director
Ding Yanhua
Address
No. 71 Xinmin Street, Chaoyang District,
Changchun, Jilin, China
Postal Code
130000
Tel.
0431-88782168
Mobile Phone
18186879768
Fax
0431-88786098
E-mail
dingyanhua2003@126.com
CRO
Company name
WuXi Clinical Development Services (Shanghai) Co., Ltd.
Study Director
Wang Xiaojun
Address
19th Floor, Building A, SOHO Fuxing
Plaza, No. 388 Madang Road., Shanghai,
China
Postal
Code
200025
Tel.
021-23158000
Mobile
Phone
18224048444
Fax
021-53061029
E-mail
wang_xiaojun0701@wuxiapptec.com


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Product Name: IBI305
Protocol Number: CIBI305A201
Version: v 1.0
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Statistician
Company name
WuXi Clinical Development Services (Shanghai) Co., Ltd.
Study Director
Luo Zhaoyu
Address
19th Floor, Building A, SOHO Fuxing Plaza, No.
388 Madang Road., Huangpu District, Shanghai,
China
Postal Code
200025
Tel.
021-23158097
Fax
021-53061029
E-mail
shelly_luo@wuxiapptec.com
Bioanalysis (anti-drug antibody assay)
Company
name
Wuxi AppTec (Shanghai) Co., Ltd.
Study Director
Xiong Wengang
Address
No. 288 Fute Zhong Road, Waigaoqiao Free
Trade Zone, Shanghai, China
Postal
Code
200131
Tel.
021-50465059
Mobile Phone
13801894720
Fax
021-50461000
E-mail
xiong_wengang@wuxiapptec. com
Bioanalysis (PK assay and NAb assay)
Company name
United-Power Pharma Tech Co., Ltd.
Study Director
Dong Lihou
Address
Block B, Zhengdan International, No.
33 Science Park Road, Changping District,
Beijing, China
Postal
Code
102206
Tel.
010-8070588-8019
Mobile Phone
13241703103
Fax
010-8070588-8050
E-mail
leodong@up-pharma.com


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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................ 6
LIST OF ABBREVIATIONS........................................................................................................10
PROTOCOL SYNOPSIS.............................................................................................................. 13
1
BACKGROUND..................................................................................................................... 17
1.1
Investigational Drug......................................................................................................17
1.1.1
Description of IBI305......................................................................................17
1.1.2
Preclinical studies............................................................................................17
1.1.3
Clinical study...................................................................................................20
1.2
Study Principle and Risk/Benefit Assessment.............................................................. 20
1.2.1
Study principle................................................................................................ 20
1.2.2
Justification for the selection of bevacizumab................................................ 20
1.2.3
Risk/Benefit assessment..................................................................................20
1.3
About This Study.......................................................................................................... 22
1.3.1
Study objectives.............................................................................................. 22
1.3.2
Study design.................................................................................................... 22
2
SELECTION OF SUBJECT POPULATION......................................................................... 24
2.1
Number of Subjects.......................................................................................................24
2.2
Inclusion Criteria...........................................................................................................24
2.3
Exclusion Criteria..........................................................................................................24
2.4
Screening Failure.......................................................................................................... 26
2.5
Subject Restrictions.......................................................................................................26
2.6
Withdrawal and Replacement....................................................................................... 26
3
STUDY DRUGS..................................................................................................................... 28
3.1
Investigational Drug......................................................................................................28
3.2
Control Drug................................................................................................................. 28
3.3
Group Assignment and Blinding...................................................................................28
3.4
Method of Drug Administration....................................................................................29
3.5
Concomitant Medications and Therapies......................................................................29
3.5.1
Permitted concomitant medications and therapies..........................................29


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3.5.2
Prohibited concomitant medications and therapies.........................................29
3.5.3
Emergency treatments.....................................................................................30
3.6
Drug Management.........................................................................................................30
3.7
Packaging, Labeling, Storage, and Tallying................................................................. 30
4
TRIAL PROCESS FLOW.......................................................................................................32
4.1
Visiting Procedure.........................................................................................................36
4.1.1
Screening period (D-14 to D-1 pre-dose)........................................................36
4.1.2
D1....................................................................................................................37
4.1.3
D2....................................................................................................................38
4.1.4
D3....................................................................................................................38
4.1.5
D5....................................................................................................................38
4.1.6
D8....................................................................................................................39
4.1.7
D15..................................................................................................................39
4.1.8
D22..................................................................................................................39
4.1.9
D29..................................................................................................................39
4.1.10
D43..................................................................................................................40
4.1.11
D57..................................................................................................................40
4.1.12
D64..................................................................................................................40
4.1.13
D71..................................................................................................................41
4.1.14
D85..................................................................................................................41
4.1.15
D99 (Study completion)..................................................................................41
4.1.16
Withdrawal......................................................................................................42
4.2
Dietary Restrictions.......................................................................................................42
4.3
Activities and Exercises................................................................................................ 42
4.4
Other Restrictions..........................................................................................................43
5
PHARMACOKINETICS AND IMMUNOGENICITY STUDIES........................................ 44
5.1
Collection and Handling of Blood Samples..................................................................44
5.2
Pharmacokinetic Blood Sampling Time Windows.......................................................45
5.3
Bioanalysis.................................................................................................................... 45
6
CALCULATION OF PHARMACOKINETIC PARAMETERS............................................46


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7
SAFETY EVALUATION....................................................................................................... 47
7.1
Assessment of Physical Examination and Laboratory Safety Parameters....................47
7.2
AEs................................................................................................................................48
7.2.1
Definition........................................................................................................ 48
7.2.2
Severity of AEs............................................................................................... 49
7.2.3
Relationship between AEs and study drugs.................................................... 50
7.2.4
SAE Reporting................................................................................................ 51
7.2.5
Handling of AEs and visits..............................................................................51
7.2.6
Adverse events of special interest (AESI).......................................................52
7.2.7
Pregnancy........................................................................................................52
7.2.8
Collection, documentation, and reporting of AEs...........................................52
8
DATA MANAGEMENT........................................................................................................ 54
8.1
Data Traceability and eCRF Completion and Transfer.................................................54
8.2
Database Creation......................................................................................................... 54
8.3
Data Verification...........................................................................................................55
8.4
Data Quality Assurance.................................................................................................55
8.5
Database Locking..........................................................................................................55
8.6
Blind Verification and Unblinding................................................................................55
9
DATA ANALYSIS AND STATISTICAL METHODS......................................................... 57
9.1
Sample Size Determination...........................................................................................57
9.2
General Analysis........................................................................................................... 57
9.3
Analysis Sets................................................................................................................. 57
9.4
Subject Distribution...................................................................................................... 58
9.5
Demographics and Other Baseline Characteristics.......................................................58
9.6
Compliance and Drug Exposure Analysis.................................................................... 58
9.7
Pharmacokinetic Analysis.............................................................................................58
9.7.1
Analysis of Primary PK Endpoints................................................................. 58
9.7.2
Analysis of Secondary PK Endpoint...............................................................58
9.8
Safety Analysis..............................................................................................................59
9.8.1
AEs..................................................................................................................59


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9.8.2
Laboratory tests...............................................................................................59
9.8.3
ECG.................................................................................................................59
9.8.4
Vital signs, physical examination and other safety-related examinations...... 59
9.8.5
Concomitant medications................................................................................59
9.9
Interim Analysis............................................................................................................59
10 STUDY MANAGEMENT...................................................................................................... 61
10.1 Statement.......................................................................................................................61
10.2 Ethics.............................................................................................................................61
10.3 Source Record Verification...........................................................................................61
10.4 Quality Assurance and Review..................................................................................... 61
10.5 Informed Consent Form................................................................................................ 62
10.6 Liabilities and Insurance............................................................................................... 62
10.7 Modifications to Clinical Protocol................................................................................62
10.8 Monitoring.....................................................................................................................62
10.9 Premature Termination..................................................................................................63
10.10 Confidentiality...............................................................................................................63
10.11 Data Retention...............................................................................................................63
10.12 Publishing Policy.......................................................................................................... 63
11 REFERENCES........................................................................................................................ 65
LIST OF TABLES
Table 1. Schedule of study procedures.......................................................................................... 33
Table 2. PK blood sampling time windows...................................................................................45
Table 3. Assessment of causality between the investigational drug and AE.................................50
Table 4. AE reporting and follow-up.............................................................................................53
List of Figures
Figure 1. Schematic of study design..............................................................................................23


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LIST OF ABBREVIATIONS
AE
AEs
ADA
Anti-drug antibody
AESI
Adverse events of special interest (AESIs)
ALT
Alanine aminotransferase
APTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical classification system
AUC0-∞
Area under the serum concentration–time curve from time 0 to infinity (∞)
AUC0-t
Area under the serum concentration–time curve from time 0 to t
BMI
Body mass index
CDISC
Clinical Data Interchange Standards Consortium
CFDA
China Food and Drug Administration (now National Medical Products Administration)
CI
Confidence interval
CL
Plasma clearance
Cmax
Maximum serum concentration
CRA
Clinical research associate
CRO
Contract research organization
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
DBP
Diastolic blood pressure
D-D
D-dimer
DM
Data Manager
ECG
ECG
eCRF
Electronic case report form
EDC
Electronic Data Capture in clinical trials
GCP
Good Clinical Practice
HBsAg
Hepatitis B virus surface antigen
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
ICF
Informed consent form
ICH
International Conference on Harmonization
INR
International normalized ratio
NAb
Neutralizing antibody


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PK
Pharmacokinetics:
PKAS
Pharmacokinetic analysis set
PT
Preferred Term
PTT
Partial thromboplastin time
QA
Quality Assurance
SAE
Serious adverse event
SBP
Systolic blood pressure
SDV
Source data verification
SOP
Standard Operation Procedure
SS
Safety set
t1/2
Elimination half-life
TEAE
Treatment-emergent adverse events
VEGF
Vascular endothelial growth factor
V
Apparent volume of distribution
WHO-DD
World Health Organization Drug Dictionary


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STUDY PROTOCOL AND AMENDMENTS
Not applicable.


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PROTOCOL SYNOPSIS
Study title:
A randomized, double-blind, parallel-controlled Phase I clinical trial of
single-dose IBI305 vs. bevacizumab to assess pharmacokinetic (PK) profile,
safety, tolerability, and immunogenicity in healthy male subjects
Brief summary:
The primary objective of this study is to demonstrate PK similarities between
IBI305 and bevacizumab in healthy volunteers after a single intravenous
infusion.
In this study, PK similarities are evaluated by comparing the AUC0-t and
AUC0-∞of IBI305 with that of bevacizumab. In addition, safety, tolerability,
and immunogenicity of IBI305 is assessed.
Study drugs:
Investigational drug: Recombinant anti-vascular endothelial growth factor
(VEGF) humanized monoclonal antibody (IBI305) injection, with strength
of 4 mL/100 mg. Control drug: Bevacizumab injection, with strength of
4 mL/100 mg
Project number:
CIBI305A201
Study phase:
Phase I
Study duration:
Each subject receives a single dose of IBI305 or bevacizumab and
participates in the study for a period up to about 16 weeks (including 2-week
screening period)
Subject population:
A total of 100 healthy male subjects
Inclusion criteria:
Subjects must meet all of the following inclusion criteria to be enrolled in the
study:
1.
Fully understand the study objectives and have a basic understanding of
the pharmacological effects of the study drugs and potential adverse
reactions; voluntarily sign a written informed consent form (ICF) in
accordance with the Declaration of Helsinki
2.
Healthy male subjects aged ≥18 years and ≤50 years
3.
Body weight ≥50 kg and ≤100 kg, and body mass index (BMI) ≥
19 and ≤28 kg/m2
4.
Various systemic laboratory parameters within the normal range, or
abnormal test results deemed clinically insignificant by the investigator
5.
Subjects agree that they and their partners will take effective contraceptive
measures (such as sexual abstinence, sterilization, contraceptives, injection
of medroxyprogesterone, or contraceptive implants, etc.) during the study
and within 6 months after the infusion of the study drug.
Exclusion criteria:
Subjects meeting any of the followings are not enrolled in the study:
1.
A history of hypertension or abnormal blood pressure measured at
screening/baseline [systolic blood pressure (SBP) > 140 mmHg and/or
diastolic blood pressure (DBP) > 90 mmHg confirmed by one repeat
measurement on the same day]
2.
Proteinuria deemed clinically significant by the investigator (urine
protein 2+ or above by urinalysis) or a history of proteinuria
3.
Received any antibody or protein therapy targeting VEGF or VEGF
receptor in the past 1 year


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4.
Used any biological product or inoculated with any live virus vaccine
within 3 months prior to the infusion of the study drug, or used any
monoclonal antibody within 12 months
5.
With inherited bleeding tendency or coagulopathy, or a history of
thrombosis or hemorrhagic disorder
6.
A history of gastrointestinal perforation or gastrointestinal fistula
7.
With unhealed wounds, ulcers or fractures, or underwent any major
surgery within 2 months prior to randomization or expected to undergo
any major surgery during the study or within 2 months after the end of
the study
8.
Used any prescribed or over-the-counter drug or any nutritional
supplement within 5 half-lives of such drug or nutritional supplement or
within 2 weeks prior to the administration of the study drug (whichever
is longer). Use of herbal health products should be discontinued 28 days
prior to the administration of the study drug
9.
Tested positive for HBsAg, hepatitis C virus (HCV) antibody, human
immunodeficiency virus (HIV) antibody, or treponema pallidum (TP)
antibody
10. Known allergy to bevacizumab or any excipient of bevacizumab
11. Known history of allergic disorders or allergic constitution
12. Has donated blood 3 months prior to the infusion of the study drug
13. Treated with any other study drug or participated in another
interventional clinical trial within 3 months prior to screening
14. A history of alcohol abuse or drug abuse within 12 months prior to
screening; the subject fails to abstain from alcoholism within 72 h pre-
dose and throughout the study
15. A history of psychosis
16. Subject whose spouse is planning to become pregnant
17. Unable to complete the study in accordance with the protocol during the
study
18. Other circumstances deemed inappropriate for enrollment by the
investigator
Planned enrollment:
This study plans to enroll a total of 100 subjects. Subjects are randomly
assigned to the IBI305 or bevacizumab groups at a ratio of 1:1, i.e., subjects
in IBI305 group : subjects in bevacizumab group = 50:50.
Study groups:

A. IBI305 group: IBI305;
single dose, 3 mg/kg, intravenously infused for 90 min

B. Bevacizumab group: bevacizumab;
single dose, 3 mg/kg, intravenously infused for 90 min
Primary endpoint analysis:

Area under the serum concentration–time curve from time 0 to t (AUC0-t)

Area under the serum concentration–time curve from time 0 to infinity
(∞) (AUC0-∞)


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Secondary endpoint analysis:

Maximum serum concentration observed post-dose (Cmax)

Elimination half-life (t1/2)

Clearance (CL)

Apparent volume of distribution (V)
Safety assessment

Vital signs;

Physical examination;

Laboratory tests (blood routine examination, blood chemistry, coagulation,
and urinalysis)

12-lead ECG

AEs

Immunogenicity: ADA positive rate and Nab positive rate
Calculation of sample size:
50 subjects per group (100 subjects in total) shall provide a power-of-test of
85% to confirm the bioequivalence between IBI305 and bevacizumab. In
estimation of this sample size, it is assumed that the significance level of
two one-sided tests is 0.05, the coefficient of variation (CV) is 35%, and the
dropout rate is 10%. IBI305 can be deemed equivalent to bevacizumab if
90% CI of the reference therapeutic ratio of ln-transformed AUC0-t to ln-
transformed AUC0-∞is 80–125%.
Pharmacokinetic analysis:
Mean concentration is plotted against blood sampling time point to obtain a
plasma concentration vs. time curve.
PK parameters are calculated by non-compartmental analysis (NCA).
PK analysis is carried out based on PK analysis set (PKAS). AUC0-t and
AUC0-∞served as primary PK endpoints, while the other PK parameters serve
as secondary PK endpoints.
Plasma concentrations at each scheduled blood sampling time point is
analyzed using descriptive statistics [number of subjects (N), arithmetic
mean, standard deviation (SD), CV, minimum, median, and maximum].
Concentrations below the lower limit of quantitation (LLoQ) are replaced
with "0" to facilitate descriptive statistical analysis. PK plasma concentrations
are analyzed using descriptive statistics by group.
Mean and individual plasma concentration vs. time curves after intravenous
infusion of IBI305 and bevacizumab are plotted.
The ln-transformed primary PK endpoints (AUC0-t and AUC0-∞) are analyzed
using an analysis of variance (ANOVA) model. The difference in the least
square mean (LSM) between IBI305 and bevacizumab as well as
corresponding 90% CI are calculated. Inverse transformation is applied to
calculate geometric mean ratios (GMRs) and their 90% CIs. IBI305 can be
deemed equivalent to bevacizumab if 90% CIs of the GMRs
(IBI305/Bevacizumab) of AUC0-t and AUC0-∞are between 0.8 and 1.25.


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Setting of blood sampling time
points:
PK analysis
Blood sampling time points: prior to infusion (within 60 min), immediately
after infusion (within 5 min), and at 4 h (± 10 min), 12 h (± 20 min), 24 h
(± 1 h) (D2), 48 h (± 1 h) (D3), 96 h (± 1 h) (D5), 168 h (± 8 h) (D8), 336 h
(± 12 h) (D15), 504 h (± 24 h) (D22), 672 h (± 24 h) (D29), 1008 h (± 48 h)
(D43), 1344 h (± 48 h) (D57), 1512 h (± 48 h) (D64), 1680 h (± 48 h) (D71),
and 2016 h (± 48 h) (D85) after the start of infusion
ADA/NAb assay
Blood sampling time points: prior to infusion (within 60 min) and at 336 h
(± 12 h) (D15), 1008 h (± 48 h) (D43), 1680 h (± 48 h) (D71), and 2352 h
(± 48 h) (D99) after the start of infusion
Safety analysis
All adverse events (AEs) are classified using MedDRA codes and graded
according to CTCAE version 4.03. Numbers and percentages of all subjects
with treatment-emergent AEs (TEAEs), Grade 3 or greater TEAEs, serious
adverse events (SAEs), drug-related TEAEs, drug-related SAEs, TEAEs
leading to study discontinuation, TEAEs leading to study termination, and
AEs of special interest (AESIs) are summarized by system organ class
(SOC), preferred term (PT), and group. In addition, the severity of TEAEs
and their causality with the study drug are also be summarized by SOC, PT,
and group.
For vital signs, physical examinations, laboratory tests, and 12-lead ECG,
their measurements and changes from baseline are analyzed using descriptive
statistics.
The number and percentage of subjects who develop anti-drug antibodies and
neutralizing antibodies during the study are summarized by treatment group.


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1
BACKGROUND
1.1Investigational Drug
1.1.1
Description of IBI305
IBI305 is a recombinant anti-VEGF humanized monoclonal antibody injection developed by
Innovent Biologics (Suzhou) Co., Ltd. (hereinafter referred to as the sponsor), which is capable
of binding specifically to human VEGF. With a molecular mass of about 149 kDa, IBI305 is
capable of binding specifically to VEGF-A, inhibiting the binding of VEGF-A to VEGF-R1 and
VEGF-R2, blocking the signaling pathways such as PI3K-Akt/PKB and Ras-Raf-MEK-ERK,
inhibiting the growth, proliferation, and migration of vascular endothelial cells (VECs) and
angiogenesis, decreasing the vascular permeability, blocking the blood supply to tumor tissues,
inhibiting the proliferation and metastasis of tumor cells, and inducing the apoptosis of tumor
cells, so as to produce anti-tumor effect. The active ingredient is recombinant anti-VEGF
humanized monoclonal antibody, while the excipients include sodium acetate, sorbitol, and
polysorbate 80r1. Refer to the Investigator's Brochure for the detailed structure and
physicochemical properties of IBI305.
1.1.2
Preclinical studies
Pharmaceutical studies
The Chemistry, Manufacturing, and Control (CMC) study of IBI305 has shown that IBI305 is
similar to bevacizumab in stability: They are identical in primary structure, highly similar to each
other in higher-order structures, similar in oligosaccharide distribution, charge variants
distribution, and product-related impurities, and all data of process-related impurities are within
the proposed specification range. Therefore, it can be deduced that IBI305 is highly similar to
bevacizumab in protein properties and product qualityr1.
Pharmacodynamic studies
The in vitro and in vivo pharmacodynamic (PD) studies of IBI305 have shown that,
1)
Targets: IBI305 enables specific high-affinity binding to recombinant human VEGF-A
with an affinity constant similar to that of bevacizumab, indicating that, like bevacizumab,
IBI305 is also a specific human VEGF blocker with definite targets of action.
2)
Specificity: IBI305 could have specific high-affinity binding to human VEGF-A and
certain affinity to canine VEGF-A, but had low affinity to human VEGF-B, human
VEGF-C, human VEGF-D, and human PIGF, suggesting that IBI305 recognizes specific
targets and has low risk of off-target toxicity. No significant affinity to mouse VEGF-


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A164and rat VEGF-A164, suggesting that IBI305 has high species specificity.
3)
Mechanism of action: By binding to VEGF-A specifically, IBI305 could inhibit the
activation of VEGFR-2 and ERK1/2, block the proliferation and migration of HUVEC,
and inhibit the sprouting from rat aortic ring. The above findings suggested that IBI305
blocks the proliferation and migration of VECs and inhibits neovascularization by
antagonizing VEGF-A-mediated signaling pathway, so as to reduce nutritional supply
to tumor tissues and metastasis of tumor.
4)
Anti-tumor effect: IBI305 is able to significantly inhibit the growth of human colon
cancer Ls174t and lung cancer NCI-H460 cells in xenograft-bearing nude mice,
indicating that IBI305 has significant anti-tumor effect.
Results of the in vitro and in vivo studies of IBI305 were highly similar to those of the
synchronously designed study of bevacizumab, suggesting that IBI305 is highly similar to
bevacizumab in targets of action, mechanism of action, and effectr1.
Pharmacokinetic studies
The in vitro and in vivo pharmacokinetic (PK) studies of IBI305 have shown that,
1)
Tissue specificity: IBI305 had no cross-reactivity with normal human tissues and
cynomolgus monkey tissues, except cross-reactivity with the positive-control, i.e.,
human angiosarcoma tissue, suggesting high tissue targeting specificity of IBI305 so
that IBI305 acts on tumor issues only rather than normal human tissues and has thus
very low target-related toxicity.
2)
Linearity: Significant linear PK profile was observed in single-dose or repeated-dose
intravenous injection of IBI305 (2–50 mg/kg) in cynomolgus monkeys, thus
significantly reducing the risk of abrupt increase in toxicity with increasing clinical
dose.
3)
Immunogenicity: After single-dose and repeated-dose intravenous injection of
IBI305 or bevacizumab in cynomolgus monkeys, abnormal variations in plasma
concentration vs. time curve were observed in particular animals, in combination
with the anti-drug antibody test, indicating that IBI305 is immunogenic to some
extent; at the same dose, IBI305 and bevacizumab are similar in immunogenicity.
4)
Accumulation: After repeated-dose intravenous injection of IBI305 or bevacizumab
in cynomolgus monkeys, the drug exposure of the last dose was significantly higher
than that of the first dose, and steady-state drug concentration after repeated doses
was higher than that after a single dose, suggesting probable in vivo drug


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accumulation.
The results of tissue cross-reactivity and PK/TK studies in cynomolgus monkeys showed that
IBI305 is similar to bevacizumab in tissue cross-reactivity and PK/TK profilesr1.
Toxicological studies
Toxicological studies of IBI305 have shown that,
1)
Single dose: A single intravenous infusion of IBI305 (up to 300 mg/kg) in
cynomolgus monkeys showed good tolerability without any abnormal clinical
symptom or toxicity. As converted based on body surface area, the dose is about 48
times the proposed clinical dose for human. In the safety pharmacology study, a
single intravenous injection of IBI305 (50 mg/kg) in cynomolgus monkeys had no
significant impact on the central nervous system (CNS), respiratory system, and
cardiovascular system, This finding suggested very high safety in a single
intravenous injection of IBI305.
2)
Repeated doses: Repeated intravenous injection of IBI305 (up to 50 mg/kg) in
cynomolgus monkeys twice weekly for 9 consecutive doses equivalent to 20 times
the proposed dose for human (based on body weight) had only resulted in minimal to
mild linear growth arrest of metaphyses at knee joints and chondrocytosis associated
with disordered arrangement, minimal tingible-body macrophagocytosis in white
pulp of the spleen, pulmonary (including bronchial) hemorrhage, and hemosiderin
hyperpigmentation in lymphoid tissue of bronchial mucosa, thus the main target
organs of toxicity are the bone, spleen, and lungs.
3)
Immunotoxicity and immunogenicity: Repeated intravenous injection of IBI305 in
cynomolgus monkeys twice weekly for 9 consecutive doses was immunotoxic to the
spleen to some extent. IBI305 at each dose was likely to produce ADA, a portion of
which were neutralizing antibodies (NAbs), indicating that IBI305 is immunotoxic
and immunogenic to some extents.
4)
Local irritation study: After repeated intravenous injection of IBI305 in cynomolgus
monkeys, no injection site irritation was observed, suggesting that administration of
IBI305 by intravenous injection is safe and feasible.
5)
In vitro hemolysis assay: When IBI305 was administered at the maximum proposed
clinical concentration (9 mg/mL), no hemolysis occurred, suggesting that IBI305 is
suitable for intravenous injection.
The results of safety pharmacology study, chronic toxicity study, immunotoxicity study,
immunogenicity study, local irritation study, and hemolysis assay of IBI305 were highly similar


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to those of synchronously designed studies of bevacizumab injection, respectively1.
1.1.3
Clinical study
Preclinical studies have demonstrated that IBI305 is highly similar to bevacizumab in CMC, PD,
PK, and toxicology. This finding lays solid foundation for the test of IBI305 in human. Based on
the results of preliminary in vivo and in vitro studies, this study was conducted to compare the
PK, safety, tolerability, and immunogenicity of IBI305 vs. bevacizumab in healthy males. A
Phase III study will be conducted to compare the efficacy, safety, and immunogenicity of IBI305
plus paclitaxel/carboplatin vs. bevacizumab plus paclitaxel/carboplatin in treatment-naive
patients with advanced or recurrent non-squamous cell non-small cell lung cancer (NSCLC).
1.2
Study Principle and Risk/Benefit Assessment
1.2.1
Study principle
A biosimilar refers to a therapeutic biological product analogous to a market-approved RLD in
terms of quality, safety, and efficacy2. Developed by the sponsor, IBI305 is a biosimilar of the
commercially available bevacizumab, which can be administered via the same administration
method as bevacizumab, to treat advanced, metastatic or recurrent NSCLC.
This study is conducted in accordance with the "Technical Guidelines on Development and
Evaluation of Biosimilars (Tentative)" issued by CFDA (now NMPA)r2. Based on preclinical in
vitro, in vivo, and toxicological studies, IBI305 is similar to bevacizumab in CMC, PD, PK, and
toxicological profiles.
1.2.2
Justification for the selection of bevacizumab
The RLD in this study is bevacizumab. At doses of 1–10 mg/kg, PK of bevacizumab exhibited
linear relationship with the dose3,4. Therefore, the dose for this study can be selected within the
above dose range. In balanced consideration of the safety of healthy subjects, it is essential to
obtain PK parameters of IBI305/bevacizumab, including AUC, and PK parameters of IBI305 can
be compared with that of bevacizumab, hence a low dose, i.e., 3 mg/kg, is chosen as the dose for
this study.
1.2.3
Risk/Benefit assessment
Developed by the sponsor, IBI305 is a biosimilar of bevacizumab. Based on the clinical
pharmacology and toxicity profile of IBI305, the risks and benefits are expected to be similar to
those of bevacizumab.
For treatment-related risks of bevacizumab, please refer to its patient package insertr4.


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Only healthy male subjects are enrolled in this study and they will not receive any therapeutic
effect from this study. As unexpected adverse reactions may occur during the study, the
following measures are taken to ensure minimal hazard to the subjects: Adverse events (AE)
occurring before, during, and after infusion are closely observed, and once any related adverse
reaction occurs, the study physician would take corresponding measures immediately to
guarantee the safety of the subject; in addition, the subject would stay at the study center until
96 h (D5) after the start of infusion and leave the study center only after completing related
examinations, so that prompt treatment can be administered in the case of any emergency.
1.3
About This Study
This study was intended to assess the PK, safety, tolerability, and immunogenicity of IBI305 vs.
bevacizumab in healthy male subjects.
1.3.1
Study objectives
Primary objective: To perform PK comparability study after single-dose infusion of IBI305 or
bevacizumab in healthy male subjects.
Secondary objectives: To compare the safety, tolerability, and immunogenicity of IBI305 vs.
bevacizumab after single-dose infusion of IBI305 or bevacizumab in healthy male subjects.
1.3.2
Study design
This study is a randomized, double-blind, controlled single-dose Phase I study. As planned,
100 healthy male subjects aged 18–50 years are randomly assigned to the IBI305 group or
bevacizumab group at a ratio of 1:1. Subjects receive a single dose of bevacizumab or IBI305 (3
mg/kg) via intravenous infusion, before PK analysis and immunogenicity (ADA/NAb) assay are
performed.
Refer to Figure 1 for the study design.


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Figure 1. Schematic of study design.
1 Randomization can be carried out after the review of inclusion/exclusion criteria on D-1 and prior to
administration.
Discussion of study design
This is a randomized double-blind study, which eliminates biases in subject grouping, AE
observation, follow-up, etc. The half-life of bevacizumab is about 20 daysr4, thus a duration of
about 4 half-lives (85 days) is selected to guarantee a full understanding of PK profile.
Primary endpoint analysis

Area under the serum concentration–time curve from time 0 to t (AUC0-t)

Area under the serum concentration–time curve from time 0 to infinity (∞) (AUC0-∞)
Secondary endpoint analysis

Maximum serum concentration observed post-dose (Cmax)

Elimination half-life (t1/2)

Clearance (CL)

Apparent volume of distribution (V)
Single dose, IBI305, 3 mg/kg (50 subjects)
Screening
period
Randomizationr1
Single dose, bevacizumab, 3 mg/kg (50 subjects)
D-14
Immunogenicity
analysis
PK analysis
Infusion of study drug
D99
Study completion
D85
D71
D43
D15
D1
D-1


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2
SELECTION OF SUBJECT POPULATION
Subject population: Healthy male volunteers.
2.1
Number of Subjects
Fifty subjects per group (100 subjects in total) shall provide a power-of-test of 85% to confirm
the bioequivalence between IBI305 and bevacizumab. The following assumptions were made in
the estimation of sample size: two one-sided test has 5% significance level, coefficient of
variation (CV) is 35%, and the dropout rate is 10%. IBI305 can be deemed equivalent to
bevacizumab if 90% CI of the reference therapeutic ratio of ln-transformed AUC0-t to ln-
transformed AUC0-∞is 80–125%.
If dropout rate of the subjects during the study is greater than 10% (more than 10 subjects cannot
be involved in PK analysis), then more eligible subjects will be enrolled to ensure that there are
90 PK data-centered cases.
2.2
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be enrolled in the study:
1)
Fully understand the study objectives and have a basic understanding of the
pharmacological effects of the study drugs and potential adverse reactions; voluntarily
sign a written ICF in accordance with the Declaration of Helsinki
2)
Healthy male subjects aged ≥18 years and ≤50 years
3)
Body weight ≥50 kg and ≤100 kg, and body mass index (BMI) ≥19 kg/m2 and ≤28 kg/m2
4)
Various systemic laboratory parameters within the normal range, or abnormal test
results deemed clinically insignificant by the investigator
5)
Subjects agree that they and their partners will take effective contraceptive measures
(such as sexual abstinence, sterilization, contraceptives, injection of
medroxyprogesterone, or contraceptive implants, etc.) during the study and within
6 months after the infusion of the study drug
2.3
Exclusion Criteria
Subjects meeting any of the followings are not enrolled in the study:
1)
A history of hypertension or abnormal blood pressure measured at screening/baseline
(SBP > 140 mmHg and/or DBP > 90 mmHg confirmed by one repeat measurement on
the same day)


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2)
Proteinuria deemed clinically significant by the investigator (urine protein 2+ or above
by urinalysis) or a history of proteinuria
3)
Received any antibody or protein therapy targeting VEGF or VEGF receptor in the past
1 year
4)
Used any biological product or inoculated with any live virus vaccine within 3 months
prior to the infusion of the study drug, or used any monoclonal antibody within 12 months
5)
With inherited bleeding tendency or coagulopathy, or a history of thrombosis or
hemorrhagic disorder
6)
A history of gastrointestinal perforation or gastrointestinal fistula
7)
With unhealed wounds, ulcers or fractures, or underwent any major surgery within
2 months prior to randomization or expected to undergo any major surgery during the
study or within 2 months after the end of the study
8)
Used any prescribed or over-the-counter drug or any nutritional supplement within
5 half-lives of such drug or nutritional supplement or within 2 weeks prior to the
administration of the study drug (whichever is longer). Use of herbal health products
should be discontinued 28 days prior to the administration of the study drug
9)
Tested positive for HBsAg, hepatitis C virus (HCV) antibody, human
immunodeficiency virus (HIV) antibody, or treponema pallidum (TP) antibody
10) Known allergy to bevacizumab or any excipient of bevacizumab
11) Known history of allergic disorders or allergic constitution
12) Has donated blood 3 months prior to the infusion of the study drug
13) Treated with any other study drug or participated in another interventional clinical trial
within 3 months prior to screening
14) A history of alcohol abuse or drug abuse within 12 months prior to screening; the
subject fails to abstain from alcoholism within 72 h pre-dose and throughout the study
15) A history of psychosis
16) Subject whose spouse is planning to become pregnant
17) Unable to complete the study in accordance with the protocol during the study
18) Other circumstances deemed inappropriate for enrollment by the investigator


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2.4
Screening Failure
Screening failure occurs when a subject who has signed the informed consent form fails to meet
the inclusion criteria. In the event of screening failure, the demographic data of the ineligible
subject and noncompliance with the inclusion/exclusion criteria should be documented in the
source document and electronic case report form (eCRF). Subjects who failed screening due to
any transient disease are allowed to undergo another screening.
2.5
Subject Restrictions
The subjects agree that they and their partners will take effective contraceptive measures during
the study and within at least 6 months after study medication to avoid pregnancy.
For restrictions on medication during the study, please refer to Section 3.5.
2.6
Withdrawal and Replacement
All subjects might withdraw from this study at any time, with or without providing a reason.
Subjects who withdraw from the study would not be subject to discrimination or retaliation, and
their medical treatment would not be affected. If a subject who fails to meet inclusion criteria is
inadvertently enrolled, the investigator must notify the sponsor or its representative immediately
to discuss the safety and health status of the subject, and whether the subject should continue
participating in the study. When consensus is not achieved, the subject has to withdraw from the
study and where possible, undergo follow-up.
In addition, subjects might withdraw from the study in the following circumstances:

Subjects voluntarily withdraw from the study;

Subjects who use other drugs that affect the trial results (as assessed by the investigator);

Subjects with drug allergies or serious adverse events, and are deemed unsuitable by the
investigator to continue the trial;

Subjects who experience diseases or other conditions during the trial which prevente
them from continuing the trial;

Subjects with significant deviations or other reasons (such as loss to follow-up) during
the clinical trial that makes it difficult to assess drug efficacy;

Subjects who should withdraw from the study as determined by the study doctor;

Study termination by the investigator or sponsor for any reason;


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
The government department or ethics committee discontinues the study for any reason.
Subjects who withdraw from the study are required to complete the withdrawal procedure
according to the visit flow chart. Subjects who withdraw from the study would not be replaced.
Subjects who withdraw their informed consent are not be contacted again unless they clearly
indicate the willingness to be contacted. The sponsor could use the clinical trial data obtained
from the subjects before their withdrawal of the informed consent.
Subjects should be examined and observed as much as possible upon withdrawal. At the same
time, the date of withdrawal, reason for withdrawal, and the tests and observation results at the
time of withdrawal are documented in the source document and eCRF. If necessary, the subject
can be appropriately treated and followed up until the symptoms (test values) return to the state
before initialization of the clinical study or until there is no medical issue, and the results will be
documented in the source document and eCRF.


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3
STUDY DRUGS
The study drugs in this study are IBI305 and bevacizumab.
IBI305 is a biosimilar of bevacizumab. Both drugs contain humanized anti-VEGF monoclonal
antibody as the active ingredient. Bevacizumab is a standard commercially available drug. Both
drugs were provided by the sponsor.
3.1
Investigational Drug
Name: IBI305
Appearance: Sterile solution for intravenous injection with pH 5.2. Clear colorless liquid that is
free of foreign matter, floc, and precipitate
Strength: 4 mL/100 mg
Source: Innovent Biologics (Suzhou) Co., Ltd.
3.2
Control Drug
Name: Bevacizumab
Appearance: Sterile solution for intravenous injection with pH 5.9–6.3. Clear to slightly
opalescent, colorless to light brown liquid
Strength: 4 mL/100 mg
Source: Roche Pharma (Schweiz) Ltd.
3.3
Group Assignment and Blinding
After the eligibility (meet all inclusion criteria) of a subject has been verified, the operator at the
study center logs into the Interactive Web Response System (IWRS) and enters the subject
information into IWRS, which allocates a random number to the subject and provides a
medication number of the drug to be received by the subject.
This study is a randomized, double-blind, controlled single-dose Phase I study. As IBI305 and
bevacizumab cannot be made to appear identical, the study center has to designate non-blinded
pharmacists and research nurses to prepare the study drugs and complete relevant records. The
non-blinded research nurses and pharmacists responsible for preparing and verifying the study
drug are not allowed to disclose any information regarding treatment allocation to the subjects,
their families, or other personnel including the physicians and relevant study personnel.
Unblinding: Subject unblinding should only be performed after database locking.


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Emergency unblinding: In emergencies where the investigator has to be aware of the medication
administered to a subject, the investigator should perform emergency unblinding for the subject
and notify the sponsor and the contract research organization (CRO) immediately. Moreover, the
investigator should document the reason for unblinding, date of unblinding, and outcome of
unblinding in the source document and eCRF of the subject.
3.4
Method of Drug Administration
In this study, each subject receives single doses (3 mg/kg) of IBI305 or bevacizumab via
intravenous infusion for 90 min. The dose needed by each subject is calculated based on body
weight of the subject: Dose (mg) = 3 mg/kg × Body weight of the subject (kg). The calculated
dose is then converted into the required volume of the drug. An equal volume of liquid will be
drawn from a 100 mL infusion bag containing 0.9% normal saline and then discarded or used to
flush the infusion device. Based on the calculated required volume, the corresponding drug
volume is drawn and added into the infusion bag. The solution in the infusion bag is gently
mixed by inversion and avoided the formation of foam, drug agglomerates, and precipitates.
Subjects should remain in bed from the start of infusion to 2 h after completion of the infusion.
When the infusion is completed, 30 mL of 0.9% normal saline is used to flush the injection line
according to routine clinical practice.
If an infusion-related reaction occurs, it should be handled according to routine clinical practice
at the study site.
In the event of suspension of infusion/adjustment of infusion rate due to any infusion-related
reaction in a subject, PK blood samples will still be collected at the scheduled time points.
3.5
Concomitant Medications and Therapies
All medications except the study drugs, including Chinese herbal medicines and other non-
traditional therapies, are considered as concomitant medications. All concomitant medications
within 30 days prior to subject screening should be documented in eCRF, including their generic
name, route of administration, start date, end date, and indications.
3.5.1
Permitted concomitant medications and therapies
Use of acetaminophen at the daily recommended dose (≤2 g/24 h and ≤1 g/4 h) is permitted.
3.5.2
Prohibited concomitant medications and therapies
Use of prescribed or over-the-counter formulations, including antacids, analgesics (except
acetaminophen), dietary supplements, or herbal medicines, is not permitted during the study,


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unless required to treat AEs or current medical issues.
3.5.3
Emergency treatments
During the study, the investigator must ensure that adequate treatment is administered when any
adverse reaction occurs.
3.6
Drug Management
As IBI305 and bevacizumab cannot be made to appear identical, the study center has to
designate non-blinded pharmacists and research nurses to prepare the study drugs and complete
relevant records. After the verification of AE and SAE data, used portions of IBI305 and
bevacizumab are destroyed on site according to the relevant operating procedures, and the
destruction log is filled out by the study center. Unused portions of IBI305 and bevacizumab are
tallied up by the study center and returned to the sponsor to be destroyed. Infusion-related
containers, empty vials, and syringes can be destructed on site and documented in accordance
with applicable guidelines and operating procedures established by the study center and local and
institutional authorities.
The non-blinded clinical research associate (CRA) is responsible for verifying the supply,
transport, reception, storage, distribution, destruction, recovery, and related records of the study
drugs used in the clinical study.
3.7
Packaging, Labeling, Storage, and Tallying
Study drugs (IBI305 and bevacizumab) should be packed and labeled in accordance with
relevant regulations. Study drugs should be stored according to the specifications on the drug
labels.
IBI305 and bevacizumab are stored at 2–8 °C in the dark before being transported via cold-chain
logistics to each center without being frozen or shaken. Upon the receipt of study drugs, the
person designated by the study center should check transportation temperature, tally drugs up,
verify and sign the receipt, and the related records should be retained in the investigator's folder.
Drug storage temperature should be recorded on a daily basis, and the following items should be
recorded on the inventory log: Date of receipt, quantity, lot numbers, quantity released, and
remaining stock.
Study drugs can only be handled by authorized persons. Volume of drugs required by the subject
is calculated based on 3 mg/kg. IBI305 and bevacizumab are diluted with 0.9% sodium chloride
to obtain 100 mL for immediate infusion. In the event that intravenous infusion cannot be
performed immediately on account of the subject or any other reason, the prepared solutions can


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be stored at 2–8 °C but the intravenous infusion must be completed within 12 h. Otherwise, the
solutions should be destroyed at the study center and documented by a drug administrator.


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4
TRIAL PROCESS FLOW
This is a randomized, double-blind, controlled Phase I trial. The study plans to enroll 100 healthy
male subjects aged 18–50 years, who will be randomly assigned at a ratio of 1:1 to receive single
intravenous infusion (3 mg/kg) of IBI305 or bevacizumab.
The schedule of procedures is detailed in Table 1.


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T1Table 1. Schedule of study procedures.
Screening
Admission
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Days of visits
Screening period
D1–D2 (h)
D3
D5
D8
D15
D22
D29
D43
D57
D64
D71
D85
D99
Withdrawal
D-14 to
D-2
D-1
Before
infusiona
0
Immediately
after
infusion
4
8
12
24
48
96
168
336
504
672
1008
1344
1512
1680
2016
2352
Admission to study
site
X
Discharge from study
site
X
Signing of informed
consent form
X
Inclusion/exclusion
criteria
X
X
Demographic
characteristics
X
Body weight and
height
X
Xb
Xb
Xb
Medical
history/previous
medication
X
X
Vital signsc
X
X
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examinationc
X
X
X
X
X
X
X
X
X
X
Blood routine
examinationc,e
X
Xf
X
X
X
X
X
X
X
X
Urinalysisc,g
X
Xf
X
X
X
X
X
X
X
X
Blood chemistryc,h
X
Xf
X
X
X
X
X
X
X
X
Coagulationc,i
X
Xf
X
X
X
X
X
X
X
X
HBV Assay
X


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Screening
Admission
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Days of visits
Screening period
D1–D2 (h)
D3
D5
D8
D15
D22
D29
D43
D57
D64
D71
D85
D99
Withdrawal
D-14 to
D-2
D-1
Before
infusiona
0
Immediately
after
infusion
4
8
12
24
48
96
168
336
504
672
1008
1344
1512
1680
2016
2352
Treponema pallidum
antibody
X
Anti-HCV antibody
assay
X
Anti-HIV antibody
assay
X
12-lead ECGc
X
X
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization and
grouping
Xj
Administration via
intravenous infusion
X
PK blood samplingc,k
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA/NAb blood
samplingc,l
X
X
X
X
X
X
AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: HIV = human immunodeficiency virus; HBV = hepatitis B virus; HCV = hepatitis C virus; PK = pharmacokinetics; ADA = anti-drug antibody;
NAb = neutralizing antibody.
a.
60 min prior to infusion;
b.
Body weight measurement only;


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c.
If multiple evaluations are to be carried out at the same time, then samples/data should be collected or acquired in the following order under non-rescue
situations: blood sampling, 12-lead ECG, vital signs, and physical examination;
d.
For vital signs and 12-lead ECG, the measurements obtained within 60 min prior to the infusion will be used as baseline values;
e.
Hematology tests include hemoglobin, hematocrit, differential white blood cell (WBC) count (neutrophil count, absolute lymphocyte count, monocyte
count, eosinophil count, and basophil count), platelet count, and red blood cell (RBC) count;
f.
If blood routien test, urinalysis, blood chemistry, and coagulation test are carried out within 7 days prior to the infusion, then screening results can serve as
baseline data, and such examinations may be not required at this visit; otherwise, repeat examinations will be required;
g.
Urinalysis consists of specific gravity (SG) of urine, pH value, urine ketone body, urine glucose, urine protein, urine nitrite, urine occult blood, urine WBC,
urobilinogen, and urine bilirubin;
h.
Blood chemistry consists of creatinine, blood urea nitrogen, total protein, albumin, total bilirubin, triglycerides, total cholesterol, alkaline phosphatase
(ALP), AST, ALT, fasting blood glucose, sodium, potassium, chlorine, calcium, phosphorus, and magnesium;
i.
Coagulation test consists of international normalized ratio (INR), activated partial thromboplastin time (APTT) and partial thromboplastin time (PTT), and
D-dimer (D-D);
j.
Randomization can be carried out after the review of inclusion/exclusion criteria on D-1 and prior to administration;
k.
PK blood sampling time points: prior to infusion (within 60 min), immediately after the infusion (within 5 min), and at 4 h (± 10 min), 12 h (± 20 min), 24 h
(± 1 h) (D2), 48 h (± 1 h) (D3), 96 h (± 1 h) (D5), 168 h (± 8 h) (D8), 336 h (± 12 h) (D15), 504 h (± 24 h) (D22), 672 h (± 24 h) (D29), 1008 h (± 48 h)
(D43), 1344 h (± 48 h) (D57), 1512 h (± 48 h) (D64), 1680 h (± 48 h) (D71), and 2016 h (± 48 h) (D85) after the start of the infusion;
l.
ADA/NAb blood sampling time points: prior to infusion (within 60 min) and at 336 h (± 12 h) (D15), 1008 h (± 48 h) (D43), 1680 h (± 48 h) (D71), and
2352 h (± 48 h) (D99) after the start of the infusion.


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4.1
Visiting Procedure
4.1.1
Screening period (D-14 to D-1 pre-dose)
Screening visits are completed from D-14 to D-2 prior to the start of study medication. The
following procedure must be completed at each screening visit to ensure that the subject meets
the requirements for enrollment in this study:

Signing of informed consent form

Check against the inclusion/exclusion criteria

Record demographic data (sex, ethnicity, age, etc.)

Measure body weight and height

Record medical history and previous medications (within 30 days prior to screening)

Vital signs

Physical examination

Laboratory tests (blood routine examination, coagulation, blood chemistry, and
urinalysis)

HBV assay, anti-HCV antibody assay, anti-HIV antibody assay, and anti-TP antibody
assay

12-lead ECG

Recording the AEs and concomitant medications
The investigator will assess all results of screening visits. Only subjects who meet the inclusion
criteria but not any of the exclusion criteria could proceed to the next visit. Subjects not eligible
for enrollment are asked to withdraw from the study and deemed as screening failure. The
investigator should document all the reasons for withdrawal/screening failure of subjects.
The subjects are admitted to the study center on D-1 (1 day prior to infusion of study drug) until
their discharge on D5. Each subject is required to complete the following procedure on D-1:

Check against the inclusion/exclusion criteria

Randomization*

Measure body weight and calculate dosage amount

Record medical history and previous medications


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
Vital signs

Physical examination

Laboratory tests (blood routine examination, coagulation, blood chemistry, and
urinalysis)§

12-lead ECG

Recording the AEs and concomitant medications
* Randomization can be carried out after the review of inclusion/exclusion criteria on D-1 and
prior to administration on D1
§ If laboratory screening tests (blood routine examination, coagulation, blood chemistry, and
urinalysis) are performed within 7 days prior to infusion of the study drug, then the results of the
screening tests could serve as baseline data and such tests are not required at this visit.
4.1.2
D1
After fasting overnight for at least 8 h, each subject should complete the following procedure
before the infusion of study drug:

PK and immunogenicity blood sampling

12-lead ECG*

Vital signs*

Recording the AEs and concomitant medications
* 12-Lead ECG and vital signs: Measurements prior to infusion are used as baseline values.
After the start of study drug infusion, the following procedure must be completed:

PK blood sampling (immediately post-dose, and at 4 h and 12 h after the start of
infusion)

12-Lead ECG (immediately post-dose, and at 4 h, 8 h, and 12 h after the start of
infusion)

Vital signs (immediately post-dose, and at 4 h, 8 h, and 12 h after the start of infusion)

Recording the AEs and concomitant medications
Note: Subjects need to fast for 8 h prior to infusion and do not consume fluids from 1 h pre-dose
to 1 h post-dose. A standard meal is offered by the study center 1 h after the completion of


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infusion.
4.1.3
D2
Each subject needs to complete the following procedure:

PK blood sampling (24 h after the start of infusion)

Laboratory tests (blood routine examination, blood chemistry, coagulation, and
urinalysis)

12-Lead ECG

Vital signs

Physical examination

Recording the AEs and concomitant medications
4.1.4
D3
Each subject needs to complete the following procedure:

PK blood sampling (48 h after the start of infusion)

12-Lead ECG

Vital signs

Recording the AEs and concomitant medications
4.1.5
D5
Each subject needs to complete the following procedure:

PK blood sampling (96 h after the start of infusion)

Laboratory tests (blood routine examination, blood chemistry, coagulation, and
urinalysis)

12-Lead ECG

Vital signs

Physical examination

Recording the AEs and concomitant medications

Discharge from study site


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Subjects do not stay at the study center from D5 on.
4.1.6
D8
Subjects pay a return visit to the study center on D8. Subjects should complete the following
procedures during this visit:

PK blood sampling (168 h after the start of infusion)

Vital signs

Recording the AEs and concomitant medications
4.1.7
D15
Subjects pay a return visit to the study center on D15. Subjects should complete the following
procedures during this visit:

PK and immunogenicity blood sampling (336 h after the start of infusion)

Laboratory tests (blood routine examination, blood chemistry, coagulation, and
urinalysis)

12-Lead ECG

Vital signs

Physical examination

Recording the AEs and concomitant medications
4.1.8
D22
Subjects pay a return visit to the study center on D22. Subjects should complete the following
procedures during this visit:

PK blood sampling (504 h after the start of infusion)

12-Lead ECG

Vital signs

Recording the AEs and concomitant medications
4.1.9
D29
Subjects pay a return visit to the study center on D29. Subjects should complete the following
procedures during this visit:


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
PK blood sampling (672 h after the start of infusion)

Laboratory tests (blood routine examination, blood chemistry, coagulation, and
urinalysis)

Vital signs

Physical examination

Recording the AEs and concomitant medications
4.1.10
D43
Subjects pay a return visit to the study center on D43. Subjects should complete the following
procedures during this visit:

PK and immunogenicity blood sampling (1008 h after the start of infusion)

12-Lead ECG

Vital signs

Recording the AEs and concomitant medications
4.1.11
D57
Subjects pay a return visit to the study center on D57. Subjects should complete the following
procedures during this visit:

PK blood sampling (1344 h after the start of infusion)

Laboratory tests (blood routine examination, blood chemistry, coagulation, and
urinalysis)

12-Lead ECG

Vital signs

Physical examination

Recording the AEs and concomitant medications
4.1.12
D64
Subjects pay a return visit to the study center on D64. Subjects should complete the following
procedures during this visit:

PK blood sampling (1512 h after the start of infusion)


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
Vital signs

Recording the AEs and concomitant medications
4.1.13
D71
Subjects pay a return visit to the study center on D71. Subjects should complete the following
procedures during this visit:

PK and immunogenicity blood sampling (1680 h after the start of infusion)

Laboratory tests (blood routine examination, blood chemistry, coagulation, and
urinalysis)

12-Lead ECG

Vital signs

Physical examination

Recording the AEs and concomitant medications
4.1.14
D85
Subjects pay a return visit to the study center on D85. Subjects should complete the following
procedures during this visit:

PK blood sampling (2016 h after the start of infusion)

Vital signs

Recording the AEs and concomitant medications
4.1.15
D99 (Study completion)
Subjects pay a return visit to the study center on D99. Subjects should complete the following
procedures during this visit:

Immunogenicity blood sampling (2352 h after the start of infusion)

Laboratory tests (blood routine examination, blood chemistry, coagulation, and
urinalysis)

12-Lead ECG

Vital signs

Physical examination


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
Body weight measurement

Recording the AEs and concomitant medications
4.1.16
Withdrawal
To terminate the study prematurely, a subject is required to complete the following procedure:

PK and immunogenicity blood sampling

Laboratory tests (blood routine examination, blood chemistry, coagulation, and
urinalysis)

12-Lead ECG

Vital signs

Body weight measurement

Physical examination

Recording the AEs and concomitant medications
4.2
Dietary Restrictions
Subjects are informed not to consume food or drink caffeinated food or beverages (e.g.,
chocolate, tea, coffee, cola, energy drinks, etc.), not to take methylxanthine, grapefruit, and
grapefruit juice, and not to consume alcohol or cigarettes from 48 h prior to the administration of
study drug to the end of this study.
While hospitalized in the Phase I ward, the subjects are provided with standard meals and drinks.
On the day of study drug administration, each subject should have fasted for 8 h prior to the
infusion and deprived of fluids from 1 h pre-dose to 1 h post-dose. A standard meal is provided
by the study center 1 h after the completion of infusion.
4.3
Activities and Exercises
Subjects should refrain from high-intensity exercises, sauna, steam bath, and sunbathing during
the study. Subjects should remain in bed from the start of study drug infusion to 2 h after
completion of the infusion. During the study, subjects should also avoid TCM physical therapies,
such as skin scraping and cupping.


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4.4
Other Restrictions
No vaccine regardless of dosage form may be used.
Any concomitant medication should be determined by the investigator in comprehensive
consideration of medical condition and its impact on study outcome, as shown in Section 3.5.
Subjects may not donate sperms throughout the study and within 3 months after completion of
the study.
Subjects must agree that they and their partners will take effective contraceptive measures
(such as sexual abstinence, sterilization, contraceptives, injection of medroxyprogesterone, or
contraceptive implants, etc.) during the study and within 6 months after the infusion of the study
drug.


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5
PHARMACOKINETICS AND IMMUNOGENICITY STUDIES
5.1
Collection and Handling of Blood Samples
PK blood samples are collected at the following time points: prior to infusion (within 60 min),
immediately after infusion completion (within 5 min), and at 4 h (± 10 min), 12 h (± 20 min),
24 h (± 1 h) (D2), 48 h (± 1 h) (D3), 96 h (± 1 h) (D5), 168 h (± 8 h) (D8), 336 h (± 12 h) (D15),
504 h (± 24 h) (D22), 672 h (± 24 h) (D29), 1008 h (± 48 h) (D43), 1344 h (± 48 h) (D57),
1512 h (± 48 h) (D64), 1680 h (± 48 h) (D71), and 2016 h (± 48 h) (D85) after the start of the
infusion. Collection date and time of each blood sample is documented in eCRF.
Immunogenicity (ADA/NAb) blood samples are collected at the following time points: prior to
infusion (within 60 min) and at 336 h (± 12 h) (D15), 1008 h (± 48 h) (D43), 1680 h (± 48 h)
(D71), and 2352 h (± 48 h) (D99) after the start of the infusion. Collection date and time of each
blood sample is documented in eCRF.
Since hemolysis of a sample affects the assay of its drug concentration, the sample hemolysis is
paid attention to during the blood sampling process. The relevant nurses receive training prior to
blood sample collection to ensure gentle manipulation during blood sampling. Personnel in
charge of centrifugation should communicate with the blood sampling nurses in a timely manner
to minimize the rate of hemolysis.
Note: For the frozen storage of samples, it is recommended to use a medical cryogenic freezer
with small fluctuation of temperature; a cryogenic freezer with a defrost cycle function should
not be used to prevent repeated freeze-thaw.
Blood samples are stored in a freezer at -80 °C (-80 °C ± 10 °C) at the clinical study center until
they are taken out and sent to the analysis center. Serum samples in sample tubes are transported
in styrofoam packages containing a sufficient amount of dry ice to ensure the samples remain
frozen for at least 24 h. Under such conditions, the frozen samples were promptly sent to various
central laboratories. The blood samples for PK and NAb assays will be delivered to United-
Power Pharma Tech Co., Ltd. for analysis, while the blood samples for ADA assay will be
delivered to Wuxi AppTec (Shanghai) Co., Ltd. for analysis. Detailed description of sample
collection, handling, labeling, storage, transportation, and analysis is listed in laboratory manual
of the center.


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5.2
Pharmacokinetic Blood Sampling Time Windows
Time windows for PK blood sampling are shown in Table 2.
T2T2Table 2. PK blood sampling time windows.
Blood sampling point (based on start time of infusion)
Allowed time window
Before infusion
Within 60 min
Immediately at the end of infusion
+ 5 min
4 h after the start of infusion
± 10 min
12 h after the start of infusion
± 20 min
24 h (D2), 48 h (D3), and 96 h (D5) after the start of infusion
± 1 hr
168 h after the start of infusion (D8)
± 8 hr
Blood sampling point (based on start time of infusion)
Allowed time window
336 h after the start of infusion (D15)
± 12 hr
504 h (D22) and 672 h (D29) after the start of infusion
± 24 hr
1008 h (D43)–2016 h (D85) after the start of infusion
± 48 hr
5.3
Bioanalysis
The blood samples for PK and NAb assays will be delivered to United-Power Pharma Tech Co.,
Ltd. for analysis, while the blood samples for ADA assay will be delivered to Wuxi AppTec
(Shanghai) Co., Ltd. for analysis. Verification methods and the final report of sample analysis
will be provided separately and included in study-related documents.


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6
CALCULATION OF PHARMACOKINETIC PARAMETERS
PK parameters are calculated using WinNonlin v6.4. PK parameters, which include:
– Area under the serum concentration–time curve from time 0 to t (AUC0-t)
– Area under the serum concentration–time curve from time 0 to infinity (∞) (AUC0-∞)
– Maximum serum concentration observed post-dose (Cmax)
– Elimination half-life (t1/2)
– Clearance (CL)
– Volume of distribution (V)


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7
SAFETY EVALUATION
Patients who have signed the ICF are required to undergo safety assessment [vital signs, physical
examination, body height, body weight, AEs, ECG, blood routine examination, urinalysis, blood
chemistry (liver function, kidney function, electrolyte, blood lipid, and blood glucose), and
coagulation, etc.]. The time interval to be assessed should span from the time of ICF signing to
the end of the study, and AEs or SAEs occurring during this period should be followed up until
they return to normal or are stabilized. All reported AEs are listed and analyzed.
7.1
Assessment of Physical Examination and Laboratory Safety Parameters
Changes in laboratory measurements of each subject relative to baseline values are evaluated,
each laboratory abnormality is evaluated for clinical significance, and clinically significant
abnormalities relative to baseline value are documented as AEs in the case report form.
Clinically significant laboratory measurements during screening should be documented as AEs.
Physical examination
The investigator or any other authorized qualified investigator conduct specified physical
examination, including the following: general condition, skin, head, neck, ears, eyes, nose,
mouth, throat, respiratory organs/lungs, cardiovascular system, gastrointestinal tract/abdomen,
genitourinary system, lymphatic system, musculoskeletal system/limbs, nerves, and others.
During each visit, the investigator documentes symptoms reported by the subject and
abnormalities observed in physical examination. All clinically significant abnormalities are
reported as AEs.
Monitoring of vital signs
At each visit, vital signs of each subject (including axillary temperature, heart rate, and blood
pressure) were monitored, documented, and evaluated. All clinically significant abnormalities
should be reported as AEs. During the study, the investigator could carry out more vital sign
measurements based on actual conditions (e.g., for safety reasons).
12-lead ECG
12-lead ECG is carried out at specified time points. Frequency of ECG could be increased during
the study, according to the opinion of the investigator.
ECG parameters such as heart rate, PR interval, QRS complex duration, QT interval, and QTc
interval should be documented. Subjects should rest in the supine position for at least 5 min prior
to 12-lead ECG examination. All ECG are evaluated by qualified physicians. All clinically
significant abnormalities should be reported as AEs.


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Hematological parameters
To determine the maximum level of myelosuppression due to study drug, the most serious
changes in neutrophil count, WBC count, platelet count, and the level of hemoglobin occurring
throughout the study will be summarized and analyzed as per NCI CTCAE version 4.03. The
number of subjects with Grade 3 or 4 hematological toxicity post-dose and corresponding
incidence rate should be listed and analyzed.
Clinical biochemical parameters
Measurements of ALP, ALT, AST, total bilirubin, and creatinine are summarized and analyzed
according to NCI CTCAE version 4.03, to evaluate the effects of the study drug on liver and
kidney functions in the subjects. The number of subjects with the most serious changes in liver
and kidney functions throughout the study and their incidence rates should be summarized and
analyzed according to NCI CTCAE version 4.03. The number of subjects with Grade 3 or 4
blood chemistry abnormalities post-dose and their incidence rates should be listed.
Immunogenicity evaluation
Within 60 min prior to infusion, and on D15, D43, D71, and D99, blood samples are collected
for ADA assay and NAb assay (Table 1). Tests are conducted in the relevant site laboratory.
Detailed description of sample collection, handling, labeling, storage, transportation, and
analysis is listed in laboratory manual of the center.
Assessment of other toxicities
The clinical investigator analyzes and documentes toxicities observed during the study in the AE
log or SAE log in accordance with the study protocol. AEs happening from the start of treatment
to the end of each visit, as graded by the clinical physician, should be summarized and analyzed.
7.2
AEs
7.2.1
Definition
AEs
An AE refers to any untoward medical occurrence in a subject involved in a clinical study and
may not have a definite causal relationship with the treatment. Thus, an AE can be any adverse
and unexpected sign (including laboratory abnormalities), symptom, or any disease with
temporal dependence on study medication, regardless of causality with the study drug.


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Serious adverse event
An SAE refers to any unfavorable medical occurrence in a clinical study (may not have a definite
causal relationship with the study drug), which meets at least one of the following criteria:
(1)
Events resulting in death.
(2)
Life-threatening events (a "life-threatening" AE is defined as an AE that will lead to
immediate death of the subject upon its onset, excluding the AEs that will lead to death
only upon further progression).
(3)
Events requiring hospitalization or prolonged length of stay. The following
circumstances are excluded herein: Hospitalization and/or surgery that had been
scheduled before or during the study for a pre-existing illness or disease prior to
enrollment (which does not worsen during the study), hospitalization for the sake of
medical insurance reimbursement rather than an illness, elective surgery, or conditions
not requiring hospitalization or SAE reporting in the opinion of the study physician.
(4)
Events leading to permanent or serious disability/incapacity.
(5)
Events leading to congenital abnormalities/birth defects.
(6)
Other significant medical events: Important medical events that may not result in death,
be life threatening, or require hospitalization may be considered serious, when based
upon appropriate medical judgment, they may jeopardize the patient or subject and may
require medical or surgical intervention to prevent one of the outcomes listed in this
definition.
7.2.2
Severity of AEs
Severity of AEs are evaluated according to CTCAE version 4.03 and graded as follows:

Grade 1
Mild; asymptomatic or with mild symptoms; clinical or diagnostic
observation only, medical intervention not indicated

Grade 2
Moderate; minimal, local or non-invasive intervention required; limiting
age-appropriate instrumental activities of daily living (the instrumental activities of
daily living refer to cooking, buying sundry goods or clothes, using the telephone,
managing money matters, etc.)

Grade 3
Serious or medically significant, but not immediately life-threatening;
leading to hospitalization or prolonged length of stay; disabling; limiting self-care
activities of daily living (the self-care activities of daily living refer to bathing, dressing


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and undressing, feeding oneself, using the toilet, taking medications, but not bedridden)

Grade 4
Life-threatening; urgent intervention indicated

Grade 5
AE-related death
7.2.3
Relationship between AEs and study drugs
There are five types of causal relationships between the investigational product and AE: Related,
possibly related, possibly unrelated, unrelated, and not evaluable. The evaluation method is
detailed as follows (Table 3):
T3Table 3. Assessment of causality between the investigational drug and AE.
Causality
Criteria
Related

AE occurrence has a reasonable temporal relationship with administration time;

AE has significant reasonable causal relationship with the investigational drug, as compared
to any other cause (e.g., concurrent disease, environment, toxicity, or other therapy received,
etc.)

AE is resolved or alleviated after discontinuation or dose reduction

The event meets the definition of any known AE type related to a suspected drug or its
analog

AE recurs after re-administration
Possibly Related

AE occurrence has a reasonable temporal relationship with administration time;

AE has equally reasonable causal relationship with the investigational drug, as compared to any
other cause (e.g., concurrent disease, environment, toxicity, or other therapy received, etc.).

AE is resolved or alleviated after discontinuation or dose reduction (if applicable)
Possibly
Unrelated

AE has more reasonable causal relationship with other causes (e.g., concurrent disease,
environment, toxicity, or other therapy received, etc.), as compared to the investigational drug

AE is not resolved or alleviated after discontinuation or dose reduction (if applicable) or in
the event of unclear circumstances

AE does not recur after re-administration or in the event of unclear circumstances
Unrelated

AE occurrence has no reasonable temporal relationship with administration time, or

AE has significant causal relationship with other factors (such as concurrent disease,
environment, toxicity, or other therapy received by the subject, etc.)
Cannot
Evaluable

The above information is unclear, the AE is not evaluable based on existing information in
the opinion of the investigator, and the investigator fails to get further follow-up information


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7.2.4
SAE Reporting
Any SAE occurring during the study, regardless of causality with treatment, should be reported
according to SAE reporting procedure issued by relevant regulatory authority or an Independent
Ethics Committee (IEC). The investigator should make clinical diagnosis where possible based
on vital signs and symptoms of the subject, and when such diagnosis is definite, the investigator
should report the diagnosis result rather than symptoms.
The investigator should take the following measures:

Take appropriate medical measures immediately;

Send the completed SAE report immediately (within 24 h after the study center
becomes aware of this event or the latest information of this event) by fax to the
sponsor: 021-31652800. The sponsor's email address for SAE reporting:
drugsafety@innoventbio.com (when reporting SAE via email, it is recommended to
encrypt the SAE report and send the sponsor the password in a second email);

Document this SAE in the AE log and SAE log of eCRF and in the source document;

This signed and dated SAE form will be immediately (in 24 h) sent by the investigator
to the IEC, CFDA (now NMPA), health department, and local drug administration
authorities;

Follow up and document the SAE process until the event has been resolved or
recovered to an outcome that follow-up is no longer required in the opinion of the
investigator.
In addition, the sponsor or a representative thereof (e.g., CRO) should report the SAE to the
corresponding regulatory authority and other investigators in accordance with requirements of
the regulatory authority and local regulations.
7.2.5
Handling of AEs and visits
The investigator is obliged to conduct proper medical treatment of any AE (pointing out the
treatment methods, such as interruption/discontinuation of study medication, dose modification,
administering drug therapy, etc.). When an AE occurs, the investigator should actively take
appropriate measures to ensure the safety of the subject. Any AE observed from the signing of
ICF to the protocol-specified time (Table 4) should be followed up.
Any SAE occurring beyond the protocol-specified time (Table 4), if deemed by the investigator
to be related to the study drug, should be reported to the sponsor.


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7.2.6
Adverse events of special interest (AESI)
The AESI for this study include:

Hypertension

Proteinuria

Gastrointestinal perforation

Hemorrhage event

Cardiotoxicity

Phlebitis

Thrombus

Intestinal fistula

Posterior reversible encephalopathy syndrome

Hypersensitivity reaction, infusion-related reaction
The above AESIs should be closely observed and promptly managed by the investigator during
the study. If criteria for SAE is met, AESIs should be reported to the sponsor in accordance with
the SAE reporting procedure within the specified duration.
7.2.7
Pregnancy
In the event that the female partner of a subject gets pregnant within 6 months after the start of
study medication, the investigator should be notified immediately and is required to submit the
completed pregnancy report to the sponsor within 24 h, in accordance with the SAE reporting
procedure. The investigator should discuss with the subject and the partner thereof about the risk
of continuing such pregnancy and its impact on the fetuses. The pregnancy should be monitored
until the completion of pregnancy. Any other SAE occurring during pregnancy should be
reported in accordance with the SAE reporting procedure. In the event of any congenital
abnormality/birth defect or any other SAE, a SAE report should be filled out and submitted in
accordance with the SAE reporting procedure.
7.2.8
Collection, documentation, and reporting of AEs
All AEs occurring from the time of signing the ICF until a study-specified time (Table 4),
regardless of severity, should be collected and documented in the AE page of eCRF (all SAEs and
non-SAEs). Clinically significant laboratory findings during screening should also be


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documented as AEs.
The investigator should enter all essential information, including AE description, start date, end
date, severity level, countermeasures, outcome, and causal relationship between severity and the
investigational drug, and should document each AE separately.
T4Table 4. AE reporting and follow-up.
Reporting Time Limit
Visit Time Limit
AEs
From signing of ICF to the end of visit
Until the event is resolved or has
reached an outcome that can be
reasonably interpreted without the need
of further follow-up in the opinion of
the investigator (e.g., recovering or not
recoverable, etc.)
Adverse events of
special interest
(AESIs)
From signing of ICF to the end of visit
Until the event is resolved or has
reached an outcome that can be
reasonably interpreted without the need
of further follow-up in the opinion of
the investigator (e.g., recovering or not
recoverable, etc.)
Serious adverse event
From signing of ICF to the end of visit
Until the event is resolved or has
reached an outcome that can be
reasonably interpreted without the need
of further follow-up in the opinion of
the investigator (e.g., recovering or not
recoverable, etc.)
The subject's partner
becomes pregnant
From the first dose to 6 months after
administration of study drug
Until outcome of this event


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8
DATA MANAGEMENT
Data in this study are acquired in the form of eCRF.
8.1
Data Traceability and eCRF Completion and Transfer
Only subject number can be shown in the eCRF system. As part of the related study report,
eCRF is used to document clinical study information of the subject. The eCRF is completed by
the investigator or an authorized person (which should be indicated in the study authorization
form). Prior to database locking, the eCRF should be electronically signed by the investigator or
the authorized person to state that all information in the eCRF system is true.
After each examination in the clinical study, an eCRF has to be completed to document the
physical condition of the subject.
Medical record and other records of the subject are kept by the investigator. These records should
contain the source data, copies of laboratory data, and other medical testing results (e.g., ECG).
During the study, subject information is not directly documented in eCRF system but in the
source document of each subject as part of the source data, and later is transcribed to the eCRF
system.
Data in this study is managed by the data department of WuXi Clinical Development Services
(Shanghai) Co., Ltd., in order to ensure that the clinical study data are true, complete, private,
and traceable.
All data in eCRF originated from the source document and are filled out by the investigator or
any person designated by the investigator to ensure information integrity and accuracy. Along
with any modification or correction of data in eCRF system, names of the data modifier and
dates of changes are automatically recorded.
Once completed, eCRF should be submitted via internet in a timely manner, and the data in
eCRF system is subjected to source data verification (SDV), review by data manager (DM), and
query to verify that they are unquestionable, and have to be acknowledged by the investigator by
e-signing prior to data locking.
8.2
Database Creation
The data department of Wuxi Clinical Development Services (Shanghai) Co., Ltd. should create
a database in accordance with FDA 21 CFR Part 11 to manage traces of system login, data entry,
modification, and deletion, and such database should be created as per CDISC standard, where
possible.


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After the final data are verified in a data review meeting, the PI, sponsor, and statistician co-sign the
related documents and lock the database. In principle, the locked database may not be altered any
longer. Any issue found after data locking should be verified. Following verification, corrections
may be made in the statistical analysis procedure, and a written record should be retained.
8.3
Data Verification
Data verification consists of computerized edit check, manual check, and data verification
meeting. Any data query in the verification should be promptly corrected by the investigator or
any person designated by the investigator.
8.4
Data Quality Assurance
Quality assurance of data is organized, conducted, and reported pursuant to the study protocol
and SOPs released by the sponsor. In ICH E6, quality assurance (QA) is defined as “all proposed
systematic actions intended to ensure that the conduct of the study and generation,
documentation, and reporting of the data comply with GCP and applicable regulatory
requirements”. In this study, quality control (QC) and data validation procedures are used to
ensure the reliability and accuracy of the clinical database. Data entry, collation, clarification,
and validation procedures that all relevant research staff must follow are detailed in the
monitoring plan and data management plan, to ensure compliance with GCP and GLP.
8.5
Database Locking
Following review and verification of the created database, the database is jointly locked by
the PI, sponsor, and statistician. In principle, the locked database may not be altered any longer.
Any issue found after data locking should be verified. Following verification, corrections may
be made in the statistical analysis procedure, and a written record should be retained.
Thereafter, the database is statistically analyzed by the statistician according to the statistical
analysis plan, and a statistical analysis report is provided.
8.6
Blind Verification and Unblinding
ICH Biostatistics Guideline E9 recommends investigators to perform blind verification before
unblinding for two purposes:

To discuss each issue in the blinded state to determine dataset size

To review study data in the blinded state
Study groups are unblinded after the minutes of the verification meeting are signed and dated.
Prior to unblinding, one written credential for confirmation of database locking is submitted by


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the head statistician.


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9
DATA ANALYSIS AND STATISTICAL METHODS
Statistical analytical procedure and information used in this study are detailed in a separate
statistical analysis plan. In the event of protocol amendment and that such amendment will have
major impact on statistical analytical procedure and information in the opinion of the sponsor
and/or PI, the statistical analysis plan should be revised accordingly to remain consistent with
this protocol.
9.1
Sample Size Determination
Fifty subjects per group (100 subjects in total) shall provide a power-of-test of 85% to confirm
the bioequivalence between IBI305 and bevacizumab. The following assumptions are made in
the estimation of sample size: two one-sided test has 5% significance level, coefficient of
variation (CV) is 35%, and the dropout rate is 10%. IBI305 can be deemed equivalent to
bevacizumab if 90% CI of the reference therapeutic ratio of ln-transformed AUC0-t to
ln-transformed AUC0-∞is 80–125%.
9.2
General Analysis
For continuous variables, descriptive statistics should include the count, mean, standard deviation,
median, maximum, and minimum. For categorical variables, descriptive statistics consists of
frequency and absolute or relative rate. Statistical analysis in this study is conducted using SAS.
Data of dropout subjects are included in the analyses of primary and secondary endpoints.
The procedure for the handling of missing data is detailed in the statistical analysis plan.
9.3
Analysis Sets
Safety analysis set (SS): Include all randomized subjects who receive the study drug with
available post-medication safety evaluation data. Subjects are analyzed by group. SS is used in
all safety analyses.
PK analysis set (PKAS): Include all randomized subjects who receive the study drug, for whom
at least AUC0-t and AUC0-∞could be reliably calculated, the absorption, distribution, metabolism,
and elimination of the study drug are not seriously affected, and positive ADA is detected at
baseline. PKAS is used as the primary analysis set in PK equivalence analysis. PKAS and SS
are used in demographics and baseline characterization.
Immunogenicity assay dataset: Include all enrolled subjects who receive the study drug with
available post-medication immunogenicity assessment data.


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9.4
Subject Distribution
The schedule of subject visit procedure is shown in Table 1. The number and percentage of
patients who have completed or dropped out of the study (including the reason for dropouts such
as loss to follow-up, AEs, and poor compliance) are summarized based on treatment groups.
The number and percentage of subjects in each analysis set are calculated based on treatment
groups.
For subjects completing the study, dropout subjects, and their distribution in each analysis set,
the number and percentage of subjects are calculated by study center.
The number and percentage of protocol violations are calculated based on treatment groups.
9.5
Demographics and Other Baseline Characteristics
Demographic characteristics such as age, height, gender, and weight, and other baseline
characteristics such as disease history are analyzed using descriptive statistics.
9.6
Compliance and Drug Exposure Analysis
Drug exposure levels in the subjects are analyzed using descriptive statistics by group.
9.7
Pharmacokinetic Analysis
PK analysis is based on PKAS.
9.7.1
Analysis of Primary PK Endpoints
The primary objective of this study was to check the bioequivalence between IBI305 and
bevacizumab. The ln-transformed primary PK endpoints (AUC0-t and AUC0-∞) are analyzed
using an ANOVA model. The difference in the least square mean (LSM) between IBI305 and
bevacizumab as well as corresponding 90% CI are calculated. Inverse transformation is applied
to calculate geometric mean ratios (GMRs) and their 90% CIs. IBI305 can be deemed equivalent
to bevacizumab if 90% CIs of the GMRs (IBI305/Bevacizumab) of AUC0-t and AUC0-∞are
between 0.8 and 1.25.
9.7.2
Analysis of Secondary PK Endpoint
The secondary PK endpoint for this study is Cmax. The difference in the least square mean of ln-
transformed Cmax between IBI305 and bevacizumab and corresponding 90% CI is calculated by
using the ANOVA model, and the GMR and its 90% CI are calculated using inverse
transformation.


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9.8
Safety Analysis
Safety analysis is based on the safety analysis set.
9.8.1
AEs
All AEs are classified by code according to MedDRA and graded according to CTCAE version
4.03. Numbers and percentages of all subjects with treatment-emergent AEs (TEAEs), Grade 3
or greater TEAEs, serious adverse events (SAEs), drug-related TEAEs, drug-related SAEs,
TEAEs leading to study discontinuation, TEAEs leading to study termination, and AEs of special
interest (AESIs) are summarized by system organ class (SOC), preferred term (PT), and group.
In addition, the severity of TEAEs and the causality with the study drug are also summarized by
SOC, PT, and group.
9.8.2
Laboratory tests
All laboratory measurements and their changes relative to baseline are analyzed by scheduled
time point and group using descriptive statistics. A cross-classification table is used to describe
normal values and abnormalities after infusion, and the laboratory abnormalities are tabulated.
9.8.3
ECG
ECG measurements and their changes relative to baseline are analyzed using descriptive statistics.
9.8.4
Vital signs, physical examination and other safety-related examinations
Vital signs and their changes relative to baseline are analyzed using descriptive statistics.
Results of physical examination are listed by group.
9.8.5
Concomitant medications
Concomitant medications are non-study medications that meet one of the followings:
(1)
All other drugs received after study medication.
(2)
Other drugs that are administered prior to study medication and continue to be used after
study medication.
The concomitant medications are coded according to the World Health Organization Drug
Dictionary (WHO-DD), and the number and percentage of cases are calculated by Anatomical
Therapeutic Chemical classification (ATC), PT, and group.
9.9
Interim Analysis
One interim analysis is planned in the study to evaluate the safety data only without adjusting α.


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The analysis is carried out when the first 50 subjects complete observation on D29.


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10
STUDY MANAGEMENT
10.1
Statement
This clinical study iscarried out in accordance with the moral, ethical, and scientific principles
specified in the Declaration of Helsinki and GCP, as well as the design and requirements in the
protocol.
10.2 Ethics
Before the drugs are delivered to the investigator, a copy of Ethics Committee Approval and a
list of documents for review have to be submitted to the sponsor. The Ethics Committee
Approval should be accompanied by a list of names of all EC members involved in approval
discussion and their respective responsibilities.
After the EC has approved this study protocol, the sponsor should submit this clinical study
protocol to CFDA (now NMPA) for registration.
Prior to initialization, the clinical trial has to be approved by the EC and relevant regulatory
authority.
Any modification to the study protocol should be submitted to the EC for review and approval.
In the event of any SAE or unexpected AE occurring during the clinical study, which is related to
safety of the clinical study and may affect safety of the subject and the conduct of the study, the
EC must be notified by the investigator.
10.3 Source Record Verification
All data obtained during the clinical study must be properly processed to guarantee the rights and
privacy of the subjects involved in the clinical study. The investigator must agree to the review
and audit of clinical study data carried out by the monitor/auditor/inspector, so as to validate the
accuracy of source data and understand the progress of the study. If it is not possible to validate
the source records, the investigator should agree to assist the monitor/auditor/inspector in further
confirmation of data QC.
10.4 Quality Assurance and Review
QA audit of this clinical study should be conducted by the sponsor or any person authorized by
the sponsor. GCP audit could also be conducted by the drug approval authority. The quality
auditor could review all medical records, study-related documents and mails, as well as informed
consent forms for this clinical trial.


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10.5 Informed Consent Form
The investigator is obliged to explain the objectives, methodology, benefits, and potential risks
of this clinical trial to each subject. An ICF signed by the subject must be obtained prior to any
operating procedure related to the clinical trial. Informed consent should be expressed in both
oral and written forms. The subject should sign and date the informed consent form in person.
The subject should retain copies of the signed ICF and its information page.
By signing the ICF, the subjects agree that the sponsor, drug approval administration, auditor,
and (or) monitor may check the obtained source data related to the clinical study, and the
reviewers must abide by the confidentiality statement.
10.6 Liabilities and Insurance
The sponsor has insured the subjects involved in this study in accordance with local laws, and
have borne the treatment cost and corresponding financial compensation for any subject having
damages related to the study drug or study procedure.
10.7 Modifications to Clinical Protocol
Following the confirmation of the final study protocol, a detailed protocol modification log has
to be in place and co-signed at least by the investigator and the sponsor, with version and date
being indicated, for any modification made to the protocol.
All modifications to the protocol have to be approved by the EC in writing, and, if necessary,
should be submitted to local drug approval authority. Simple policy-related modifications should
be sent to the EC only. All the documents should be submitted to the sponsor.
10.8 Monitoring
The sponsor has designated a monitor to perform on-site monitoring. The monitor representing
the sponsor or CRO authorized by the sponsor should adhere to the relevant in-house SOPs.
The monitor should pay regular visits from the start of the study to the end of the study.
The monitor can access the source data related to this clinical study and check eCRF as per the
relevant SOPs to ensure that the information is complete, accurate, and consistent with the source
data.
The source record, eCRF, copies of laboratory data, and medical testing results should be made
available for review by the CRA, auditor, and health authority at all times. The monitor should
examine all eCRFs and ICFs.


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10.9 Premature Termination
If the investigator and the sponsor become aware that, provided that the study is further
conducted, some conditions or events are likely to jeopardize the safety and benefits of the
subject, the study may be terminated after discussion among relevant personnel. Even if the
above finding is absent, the sponsor may also decide to terminate the study in advance.
Reasons for premature termination include but are not limited to the following:

Identification of unexpected significant or unacceptable risks to enrolled subjects

Slow enrollment

The sponsor decides to interrupt or discontinue drug development
10.10 Confidentiality
All study-related findings and documents shall be deemed confidential. The investigator and
members of the research team may not disclose such information without prior written consent
from the sponsor.
Privacy of the subject should be protected. Files in EDC system and documents to be submitted
to the sponsor or CRO should be identified by subject number, initials, and/or date of birth, and
subject name should not be shown. The investigator should maintain the confidentiality of
documents that are not needed to be submitted to the sponsor or CRO but contain information
from which identity of the subject can be determined (e.g., a signed ICF).
10.11 Data Retention
Medical record and other records of the subject are kept by the investigator. These records
should contain inpatient medical record, source radiologic data, laboratory data, other medical
testing results (e.g., ECG), and source document of this clinical trial. According to relevant
regulatory requirements, the investigator should retain the source document and relevant
information of the clinical study until 5 years after the completion of the study. The investigator
shall retain the disk of eCRF copied data.
10.12 Publishing Policy
By signing this study protocol, the investigator has agreed that the outcome of this study can be
used for registration application in or outside China, publication or the provision of information
to medical professionals. Where necessary, relevant regulatory authority shall be informed of the
name, address, qualification, and in-study responsibilities of the investigator.
Without prior communication with the sponsor, the investigator may not publish (in the form of
poster, abstract, paper, etc.) any data related to this study. Detailed information shall be


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described in other documents.


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11
REFERENCES
1.
r1Investigator's Brochure for IBI305. Innovent Biologics (Suzhou) Co., Ltd. May 11, 2016.
2.
r2China Food and Drug Administration (now National Medical Products Administration).
Technical Guidelines on Development and Evaluation of Biosimilars (Tentative). From the
following website on Jun. 16, 2016: http://www.sda.gov.cn/WS01/CL1616/115104.html
3.
r3Bevacizumab: Clinical Pharmacology/TOX Review. From the following website on Jun.
15, 2016: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/STN-
125085_Avastin_BioPharmr.pdf
4.
r4Bevacizumab: Prescribing Information (Nov. 25, 2015). From the following website on
Jun. 15, 2016:
http://www.roche.com.cn/content/dam/roche_china/zh_CN/pdf/product/Avastin_20151125
_IM%20PI%20CDS32.0-33.0.pdf

SAP_001.pdf: 
Protocol No.: CIBI305A201 
Statistical Analysis Plan 
Version: V1.0 
Sponsor: Innovent Biologics (Suzhou) Co., Ltd. 
Confidential Data 
Version Date: Sep 30, 2017 
 
1/24 
 
Statistical Analysis Plan 
 
 
A Phase I Randomized, Double-blinded, Parallel Controlled, Single-
dose Clinical Study, Comparing Pharmacokinetic Characteristics, 
Safety, Tolerance, and Immunogenicity of IBI305 and Bevacizumab 
in Male Healthy Subjects 
 
Generic Name of the 
Investigational Drug: 
Recombinant Anti-Vascular Endothelial Growth Factor (VEGF) 
Humanized Monoclonal Antibody (IBI305) 
Sponsor: 
Innovent Biologics (Suzhou) Co., Ltd. 
Statistical Analysis 
Institution: 
WuXi Clinical Development Services (Shanghai) Co., Ltd. 
Version No.: 
V 1.0 
Version Date: 
September 30, 2017 
NCT Number：   
 
NCT03083990  
 
 
Confidentiality Statement 
The information contained in this Statistical Analysis Plan is confidential which are 
properties of Innovent Biologics (Suzhou) Co., Ltd. Without permission, the 
infromation should not be disclosed, published, or made public in any other 
manner. 
 
 
 
 


Protocol No.: CIBI305A201 
Statistical Analysis Plan 
Version: V1.0 
Sponsor: Innovent Biologics (Suzhou) Co., Ltd. 
Confidential Data 
Version Date: Sep 30, 2017 
 
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Signature Page for Approval 
The following signers approved the Statistical Analysis Plan: 
 
Signature: 
 
Date: September 30, 2017 
Name: Zeng Huaxi 
Department/Position: Clinical Information Department/Senior Biostatistician 
Institution: WuXi Clinical Development Services (Shanghai) Co., Ltd. 
 
Signature: 
 
Date: September 30, 2017 
Name: Luo Zhaoyu 
Department/Position: Clinical Information Department/Biostatistics Director 
Institution: WuXi Clinical Development Services (Shanghai) Co., Ltd. 
 
Signature: 
 
Date: September 30, 2017 
Name: He Weizhi 
Department/Position: Clinical Operations/Clinical Project Manager II 
Institution: WuXi Clinical Development Services (Shanghai) Co., Ltd. 
 
Signature: 
 
Date: September 30, 2017 
Name: Wei Zhaohui 
Department/Position: Clinical Research/Head of Biostatistics (Senior Director) 
Institution: Innovent Biologics (Suzhou) Co., Ltd. 
 


Protocol No.: CIBI305A201 
Statistical Analysis Plan 
Version: V1.0 
Sponsor: Innovent Biologics (Suzhou) Co., Ltd. 
Confidential Data 
Version Date: Sep 30, 2017 
 
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Contents 
1. Introduction .............................................................................................................................. 5 
2. Objective of the Trial .............................................................................................................. 5 
3. Design of the Trial ................................................................................................................... 5 
3.1 Estimation of Sample Size .............................................................................................. 6 
3.2 Randomization ................................................................................................................... 6 
4. Research Parameters ............................................................................................................... 7 
4.1 Bioequivalence Evaluation Indicators .......................................................................... 7 
4.2 Safety Evaluation Indicators ........................................................................................... 7 
5. Definition .................................................................................................................................. 8 
5.1 Baseline ............................................................................................................................... 8 
5.2 Change Since Baseline ..................................................................................................... 8 
5.3 Number of Research Days .............................................................................................. 8 
6. Analysis Dataset ...................................................................................................................... 8 
7. Interim Analysis ....................................................................................................................... 9 
8. Data Review ............................................................................................................................. 9 
8.1 Data Processing and Transfer ......................................................................................... 9 
8.2 Data Screening ................................................................................................................... 9 
9. Statistical Method .................................................................................................................... 9 
9.1 General Considerations for Statistical Analysis.......................................................... 9 
9.1.1 General Rules ............................................................................................................. 9 
9.1.2 Processing of Missing Value or Date ................................................................... 10 
9.1.3 Export of Statistical Results .................................................................................. 10 
9.2 Subject Disposition ......................................................................................................... 10 
9.2.1 Protocol Deviations ................................................................................................. 10 
9.3 Demographics and Other Baseline Characteristics .................................................. 11 
9.3.1 Demographics ........................................................................................................... 11 
9.3.2 Prior Medical History and Surgical History ....................................................... 11 
9.3.3 Prior and Concurrent Medications ....................................................................... 11 
9.4 Pharmacokinetic and Bioequivalence Analyses ....................................................... 12 
9.4.1 Pharmacokinetic Parameter Analysis .................................................................. 12 
9.4.2 Judgment of Bioequivalence ................................................................................. 13 
9.5 Safety Analysis ................................................................................................................ 14 
9.5.1 Drug Exposure .......................................................................................................... 14 
9.5.2 Adverse Events ......................................................................................................... 14 
9.5.3 Clinical laboratory Test Value ............................................................................... 16 
9.5.4 Vital Signs ................................................................................................................. 16 
9.5.5 12-Lead ECG ............................................................................................................ 17 
9.5.6 Physical Examination ............................................................................................. 17 
9.6 Immunogenicity Analysis .............................................................................................. 17 
10. Quality Control .................................................................................................................... 18 
Appendix 1. Abbreviations ...................................................................................................... 19 


Protocol No.: CIBI305A201 
Statistical Analysis Plan 
Version: V1.0 
Sponsor: Innovent Biologics (Suzhou) Co., Ltd. 
Confidential Data 
Version Date: Sep 30, 2017 
 
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Appendix 2. Tables, Figures, and Lists ................................................................................. 20 
 
 


Protocol No.: CIBI305A201 
Statistical Analysis Plan 
Version: V1.0 
Sponsor: Innovent Biologics (Suzhou) Co., Ltd. 
Confidential Data 
Version Date: Sep 30, 2017 
 
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1. Introduction 
The Statistical Analysis Plan (SAP) is intended to describe statistical methods used in 
the Clinical Trial, Project Protocol No. CIBI305A201. The clinical trial is intended to 
compare pharmacokinetic characteristics, safety, tolerance, and immunogenicity of 
IBI305 and Bevacizumab in male healthy populations, and its main objective is to 
demonstrate pharmacokinetics similarity of IBI305 and Bevacizumab in male healthy 
volunteers. 
The Statistical Analysis Plan is based on the Clinical Study Protocol version 1.0 (date: 
Aug 3, 2016), and Case Report form (CRF) version 1.0 (date: Oct 24, 2016). Any 
revision of the trial protocol or CRF would result in update of the Statistical Analysis 
Plan as required. 
The Statistical Analysis Plan must be finalized prior to locking of the final database, 
and after approval by the Sponsor. 
2. Objective of the Trial 
Primary Objective: PK comparison is carried out after male healthy subjects are infused 
intravenously with a single dose of IBI305 or Bevacizumab. 
Secondary Objectives: Comparison of safety, tolerance, and immunogenicity between 
IBI305 and Bevacizumab is carried out after male healthy subjects are infused 
intravenously with a single dose of IBI305 or Bevacizumab. 
3. Design of the Trial 
The study is a Phase I, randomized, doubled-blinded, parallel controlled, single-dose 
study. It is planned to enroll 100 male healthy subjects aged 18-50 years, who are 
randomly assigned in the ratio of 1:1 into the IBI305 or Bevacizumab Groups. The 
subjects are infused with 3 mg/kg Bevacizumab or IBI305, to carry out PK analysis and 
immunogenicity (anti-drug antibodies and antibodies [ADA/NAb]) analysis. 


Protocol No.: CIBI305A201 
Statistical Analysis Plan 
Version: V1.0 
Sponsor: Innovent Biologics (Suzhou) Co., Ltd. 
Confidential Data 
Version Date: Sep 30, 2017 
 
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Figure 1 Principle for Study Design 
1Randomization may be carried out after review of the D-1 inclusion/exclusion criteria, 
and prior to dosing. 
 
3.1 Estimation of Sample Size 
Fifty (50) subjects per group (100 subjects in total) would provide 85% test power to 
demonstrate bioequivalence between IBI305 and Bevacizumab. The significance level 
for the one- and two-sided t test for the hypothesis of the estimated sample size is 0.05, 
the coefficient of variation (CV) is 35%, and the drop-out rate is 10%. It may consider 
that IBI305 and Bevacizumab are equivalent if the 90% confidence interval (CI) for the 
treatment reference ratio of log-transformed AUC0-t and AUC0-∞ are within 80%-125%. 
3.2 Randomization 
Random No. of subjects: The study is a Phase I, randomized, doubled-blinded, parallel 
controlled, single-dose clinical study. One hundred (100) male healthy subjects aged 
18-50 years are planned to be enrolled, and are randomly assigned in the ratio of 1:1 
into the IBI305 or Bevacizumab Groups. The subjects are infused with 3 mg/kg 
Bevacizumab or IBI305, to carry out PK analysis and immunogenicity analysis. So a 
random list and labels for 100 subjects should be prepared. 
Random no. of the drugs: The subjects in the study will receive a single dose (3 mg/kg) 
of IBI305 or Bevacizumab, intravenous infusion over 90 min. The required dose of the 
drug is calculated, based on the subject’s body weight: Dose (mg) = 3 mg/kg × Subject’s 
Body Weight (kg). The strength of the investigational injectable drug (IBI305 or 
Screening 
Stage 
Randomized 
Group1 
Single dose, IBI305, 3 mg/kg (50 subjects) 
Single dose, Bevacizumab, 3 mg/kg (50 subjects) 
Infusion of the 
investigational drug 
PK analysis 
End of the study 
Immunogenicity analysis 


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Bevacizumab) is 100 mg/vial. It is estimated that each subject (in a body weight of e.g., 
80 kg) requires 3 vials. So it is planned to enroll 100 male healthy subjects, and it is 
expected that approximately 300 vials are required. Considering comprehensively the 
Sponsor’s requirements and system requirements, the random number for the drugs are 
set as 6 effective digits (XXXXXX). The Statistical Analysis Institution must produce 
drug randomization no. and grouping information, based on the number of drugs no., 
expiration date of the drugs, and corresponding quantity of the drugs, provided by the 
Sponsor. The random number of the drugs is produced concurrently with the Phase III 
clinical study (Protocol No.: CIBI305A301, Random Analysis Plan version 2.0, dated 
Oct 28, 2016) of the drug product; so for the project, no dossier is provided to the Drug 
Packaging Institution (Fisher) and QA Department of the Sponsor. The encrypted 
electronic documents that the supplier for eCOS Stochastic System complies with the 
requirements are provided. The information includes: Drug No., Lot No., and Serial No. 
Notes: The lot no. consists of 5 digits (XXXXX): The 1st and 2nd digits denote the 
blinding number, the 3 digit denotes the group (for example, 1 denotes the Trial Group, 
and 2 denotes the Control Group), and the last 2 digits denote the expiration date. 
4. Research Parameters 
4.1 Bioequivalence Evaluation Indicators 
1) Evaluation of the Primary Endpoint 
 
Area under the plasma drug concentration-time curve from time 0 to t (AUC0-t) 
 
Area under the plasma drug concentration-time curve from time 0 to infinity (∞) 
(AUC0-∞) 
2) Evaluation of the Secondary Endpoints 
 
Maximal plasma drug concentration (Cmax) observed after administration of the 
drug 
 
Elimination half-life (t½) 
 
Clearance (CL) 
 
Apparent volume of distribution (V) 
4.2 Safety Evaluation Indicators 
 
Vital signs 
 
Physical examination 
 
Laboratory tests (hematology, blood biochemistry, and coagulation test, and urine 
test) 


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 
12-Lead ECG 
 
Adverse events (AE) 
 
Immunogenicity: Positive rate of anti-drug antibody (ADA), and positive rate of 
neutralizing antibody (NAb) 
5. Definition 
5.1 Baseline 
Baseline value of the trial: Defined as last non-missing measured value of the subject 
prior to administration of the investigational drug. 
5.2 Change Since Baseline 
Change since baseline: Defined as difference of the measured value and the measured 
baseline value 
5.3 Number of Research Days 
Number of Research days: The number of research days is calculated according to the 
date when the subject is administered with the investigational drug; the research date 
when the investigational drug is used is counted as Day1. 
If the event occurs on or after the date when the investigational drug is used: Number 
of Research Days = Event Date - Date when the Investigational Drug is used + 1; 
If the event occurs before the date when the investigational drug is used: Number of 
Research Days = Event Date - Date when the Investigational Drug is used; 
6. Analysis Dataset 
Full analysis set (FAS): 
The full analysis set is defined as subjects who are randomized and administered with 
the investigational drug. 
Safety Analysis Population Set (SS): 
The safety analysis population set includes all subjects who are randomized and 
administered with the investigational drug, and have safety evaluation data after 
administration of the drug; they will be analyzed by group. SS is used for all safety 
analyses. 
Pharmacokinetic Analysis Set (PKAS): 
The pharmacokinetic analysis set includes all the subjects who are randomized and 
administered with the investigational drug but without any severe influence on drug 
absorption, distribution, metabolism, and elimination, and baseline ADA positivity, etc., 
for whom AUC0-t and AUC0-∞ may be calculated at least. The PK analysis set will be 


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used for PK equivalence analysis, as main analysis set. The PK analysis set and SS are 
used for demographic and baseline characteristic analyses. 
Immunogenicity Analysis Set (ADA-AS): 
The immunogenicity analysis population of the study consists of all subjects who are 
enrolled, and administered with the investigational drug, and have immunogenicity 
evaluation data after administration of the drug. 
7. Interim Analysis 
In this study, 1 interim analysis is planned, in which safety data are evaluated only, 
without considering α adjustment. The analysis timepoint is when the first 50 patients 
complete Day 29 observation. 
8. Data Review 
The data used for final data are cleaned data. 
8.1 Data Processing and Transfer 
eCRP table data will be exported from the EDC system by the data management team, 
and transferred as SAS dataset to the statistical programming team. Pharmacokinetic 
analysis data will be transferred to the data management team, and will be provided by 
the data management team to the pharmacokinetic analysts. The calculated 
pharmacokinetic parameters will be transferred in EXCEL to the statistical 
programming team for further statistical analysis. 
8.2 Data Screening 
In addition to data screening based on the data management protocol, additional data 
screening are provided for the analysis data set and chart programming by the Analysis 
and Report Department. The expected data problems will be exported and confirmed 
as “problems” by the SAS Log, and picked out by SAS Macro and transferred to the 
Data Management Department. 
Prior to database lock, a further data screening will be provided for review of charts 
produced, based on the cleaned subset of the subjects. Prior to database lock, those 
charts will be discussed in the data review conference with the Sponsor, to confirm any 
data problem and seek for correction. 
9. Statistical Method 
9.1 General Considerations for Statistical Analysis 
9.1.1 General Rules 


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All trial tables will be summarized by the trial groups (investigational drug and the 
reference drug), respectively. For quantitative indicators, the descriptive statistics 
include number, mean, standard deviation, median, minimum, and maximum; for 
counting indicators, the descriptive statistics include number and percentage. 
Unless otherwise specified, the default significance level is 5%; the confidence interval 
(CI) is 95%, and all the tests are two-sided. 
For quantitative measurements, the change since baseline is calculated as: 
 
Change since Baseline = Measured Value at Visit X - Baseline Value 
The percentage since baseline is calculated as: 
 
Percentage Change since Baseline = (Measured Value at Visit X - Baseline 
Value)/Baseline × 100 
9.1.2 Processing of Missing Value or Date 
Processing of missing value: No missing value would be imputed. 
Processing of missing date: As the trial stage is relatively short, any adverse event with 
missing date will be further checked. Any other missing date would not be interpolated. 
9.1.3 Export of Statistical Results 
All statistical results will be exported directly by SAS. See separate documents for 
samples of the figures, tables, and listings. The export template is used to standardize 
the programmer’s work. In this Plan, it is not required to revise and review any non-
substantial or modificatory adjustment to the export template that does not influence 
the Plan. 
9.2 Subject Disposition 
The subject disposition is summarized for all subjects. Screening failure and screening 
failure cause, number and percentage of enrolled subjects, and number and percentage 
of subjects who complete the study and not complete the study will be calculated by 
the trial group (Investigational Drug and Reference Drug). Subjects withdraw early will 
be summarized by the main causes for withdrawal from the trial. Number and 
percentage of subjects will be calculated by group, according to disposition of subjects 
in the analysis populations. 
The list for disposition of subjects will be provided by trial group and by subject no. 
 
9.2.1 Protocol Deviations 
The protocol deviation data will be listed by trial group and subject no., and table is 


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also provided for summarize protocol deviations. 
In case of any protocol deviation, its processing will be determined, on the basis of 
listening to the opinions from the principal investigator or the statistician, etc., in the 
case conference that is held as required. 
 
Missing data for plasma drug concentration, laboratory test values, and vital signs, 
etc.: Test value data with low confidence due to data missing and hemolysis will 
not be included into dataset analysis. 
 
Not observed/examined at the specified times: When a test value has time deviation, 
its processing is determined, based on the deviation degree. 
9.3 Demographics and Other Baseline Characteristics 
Analyses of demographics and other baseline characteristics are based on SS and PKAS. 
9.3.1 Demographics 
Demographic variables will be analyzed by descriptive statistics by trial group. For 
continuous variables, t test is used to calculate statistics and P value for inter-group 
differences; for discrete variables, Chi (X2) square test or Fisher exact test (if the 
number of subjects in any one group is <5) is used to calculate P value for inter-group 
differences. The following information will be tabulated and summarized. 
 
Age (years) = Integer [(Date of Signature of the Informed Consent - Date of Birth 
+ 1)/365.25]. 
 
Sex: Male 
 
Nationality: Han Nationality, Other 
 
Height (cm) 
 
Body Weight (kg) 
 
Body Mass Index BMI (kg/m2) 
The demographics list is provided by trial group and subject no. 
9.3.2 Prior Medical History and Surgical History 
The prior medical history and surgical history are coded in accordance with the Medical 
Dictionary for Regulatory Activities (MedDRA) version 19.1, and tabulated by 
preferred term and trial group (investigational drug and reference drug). 
A list for whole prior medical history and surgical history is provided. 
9.3.3 Prior and Concurrent Medications 
Names of prior and concurrent medications are coded by WHO-Drug (version date: 
June 1, 2016) and ATC, and are summarized by ATC Code Levels 1-3 and by trial group. 


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“Prior” medications are drugs that are used and stopped prior to the first dose of the 
study drug. 
“Concurrent” medications are drugs of which: 
 
The start date is earlier, the same as, or later than the date of the first dose of the 
study drug; 
 
The stop date is the same or later than the date of the first dose of the study drug, 
or is still ongoing when the study is ended. 
A list for all concurrent medications will be provided. 
9.4 Pharmacokinetic and Bioequivalence Analyses 
Pharmacokinetic and bioequivalence analyses will be based on the pharmacokinetic 
analysis set. 
9.4.1 Pharmacokinetic Parameter Analysis 
Pharmacokinetic parameters will be estimated by WinNolin Software, using non-
compartmental model. The pharmacokinetic parameters of each subject will be 
calculated by the following method. 
Parameter 
Definition 
Computational Method 
AUC0-t 
Area [μg.h/mL] under the plasma 
drug 
concentration-time 
curve 
from time 0 to the last sample 
collection timepoint t when the 
concentration may be measured 
accurately 
Calculated 
by 
trapezoidal 
method 
(Linear Up/Log Down) 
AUC0-∞ 
Area [μg.h/mL] under the plasma 
drug 
concentration-time 
curve 
from time 0 to infinity (∞) 
AUC0-∞=AUC0-t+ (Clast/λz); where Clast is 
the 
plasma 
drug 
concentration 
corresponding to the last measurable 
timepoint Tlast 
Cmax 
Maximal 
plasma 
blood 
concentration [μg/mL] 
Derived directly from observed data 
λz 
Apparent elimination rate constant 
[1/h] 
If the log-transformed values of the final 
test timepoint, as well as several points 
traced from it (more than 3 timepoints, 
and the first timepoints must be more 
than Tmax) show a linear shift, then they 
are calculated by linear regression. 
t½ 
elimination half-life [h] 
Ln2/λz 
CL 
Apparent Clearance [mL/h/kg] 
Dose / AUC0-∞ 
Vz 
Apparent volume of distribution 
[mL/kg] 
Dose / (λz × AUC0-∞) 
AUC_% 
Extrap 
Extrapolated Area Percentage [%] 
(AUC0-∞-AUC0-t)/ AUC0-∞ × 100% 
Tmax 
Time to Peak [h] 
Derived directly from observed data 
 
The non-transformed data of plasma concentration, AUC0-t, AUC0-∞, Cmax, λz, t½, CL, 
Vz, AUC_% Extrap, and Tmax of the investigational drug product and the reference drug 


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product at the time points are summarized with descriptive statistics by stage. The 
average and individual plasma drug concentration-time curves are plotted by trial group. 
Basic rules for pharmacokinetic data processing 
1) How to process values below the lower limit of quantification (BLQ, below lower 
limit of quantification). 
If one or more non-quantifiable (NQ) values occur prior to the first measurable 
concentration, they should be set as 0. If one single NQ value occurs between two 
measurable concentrations, then it should be set as missing. If two or more NQ values 
occur between two measurable concentrations, then the curve should end at the last 
measurable concentration prior to NQ. If the NQ concentration occurs after the last 
measurable concentration, then the curve should end at the last measurable 
concentration prior to NQ. 
2) AUC_% Extrap ≥ 20% 
Generally, AUC_% Extrap is less than 20%. According to the PKAS definition in the 
protocol, it is required that AUC0-t and AUC0-∞ can be calculated reliably. Therefore, 
when AUC_% Extrap ≥20%, AUC0-∞ cannot be calculated reliably, and should be 
excluded. 
3) NCA Computational Method 
Using the practical sampling times, PK parameters are calculated by Linear Up/Log 
Down method. 
4) Selection of Concentration Points for Computation of λz 
For log transformed concentration vs time data, the linear regression method is used to 
estimate elimination rate constant. For computation of λz, at least 3 data points are 
required, and the analysis method for λz is set as Best fit. Ideally, R2 value is more than 
0.85; however in some cases, a lower R2 may also be acceptable. 
5) Decimal Point Reservation 
Concentration-time data and PK parameters are not rounded prior to statistical analysis. 
9.4.2 Judgment of Bioequivalence 
The primary objective of the study is to test bioequivalence between IBI305 and 
Bevacizumab. After log transformation, the primary PK endpoints (AUC0-t and AUC0-
∞) are analyzed by the analysis of variance model. The difference of the least square 
means between IBI305 and Bevacizumab, and its corresponding 90% CI are calculated. 
Geometric mean ratio and its 90%CI are obtained after anti-logarithmic transformation. 


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If 90% CI for the geometric mean ratio of AUC0-t and AUC0-∞ (trial/control) ranges 
between 0.8-1.25, then it is considered that IBI305 and Bevacizumab are bioequivalent. 
The secondary PK endpoint of the study is Cmax. Log transformed Cmax is analyzed by 
the analysis of variance model; the difference of the least square mean of the parameter 
between IBI305 and Bevacizumab, and its corresponding 90% CI are calculated, and 
the geometric mean ratio and its 90% CI are calculated by after anti-logarithmic 
transformation. 
If the ADA positive rate after administration of the drug is >10%, then PK parameter 
and its bioequivalence analysis are carried out for the subgroup of ADA negative 
subjects. 
9.5 Safety Analysis 
The safety analysis is based on the safety analysis set. 
9.5.1 Drug Exposure 
The total drug exposure will be calculated, and t test is used to calculate P value for 
inter-group differences; the following summaries are provided: 
• 
Practical dose (mg) 
• 
Infusion duration (min) 
9.5.2 Adverse Events 
All adverse events (AEs) will be classified in accordance with the System Organ Class 
(SOC) and Preferred Term (PT) of the ICH Medical Dictionary for Regulatory 
Activities (MedDRA). 
In this clinical trial, any adverse event of subjects, occurred from start of the 
investigational drug to end of the study, will be considered as “treatment-emergent 
adverse event (TEAE)”. 
Number and percentages of subjects with treatment-emergent adverse events (TEAEs), 
Grade 3 or higher TEAEs, severe adverse events (SAEs), TEAEs related with the 
investigational drug, TEAEs leading to discontinuation of the study, TEAEs leading to 
discontinuation of the drug, and adverse events of special interest (AESIs), and 
important adverse events will be summarized by System Organ Class, preferred term, 
and group; P values for incidences of those adverse events will be calculated by Chi 
square test or Fisher exact test (the number of subjects in at least one group is <5). 
Additionally, the severity of TEAEs, and relationship with the investigational drug will 
be also summarized by organ system, preferred term, and group. 


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In the table for overall incidences of adverse events, subjects with the same AE once 
but with different severities will be only counted once in the frequency table; its 
maximum severity will be used, applicable for SOC and PT. 
Lists for all AEs (including non-TEAE), SAEs, AEs leading to death, AEs leading to 
discontinuation of the study, AESIs, and important adverse events will be provided. 
Severity 
Severity of each TEAE will be classified as one of 5 grades (Grades 1-5) in accordance 
with the National Cancer Institute - Common Terminology Criteria for Adverse Events 
(NCICTCAE) V4.03. The incidence (frequency and percentage) will be provided by 
SOC and PT. 
TEAEs with missing severity, occurred after the first dose of the investigational drug, 
would be counted as severe. If a subject reports one TEAE more than once in SOC/PT, 
then AE with the maximum severity will be used in the summary of corresponding 
severities. 
Relationship with the Investigational Drug 
The investigator will indicate the relationship with the investigational drug, classified 
as “Related”, “Possibly Related”, “Unlikely Related”, “Unrelated”, and “Cannot Be 
Judged”. TEAE with missing relationship with the investigational drug would be 
considered as “Possibly Related” with the investigational drug. If a subject reports the 
same AE more than once in SOC/PT, then AE with the maximum severity will be used 
in the summary of corresponding relationships. Relevant TEAEs in the summary table 
include TEAEs which are “Related”, “Possibly related”, and “Cannot be judged” with 
the investigational drug. 
Adverse Events of Special Interest (AESI) 
Incidence (Frequency and Percentage) of Adverse Events of Special Interest (AESI) 
will be summarized. Including the following adverse events: 
• 
Hypertension 
• 
Proteinuria 
• 
Gastrointestinal perforation 
• 
Hemorrhagic events 
• 
Cardiac toxicity 
• 
Phlebitis 
• 
Thrombus 


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• 
Intestinal fistula 
• 
Posterior reversible encephalopathy syndrome 
• 
Hypersensitivity reaction, infusion reaction 
 
For infusion reaction, duration of TEAE, and the interval from the injection time of the 
drug will be summarized, which are calculated as follows: 
• 
Duration of Infusion Reaction (min) = End Date and Time of the Infusion Reaction 
- Start Date and Time of the Infusion Reaction 
• 
Interval (min) from the Injection Time of the Drug = Start Date and Time of the 
Infusion Reaction - Date and Time of the Last Infusion prior to Start of the Infusion 
Reaction 
Important Adverse Events 
Important adverse events means adverse events, significant hematological 
abnormalities or other significant laboratory test abnormalities requiring specific 
medical measures (such as discontinuation of the drug, reduced dose, and symptomatic 
therapy), except severe adverse events. 
Important adverse events will be determined and confirmed one by one by the medical 
team. 
9.5.3 Clinical laboratory Test Value 
The computational formula for blood urea nitrogen is: Blood Urea Nitrogen (mg/dL) = 
Urea (mg/dL) × 0.466; the remaining laboratory data are originated from eCRF. 
Continuous trial data will be described by summary statistics (number of patients, mean, 
standard deviation, median, minimum, and maximum) of measured values and changes 
since baseline by planned time point and trial group. The baseline laboratory evaluation 
results, and the worst results during the trial will be summarized in cross table. 
A list for all laboratory test values, and abnormalities converted from normal condition 
will be provided. 
9.5.4 Vital Signs 
For parameters of vital signs, measured values and changes since baseline will be 
summarized by planned time point and trial group. Abnormal values of vital signs will 
be summarized. 
See the table below for abnormal values of vital signs: 
Parameter 
Unit 
Low 
High 


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Systolic 
blood 
pressure 
mmHg 
≤90 mmHg, or change ≤ -20 
mmHg since baseline 
≥140 mmHg, and change ≥ 20 
mmHg since baseline 
Diastolic 
blood 
pressure 
mmHg 
≤50 mmHg, and change ≤ -15 
mmHg since baseline 
≥90 mmHg, and change ≥ 15 mmHg 
since baseline 
Pulse 
Bpm 
≤50 bpm, and change ≤ -15 
bpm since baseline 
≥120 bpm, and change ≥ 15 bpm 
since baseline 
Body 
temperature 
℃ 
NA 
≥37℃, AND change 1.0℃ since 
baseline 
Body 
weight 
Kg 
Percentage change ≤ -10.0% 
since baseline 
Percentage change ≥ 10.0% since 
baseline 
 
A list for all parameter values of vital signs and abnormal values will be provided 
9.5.5 12-Lead ECG 
QTc intervals in the table and list are corrected by calculated QTc F; the formula is 
provided below: 
QTc interval (msec)= 3
)
60
/(hr
QT
 
For parameters of 12-lead ECG, measured
 
values and changes since baseline will be 
summarized by planned timepoint and trial group. The baseline laboratory evaluation 
results of 12-lead ECG, and the worst results during the trial will be summarized in 
cross table. 
Abnormal values of QTc intervals will be summarized: 
Absolute values of QTc intervals will be classified as: 
• 
>450 msec 
• 
>480 msec 
• 
>500 msec 
Changes of QTC intervals since baseline will be classified as: 
• 
Prolongation >30 msec 
• 
Prolongation >60 msec 
A list of all parameter values and prolonged QTc intervals will be provided. 
9.5.6 Physical Examination 
Physical examination results will not be summarized. A list of all physical examination 
results will be provided and abnormal values will be indicated. 
9.6 Immunogenicity Analysis 
Immunogenicity analysis dataset will be used for analysis. 
Positive rate of anti-drug antibody (ADA), and positive rate of neutralizing antibody 


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(Nab) will be summarized by planned timepoint and trial group. A list for all 
immunogenicity parameters will be provided. 
10. Quality Control 
To ensure that TFL results are delivered each time at high quality level, the quality 
control procedure of TFL will be defined detailedly in the Quality Control Plan 
Document. 
 
 


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Appendix 1. Abbreviations 
AE 
Adverse Events 
ADA 
Anti-Drug Antibody 
ADA-AS 
Immunogenicity Analysis Set 
AESI 
Adverse Event of Special Interest 
ATC 
Anatomic Therapeutic Chemical Classification 
AUC0-∞ 
Area under the Plasma Drug Concentration-Time Curve from Time 0 to 
Infinity 
AUC0-t 
Area under the Plasma Drug Concentration-Time Curve from Time 0 to t 
AUC_%Extrap 
Extrapolated Area Percentage [%] 
BLQ 
Less than the Lower Limit of Quantitation 
BMI 
Body Weight Index 
CFDA 
National Medical Products Administration 
CI 
Confidence Interval 
CL 
Plasma Clearance Rate 
Cmax 
Maximal Plasma Concentration 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Variation Coefficient 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture System of Clinical Trial 
FAS 
Full Analysis Set 
ICH 
International Conference of Harmonization 
MedDRA 
ICH Medical Dictionary for Regulatory Activities 
NAb 
Neutralizing Antibody 
NQ 
Not Quantified 
PK 
Pharmacokinetics 
PKAS 
Pharmacokinetic Analysis Set 
PT 
Preferred Term 
QA 
Quality Assurance 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
Organ System 
SS 
Safety Dataset 
t½ 
Elimination Half-Life 
Tmax 
Time to Peak [h] 
TEAE 
Treatment-Emergent Adverse Event 
TFL 
Table, Figure, and List 
VEGF 
Vascular Endothelial Growth Factor 
Vz 
Apparent volume of Distribution 
WHO-DD 
World Health Organization Drug Dictionaries 
λz 
Apparent Elimination Rate Constant [1/h] 
 


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Appendix 2. Tables, Figures, and Lists 
14.1 Demographic and Baseline & Other Baseline Characteristics 
Table 14.1.1. Summary of Subjects Disposition- All Subjects 
Table 14.1.2. Major Protocol Deviation - Full Analysis Set 
Table 14.1.3. Distribution of the Analysis Population - Randomized Subjects 
Table 14.1.4.1. Demographic Summary - Safety Analysis Set 
Table 14.1.4.2. Demographic Summary - Pharmacokinetic Analysis Set 
Table 14.1.5. Summary of Smoking and Alcohol Consumption History - Safety Analysis Set 
Table 14.1.6.1. Summary of Prior Medical History by Preferred Term - Safety Analysis Set 
Table 14.1.6.2. Summary of Surgical History by Preferred Term - Safety Analysis Set 
Table 14.1.7.1. Summary of Prior Medications by the 3-Level ATC Code - Safety Analysis Set 
Table 14.1.7.2. Summary of Concomitant Medications coded by 3-Level ATC Code - Safety 
Analysis Set 
Table 14.1.8. Summary of Virological Test Results - Safety Analysis Set 
14.2. Pharmacokinetics and Bioequivalence Tables 
Table 14.2.1.1. Summary of Plasma Drug Concentration - Pharmacokinetic Analysis Set 
Table 14.2.1.2. Summary of Pharmacokinetic Parameters - Pharmacokinetic Analysis Set 
Table 14.2.2. Summary of Bioequivalence Analyses - Pharmacokinetic Analysis Set 
14.3. Tables for Safety Data 
Table 14.3.1. Summary of Drug Exposures - Safety Analysis Set 
Table 14.3.2.1. Summary of Adverse Events - Safety Analysis Set 
Table 14.3.2.2. Summary of Adverse Events by System Organ Class and Preferred Term - Safety 
Analysis Set 
Table 14.3.2.3. Summary of Adverse Events Related with the Investigational Drug by System Organ 
Class and Preferred Term - Safety Analysis Set 
Table 14.3.2.4. Summary of Serious Adverse Events by System Organ Class and Preferred Term - 
Safety Analysis Set 
Table 14.3.2.5. Summary of Adverse Events leading to Discontinuation of the Drug by System 
Organ Class and Preferred Term - Safety Analysis Set 
Table 14.3.2.6. Summary of Adverse Events leading to Discontinuation of the Study by System 
Organ Class and Preferred Term - Safety Analysis Set 
Table 14.3.2.7. Summary of Adverse Events of Special Interest by System Organ Class and 
Preferred Term - Safety Analysis Set 
Table 14.3.2.8. Summary of Important Adverse Events by System Organ Class and Preferred Term 
- Safety Analysis Set 
Table 14.3.2.9. Summary of Adverse Events by System Organ Class, Preferred Term, and Maximum 
Severity - Safety Analysis Set 
Table 14.3.2.10. Summary of Treatment-emergent Adverse Events Related with the Drug by System 
Organ Class, Preferred Term, and Maximum Severity - Safety Analysis Set 
Table 14.3.2.11. Summary of Important Adverse Events by System Organ Class, Preferred Term, 
and Maximum Severity - Safety Analysis Set 
Table 14.3.2.12. Summary of Grade 3 or higher Treatment-emergent Adverse Events by System 
Organ Class and Preferred Term - Safety Analysis Set 
Table 14.3.2.13. Summary of Adverse Events by System Organ Class, Preferred Term, and 
Relationship with the Drug - Safety Analysis Set 
Table 14.3.2.14. Summary of Infusion Reactions - Safety Analysis Set 
Table 14.3.3.1.1. Summary of Hematology Test - Safety Analysis Set 
Table 14.3.3.1.2. Cross tables prior to and after Hematology Test - Safety Analysis Set 
Table 14.3.3.1.3. List of Abnormal Hematology Test Results - Safety Analysis Set 
Table 14.3.3.2.1. Summary of Blood Biochemistry - Safety Analysis Set 
Table 14.3.3.2.2. Cross tables prior to and after Blood Biochemistry - Safety Analysis Set 
Table 14.3.3.2.3. List of Abnormal Blood Biochemistry Results - Safety Analysis Set 
Table 14.3.3.3.1. Summary of Urine Test - Safety Analysis Set 
Table 14.3.3.3.2. Cross tables prior to and after Urine Test - Safety Analysis Set 
Table 14.3.3.3.3. List of Abnormal Urine Test Results - Safety Analysis Set 
Table 14.3.3.4.1. Summary of Coagulation Test - Safety Analysis Set 


Protocol No.: CIBI305A201 
Statistical Analysis Plan 
Version: V1.0 
Sponsor: Innovent Biologics (Suzhou) Co., Ltd. 
Confidential Data 
Version Date: Sep 30, 2017 
 
21/24 
Table 14.3.3.4.2. Cross tables prior to and after Coagulation Test - Safety Analysis Set 
Table 14.3.3.4.3. List of Abnormal Coagulation Test Results - Safety Analysis Set 
Table 14.3.3.5.1. Summary of Immunogenicity Test Results - Immunogenicity Analysis Set 
Table 14.3.3.5.2. Summary of Immunogenicity Test Results - Safety Analysis Set 
Table 14.3.4.1. Summary of Vital Signs - Safety Analysis Set 
Table 14.3.4.2. Summary of Abnormal Vital Signs - Safety Analysis Set 
Table 14.3.5.1. Summary of 12-Lead ECG - Safety Analysis Set 
Table 14.3.5.2. Cross tables prior to and after 12-Lead ECG Overall Evaluation - Safety Analysis 
Set 
Table 14.3.5.3. Summary of Abnormal QTc Intervals - Safety Analysis Set 
Table 14.3.5.4. List of Abnormal 12-Lead ECG Values - Safety Analysis Set 
Table 14.3.6. List of Abnormal Values of Physical Examination - Safety Analysis Set 
14.4 Figure 
Figure 14.4.1. Mean Plasma Drug Concentration (± Standard Deviation) with Time - 
Pharmacokinetic Analysis Set 
Figure 14.4.2. Individual Plasma Concentrations - Pharmacokinetic Analysis Set 
16. Lists of Trial Data 
List 16.1.1. Distribution of Subjects - All Subjects 
List 16.1.2. Protocol Deviations - Safety Analysis Set 
List 16.1.3. Demographics - Safety Analysis Set 
List 16.1.4. Smoking and Alcohol Consumption History - Safety Analysis Set 
List 16.1.5. Prior Medical History and Surgical History - Safety Analysis Set 
List 16.1.6. Medication Records - Safety Analysis Set 
List 16.1.7. Prior and Concurrent Medications - Safety Analysis Set 
List 16.2.1. Plasma Drug Concentration - Pharmacokinetic Analysis Set 
List 16.2.2. Pharmacokinetic Parameters - Pharmacokinetic Analysis Set 
List 16.3.1.1. All Adverse Events - Safety Analysis Set 
List 16.3.1.2. Serious Adverse Events - Safety Analysis Set 
List 16.3.1.3. Adverse Events leading to Death - Safety Analysis Set 
List 16.3.1.4. Adverse Events leading to Discontinuation of the Study - Safety Analysis Set 
List 16.3.1.5. Adverse Events of Special Interest - Safety Analysis Set 
List 16.3.1.6. Important Adverse Events - Safety Analysis Set 
List 16.3.2.1. Hematology Test Results - Safety Analysis Set 
List 16.3.2.2. Blood Biochemistry Results - Safety Analysis Set 
List 16.3.2.3. Urine Test Results - Safety Analysis Set 
List 16.3.2.4. Coagulation Test Results - Safety Analysis Set 
List 16.3.2.5. Virological Test Results - Safety Analysis Set 
List 16.3.2.6. Immunogenicity Test Results - Immunogenicity Analysis Set 
List 16.3.3. Vital Signs Examination Results - Safety Analysis Set 
List 16.3.4. 12-Lead Electrocardiography Results - Safety Analysis Set