Clinical trial NCT03393208
Conditions: Healthy
Keywords: Diabetes Mellitus Glucophage Immediate Release (GIR) Bioequivalence Study
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2018-01-10; Completion date: 2018-01-29
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The study will assess the bioequivalence between single doses of glucophage immediate release (GIR) test tablets and GIR reference tablets under fed and fasted state in healthy subjects.

Detailed description:

Arms: arm 1: Participants received a single oral dose of 500 milligram (mg) of test Glucophage Immediate Release (GIR) tablet Sino-American Shanghai Squibb (SASS)/China) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GIR (Merck Santé in Semoy (MSS)/France) on Day 8 in treatment period 2 under fasting condition. There was a wash-out period of 7 days between each treatment period. arm 2: Participants received a single oral dose of 500 mg of reference GIR tablet (MSS/France) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GIR (SASS/China) on Day 8 in treatment period 2 under fasting condition. There was a wash-out period of 7 days between each treatment period. arm 3: Participants received a single oral dose of 500 mg of test GIR tablet (SASS/ China) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GIR (MSS/France) on Day 8 in treatment period 2 under fed condition. There was a wash-out period of 7 days between each treatment period. arm 4: Participants received a single oral dose of 500 mg of reference GIR tablet (MSS/ France) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GIR (SASS/China) on Day 8 in treatment period 2 under fed condition. There was a wash-out period of 7 days between each treatment period.
Interventions: intervention 1: Test GIR intervention 2: Reference GIR
Intervention descriptions: intervention 1: Participants received 500 milligrams (mg) test GIR in fasting or fed state on either Day 1 (Treatment Period 1) or Day 8 (Treatment Period 2). intervention 2: Participants received 500 mg reference GIR in fasting or fed state on either Day 1 (Treatment Period 1) or Day 8 (Treatment Period 2).

Protocol documents:
Prot_000.pdf: 
GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
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Clinical Trial Protocol
Clinical Trial Protocol Number
MS200084_0009
Title
A Randomized, Open-label, 2-Way-Crossover Study 
Assessing the Bioequivalence between Single Doses 
of 500 mg Glucophage Immediate Release (GIR) 
Tablets 
(Sino-American 
Shanghai 
Squibb 
Pharmaceuticals Ltd./ Manufactured in China) and 
500 mg GIR Tablets (Merck Santé s.a.s. in Semoy/ 
Manufactured in France) under Fed and Fasted State 
in Two Groups of Healthy Subjects
Phase
I
IND Number
Not applicable
EudraCT Number
Not applicable
Principal Investigator
Sponsor
Sino-American Shanghai Squibb Pharmaceuticals 
Ltd.
1315 Jianchuan Road, Minhang District
Shanghai 200240
P. R. China
Protocol Lead:
Merck Serono Co., Ltd.
25F, NUO Center Office
No. 2A, Jiangtai Road, Chaoyang District
Beijing 100016
P. R. China
Medical Responsible:
Merck Serono Co., Ltd.
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25F, NUO Center Office
No. 2A, Jiangtai Road, Chaoyang District
Beijing 100016
P. R. China
Clinical Trial Protocol Version
20 Nov 2017/ Version 2.0 including amendment 1.0
Replaces Version
21 Jul 2017/ Version 1.0
-
 –
This document is the property of Sino-American Shanghai Squibb Pharmaceuticals, or one of its 
subsidiaries. It is intended for restricted use only and may not – in full or part – be passed on, 
reproduced, published or used without express permission of Sino-American Shanghai Squibb 
Pharmaceuticals, or its subsidiary. Copyright © 2017 by Sino-American Shanghai Squibb 
Pharmaceuticals, or its subsidiary. All rights reserved.
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Protocol Table of Contents
Protocol Table of Contents ..................................................................................................3
Table of In-Text Tables .......................................................................................................7
Table of In-Text Figures......................................................................................................7
List of Abbreviations ...........................................................................................................8
1
Synopsis..............................................................................................10
2
Sponsor, Investigators, and Trial Administrative Structure ...............18
2.1
Trial Structure.....................................................................................18
2.2
Trial Center/Country...........................................................................18
3
Background Information.....................................................................18
3.1
Diabetes Mellitus and Treatment........................................................18
3.2
Glucophage Immediate Release .........................................................19
3.3
Study Rationale...................................................................................19
4
Trial Objectives ..................................................................................20
4.1
Primary Objectives .............................................................................20
4.2
Secondary Objectives .........................................................................20
5
Investigational Plan ............................................................................20
5.1
Overall Trial Design and Plan ............................................................20
5.2
Discussion of Trial Design .................................................................21
5.2.1
Inclusion of Special Populations ........................................................22
5.3
Selection of Trial Population..............................................................22
5.3.1
Inclusion Criteria ................................................................................22
5.3.2
Exclusion Criteria...............................................................................23
5.4
Criteria for Initiation of Trial Treatment ............................................24
5.5
Criteria for Subject Withdrawal..........................................................24
5.5.1
Withdrawal from Trial Therapy..........................................................24
5.5.2
Withdrawal from the Trial..................................................................24
5.6
Premature Termination of the Trial ....................................................24
5.7
Definition of End-of-Trial ..................................................................25
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................25
6.1
Description of the Investigational Medicinal Products ......................25
6.2
Dosage and Administration ................................................................25
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6.3
Assignment to Treatment Groups.......................................................26
6.4
Noninvestigational Medicinal Products to be Used............................27
6.5
Concomitant Medications and Therapies ...........................................27
6.5.1
Permitted Medicines...........................................................................27
6.5.2
Prohibited Medicines..........................................................................27
6.5.3
Other Interventions.............................................................................27
6.5.4
Special Precautions.............................................................................28
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................28
6.6
Packaging and Labeling of the Investigational Medicinal Product....29
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................29
6.8
Investigational Medicinal Product Accountability.............................30
6.9
Assessment of Investigational Medicinal Product Compliance .........30
6.10
Blinding ..............................................................................................31
6.11
Emergency Unblinding.......................................................................31
6.12
Treatment of Overdose .......................................................................31
6.13
Medical Care of Subjects after End-of-Trial ......................................31
7
Trial Procedures and Assessments......................................................31
7.1
Schedule of Assessments....................................................................31
7.1.1
Screening (Day -14 to Day -2)............................................................32
7.1.2
Admission to Clinical Research Unit (Day -1)...................................35
7.1.3
Period 1 (Day 1 administration to 48 hours post administration).......36
7.1.4
Washout Period...................................................................................39
7.1.5
Day 7...................................................................................................39
7.1.6
Period 2 (Day 8 administration to 48 hours post administration).......39
7.1.7
Conditional follow-up (Day 15)/Premature Withdrawal....................40
7.1.8
Estimated Blood Sample Volumes per Subject..................................41
7.2
Demographic and Other Baseline Characteristics ..............................42
7.3
Efficacy Assessments .........................................................................42
7.4
Assessment of Safety..........................................................................42
7.4.1
Adverse Events ...................................................................................42
7.4.2
Pregnancy and In Utero Drug Exposure.............................................46
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7.4.3
Clinical Laboratory Assessments .......................................................47
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............47
7.5
Pharmacokinetics................................................................................48
7.6
Biomarkers..........................................................................................49
7.7
Other Assessments..............................................................................49
8
Statistics..............................................................................................50
8.1
Sample Size ........................................................................................50
8.2
Randomization....................................................................................51
8.3
Endpoints............................................................................................52
8.3.1
Primary Endpoints ..............................................................................52
8.3.2
Secondary Endpoints ..........................................................................52
8.3.3
Safety Endpoints.................................................................................52
8.4
Analysis Sets.......................................................................................53
8.5
Description of Statistical Analyses.....................................................53
8.5.1
General Considerations.......................................................................53
8.5.2
Analysis of Primary Endpoints...........................................................53
8.5.3
Analysis of Secondary Endpoints.......................................................54
8.5.4
Analysis of Safety and Other Endpoints.............................................54
8.6
Interim and Additional Planned Analyses ..........................................56
9
Ethical and Regulatory Aspects..........................................................56
9.1
Responsibilities of the Investigator ....................................................56
9.2
Subject Information and Informed Consent .......................................56
9.3
Subject Identification and Privacy......................................................57
9.4
Emergency Medical Support and Subject Card..................................57
9.5
Clinical Trial Insurance and Compensation to Subjects.....................58
9.6
Independent Ethics Committee or Institutional Review Board..........58
9.7
Health Authorities...............................................................................58
10
Trial Management...............................................................................59
10.1
Case Report Form Handling...............................................................59
10.2
Source Data and Subject Files............................................................59
10.3
Investigator Site File and Archiving...................................................60
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................60
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10.5
Changes to the Clinical Trial Protocol................................................61
10.6
Clinical Trial Report and Publication Policy......................................61
10.6.1
Clinical Trial Report...........................................................................61
10.6.2
Publication..........................................................................................61
11
References...........................................................................................62
12
Appendices .........................................................................................64
Appendix I: 
Contraceptive Guidance and Woman of Childbearing Potential........65
Appendix II:
Signature Pages and Responsible Persons for the Trial......................67
Signature Page – Protocol Lead.........................................................................................68
Signature Page – Principal Investigator.............................................................................69
Sponsor Responsible Persons not Named on the Cover Page ...........................................70
Appendix III:
Protocol Amendments and List of Changes .......................................71
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Table of In-Text Tables
Table 1
Schedule of Assessments............................................................................... 16
Table 2
Instruction of Trial Periods............................................................................ 21
Table 3
Information of Investigational Medicinal Products....................................... 25
Table 4
Assignment to Administration Sequences..................................................... 26
Table 5
Hematology Assessments.............................................................................. 34
Table 6
Hematology Assessments for Differential White Blood Cell Counts ........... 34
Table 7
Biochemistry Assessments ............................................................................ 34
Table 8
Sampling Collection Schedule....................................................................... 38
Table 9
Estimated Blood Sample Volumes Per Subject............................................. 41
Table 10
Results From Iran Bioequivalence Study-2013 Fasting (N= 21) .................. 50
Table 11
Results From H105 Fed (N= 24) ................................................................... 50
Table 12
Sample Size and Power – Assuming Coefficient Of Variation = 17.5% For 
Cmax And 13.8% For Auc0NT (Iran Be 2013 Fasting) And Assume 5% Variation For All 
Ratios (95% To 105%).......................................................................................................... 51
Table 13
Sample Size and Power – Assuming Coefficient Of Variation = 7.6% For 
Cmax And 8.8% For Auc0NT (H105 Ir Fed) And Assume 5% Variation For All Ratios (95% 
To 105%)
51
Table 14
Randomization Allocation............................................................................. 52
Table of In-Text Figures
Figure 1
Schematic Chart of Trial Design ....................................................................21
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List of Abbreviations
ADR
Adverse Drug Reaction
AE
Adverse Event
AUC0NO
Area Under The Plasma Concentration-Time Curve From Time 0 To Infinity
AUC0Nt
Area Under The Plasma Concentration-Time Curve From Time 0 To Time t
AUCextra
Extrapolated Part Of AUC0NO Calculated By Clast/ Pz , Expressed In Percent
BE
Bioequivalence
BMI
Body Mass Index
CI
Confidence Interval
CL/f
Total Clearance Following Extravascular Administration
Cmax
The Maximum Plasma Concentration Observed
CRU
Clinical Research Unit
CV
Coefficient of Variation
DBP
Diastolic Blood Pressure
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
GCP
Good Clinical Practice
GIR
Glucophage Immediate Release
GMP
Good Manufacturing Practice
HAV
Hepatitis A Virus
HbA1C
Glycosylated Hemoglobin Type A1C
HBsAg
Hepatitis B Surface Antigen
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
Max
Maximum
MDRD
Modification of Diet in Renal Disease
MSS
Merck Santé s.a.s. in Semoy
PK
Pharmacokinetic(s)
SAE
Serious Adverse Event
SASS
Sino-American Shanghai Squibb Pharmaceuticals Ltd
SBP
Systolic Blood Pressure 
SD
Standard Deviation
SEM
Standard Error of The Mean
SOP
Standard Operating Procedure
t1/2
Half-Life
T2DM
Type 2 Diabetes Mellitus
TEAE
Treatment-emergent Adverse Event
tmax
Time of Maximum Plasma Concentration Observed
TP
Treponema Pallidum
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Vss/f
Apparent Volume of Distribution At Steady-State After Extravascular 
Administration
WOCBP
Woman of Childbearing Potential
Pz
Terminal Elimination Rate Constant
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1
Synopsis
Clinical Trial Protocol Number
MS200084_0009
Title
A Randomized, Open-label, 2-Way-Crossover 
Study Assessing the Bioequivalence between 
Single Doses of 500 mg Glucophage Immediate 
Release (GIR) Tablets (Sino-American Shanghai 
Squibb Pharmaceuticals Ltd./ Manufactured in 
China) and 500 mg GIR Tablets (Merck Santé 
s.a.s. in Semoy/ Manufactured in France) under 
Fed and Fasted State in Two Groups of Healthy 
Subjects
Trial Phase
I
IND Number
Not applicable
FDA covered trial
No
EudraCT Number
Not applicable
Principal Investigator
Sponsor
Sino-American Shanghai Squibb Pharmaceuticals 
Ltd.
Trial centers/countries
Planned trial period
(first subject in-last subject out)
Fourth quarter 2017- Second quarter 2018
Trial Registry
Chinadrugtrials.org.cn
Objectives:
Primary Objective:
To assess bioequivalence (BE) between the GIR formulation manufactured in China (test
investigational medicinal product [IMP]) and that manufactured in France (reference IMP) 
following single oral dose administrations under fasting and fed conditions.
Secondary Objectives:
1. To compare additional pharmacokinetic (PK) parameters of GIR after single dose 
administrations of test and reference products.
2. To examine the safety and tolerability of GIR after single dose administrations of test 
and reference products.
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Methodology:
This trial is designed as a Phase I, open-label, randomized, 2-period, 2-sequence, crossover 
trial to assess BE between single oral doses of GIR from different manufacturing facilities, 
each given concomitantly as a single dose in fasting or fed state. Subjects will be randomized 
to receive, in each period, either:
!
1 tablet of 500 mg test GIR (manufactured in Sino-American Shanghai Squibb 
Pharmaceuticals Ltd. [SASS]/China) or
!
1 tablet of 500 mg reference GIR (manufactured in Merck Santé s.a.s. in Semoy
[MSS]/ France).
!
Drug administration will be done with or without food depending on group allocation 
to either fed or fasted condition.
The trial has a duration for each subject of approximately 4 weeks including:
!
A screening period within 2 weeks before the first GIR administration
!
First dosing/sampling period up to 2 days (48 hours) after dosing
!
A washout period of approximately 7 days after the first GIR administration
!
Second dosing/sampling period up to 2 days (48 hours) after dosing
!
A conditional follow-up examination period (only for subjects who has AE during the 
trial and ongoing at discharge) up to 7 days following the last GIR administration.
Planned number of subjects:
A total of 44 healthy male and female Chinese subjects will be enrolled in the trial, with at least 
7 subjects of each gender in the fasted group, and at least 5 subjects of each gender in the fed 
group, representing 1/4 of the total number. The sample size provides sufficient power to 
demonstrate BE.
Primary Endpoints:
Primary Endpoints will be the PK parameters area under the (plasma) concentration-time curve 
from time 0 to time t (AUC0Nt) and maximum plasma concentration observed (Cmax) of 
metformin, the active ingredient of GIR tablet.
Secondary Endpoints:
Secondary Endpoints include time of maximum plasma concentration observed (tmax), half-life 
(t1/2), area under the plasma concentration curve from time 0 to infinity (AUC0NO), the 
extrapolated part of area under the plasma concentration curve (AUCextra), terminal elimination 
rate constant (Pz), total clearance following extravascular administration (CL/f), and apparent 
volume of distribution at steady-state after extravascular administration (Vss/f) for metformin, 
as well as safety and tolerability.
The safety assessments comprise adverse events, vital signs (blood pressure, pulse rate, 
temperature and respiration), laboratory tests (biochemistry, hematology, and urinalysis), 
electrocardiogram (ECG), physical examination, and concomitant medications.
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Pharmacokinetics:
The plasma concentrations of metformin will be determined by a validated LC/MS analytical 
method. Pharmacokinetic parameters (Primary and Secondary Endpoints) will be calculated
according to noncompartmental analysis methods. The mixed trapezoidal rule will be used to 
calculate the area under the plasma concentration curve.
Diagnosis and key inclusion and exclusion criteria:
Subjects meeting all of the following criteria will be considered for enrollment in the trial:
1. Subject has given written informed consent before any trial-related activities
2. Gender: Chinese male and female subjects (at least 1/4 of each gender per trial group)
3. Age: between 18 and 55 years, inclusive
4. Weight: 50 to 80 kg; Body mass index (BMI): 18 to 30 kg/m2
5. Nonsmoker since at least 3 months
6. Good physical and mental health status, determined on the basis of the medical 
history and a physical examination
7. All values for biochemistry and hematology tests of blood and urine within the 
normal range or showing no clinically relevant deviation as judged by the Investigator
8. Electrocardiogram recording (12-lead ECG) without signs of clinically relevant 
pathology as judged by the Investigator
9. Vital signs (blood pressure, pulse, body temperature, and respiration) in sitting 
position within the normal range or showing no clinically relevant deviation as judged 
by the Investigator (The blood pressure normal range is considered V 90 mmHg and 
W 139 mmHg for systolic blood pressure [SBP]; V 60 mmHg and W 90 mmHg for 
diastolic blood pressure [DBP])
10. All women of childbearing potential (WOCBP) are not nursing, are not pregnant, and 
are using highly effective methods of birth control (defined as those, alone or in 
combination, that result in a low failure rate (ie, less than 1 percent per year) when 
used consistently and correctly) for a period of at least 1 month before and after last
dosing. Standard birth control methods are considered to be implanted contraceptive 
therapy and intrauterine devices (oral contraceptive excluded). Female subjects may 
also be enrolled if they are postmenopausal (ie, at least 12 consecutive months of 
amenorrhea after the last menstrual period) or surgically sterilized/ hysterectomized at 
least 6 months prior to trial participation; WOCBP must have negative serum
pregnancy tests at screening and on admission (Day -1)
11. Negative screen for alcohol and drugs of abuse (cannabis, benzodiazepines, 
barbiturates, opiates, cocaine, and methyl amphetamine) at screening and on 
admission
12. Negative screen for hepatitis A virus (HAV) antibodies, hepatitis B surface antigen 
(HBsAg), hepatitis C virus (HCV) antibodies, human immunodeficiency virus (HIV)
antibodies, and Treponema pallidum (TP) antibodies.
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Subjects presenting with any of the following will not be included in the trial:
1. Participation in a clinical trial within 90 days prior to first drug administration
2. Blood donation (equal or more than 500 mL) or significant blood loss within 90 days 
prior to first drug administration
3. Any surgical or medical condition, including findings in the medical history or in the 
pretrial assessments, or any other significant disease, that in the opinion of the 
Investigator, constitutes a risk or a contraindication for the participation of the subject 
in the trial or that could interfere with the trial objectives, conduct or evaluation
4. History of surgery of the gastrointestinal tract which could influence the 
gastrointestinal absorption and/or motility according to the Investigator’s opinion
5. History or presence of relevant liver diseases or hepatic dysfunction
6. Allergy: ascertained or presumptive hypersensitivity to the active drug substance 
and/or formulations’ ingredients; history of anaphylaxis to drugs or allergic reactions 
in general, which the Investigator considers may affect the outcome of the trial
7. Receipt of any prescription or nonprescription medication within 2 weeks before the 
first IMP administration, including multivitamins and herbal products (eg, St John’s 
Wort, or traditional Chinese medicines), except paracetamol
8. Renal failure or renal dysfunction (creatinine clearance < 80 mL/min) as assessed by 
using the estimated measure with the Modification of Diet in Renal Disease (MDRD) 
equation
9. Known lack of subject compliance or inability to communicate or cooperate with the 
Investigator (eg, language problem and poor mental status)
10. Nonacceptance of trial high-fat breakfast (eg, vegetarians, vegans, and subjects who 
follow special diets)
11. Consumption of large quantities of methyl xanthine-containing beverages (> 5 cups of 
coffee/day or equivalent)
12. Consumption of grapefruit, cranberry or juices of these fruits, from 14 days prior to 
drug administration until collection of the last PK sample in Period 2
13. Any contraindication to Glucophage
14. Abnormal and clinically significant chest X-ray finding at screening
Investigational Medicinal Product: dose/mode of administration/dosing schedule:
500 mg GIR tablet (manufactured in SASS/China): oral administration, single dose on Day 1
or a single dose on Day 8 of the trial.
Reference therapy: dose/mode of administration/dosing schedule:
500 mg GIR tablet (manufactured in MSS/France): oral administration, single dose on Day 1
or a single dose on Day 8 of the trial.
Planned trial and treatment duration per subject:
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The planned treatment consists of initial screening assessments (within 14 days prior to the 
first IMP administration on Day 1) followed by 2 trial periods (consisting of IMP 
administration following 2 days of blood sampling) in a crossover trial design. Each trial period 
includes a single dose of IMP administration and the doses are separated by approximately a 
7-day Washout period. A conditional follow-up visit (Day 15) will be conducted 7 days after 
administration in Period 2 (only for subjects who has AE during the trial and ongoing at 
discharge). The overall trial duration for each subject is approximately 4 weeks (or 
approximately 28 days) including the screening and conditional follow-up visit.
Statistical methods:
Based on the results of the previously conducted BE trial, a within-subject Coefficient of 
Variation (CV) for AUC0Nt and Cmax has been calculated. In previous studies, GIR formulation 
has shown relatively low intra-individual CV. With 20 evaluable subjects in the fasting and 12
subjects in the fed group will provide at least 90% power and 99.7% power to show BE in the 
fasting group and in the fed group respectively, resulting in nearly 90% power to get both. For 
a compensation of possible drop-outs, a total of 26 subjects will be included in the fasting group 
and 18 subjects in the fed group, corresponding to a drop-out rate of around 25%. In total, 44 
subjects should be included in the trial.
Primary Endpoint analysis
The analysis of Primary Endpoints will be based on PK Population The primary variable, Cmax
and AUC0Nt in fasting and fed group will be log-transformed and mixed effect model will be 
applied. The model will include effects for sequence, treatment and period. Subject within 
sequence will be included as random effect. Bioequivalence will be assessed separately, in the 
fed and in the fasted group, and the trial will be successful only, if BE has been established in 
both groups.
Based on the residual (within-subject) variation, 90% CIs for the ratio of geometric means will 
be calculated. The BE can be established if the 90% CI on the ratios between test and reference 
of the geometric means fall within 80.00% to 125.00%.
Secondary Endpoint analysis
For tmax, the Hodges-Lehmann estimates for the pairwise treatment differences and the 
corresponding 90% CIs according to the Tukey method will be calculated. The mixed model 
as described above will also be applied to AUC0NO. A 90% CI will be calculated for the ratios 
of geometric means of the test IMP and reference IMP. Summaries using descriptive analyses 
will be applied for the remaining PK parameters.
For safety endpoints, all data recorded during the trial will be presented in individual data 
listings performed on the Safety Population. All safety variables will be analyzed using 
descriptive statistics. The continuous variables will be summarized descriptively per treatment, 
period, time point, and overall by N, arithmetic mean, median, standard deviation (SD), 
standard error of the mean (SEM), and minimum and maximum values. Categorical variables 
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will be presented in frequency tables with the counts of observations and corresponding 
percentages.
Blood pressures, pulse rate measurements and ECG recordings will be individually listed by 
treatment, subject number, period, and time point, and the abnormal values flagged according 
to reference laboratory ranges. All hematology and biochemistry parameters will be listed and 
summarized using descriptive statistics by treatment, period, and time point on observed 
values. Urinalysis will be summarized in frequency tables.
20 Nov 2017/ Version 2.0 FINAL
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Table 1
Schedule of Assessments
Assessments
Screening 
(Baseline)
Period 1
Period 2
Conditional follow-
up visit or
Premature 
Withdrawalk
Daya
-14 to -2
-1
1
2
3
7
8
9
10j
15 (or specific day)
Informed consent form signed
X
Inclusion/ exclusion criteria
X
X
Demographic informationb
X
History of alcohol and nicotine 
consumption
X
Medical history
X
X
Priorc medications
X
X
Laboratory tests including 
blood test and urinalysis
X
X
X
X
Pregnancy testd (females of 
childbearing potential)
X
X
HAV antibody, HBsAg, HCV 
antibody, HIV antibody and TP 
antibody tests
X
Urine drug abuse test and 
breath test of alcohol
X
X
Urine nicotine
X
Randomization
X
Drug administration
X
X
Meal Recording
X
X
Blood sampling for 
Pharmacokineticse
X
X
X
X
X
X
Xe
Physical examinationf
X
X
X
X
X
X
Vital signsg
X
X
Xg
Xg
Xg
X
Electrocardiogram
X
X
Xh
Xh
Xh
X
Chest X-ray
X
AE recordingi
X
X
X
X
X
X
X
X
X
Concomitant therapy recording
X
X
X
X
X
X
X
X
AE = adverse event; BMI = body mass index; HAV = hepatitis A virus; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; TP = Treponema pallidum 
a.
Subject will participate in the clinical trial on an inpatient basis during Day -1 to Day 10.
b.
Demographic data includes: date of birth, sex, race, and height and weight. The BMI (kg/m2) will be calculated.
c.
Prior medications within 30 days before the date of first signature of informed consent will be collected at screening visit. Medications 
administered before first IMP dosing will also be recognized as prior medication and used for eligibility check.
d.
Serum pregnancy test will be done at screening and at Day -1.
e.
Refer to Table 8 for detail schedule of sampling during inpatient at research center. There will be an extra PK sampling for subjects with 
premature withdrawal; for subjects having conditional follow-up visit for safety, no PK sampling is required.
f.
Physical examination includes assessments of the general appearance, skin and mucosa, superficial lymph nodes, head and neck, chest, 
abdomen, musculoskeletal, and neurological systems.
g.
Vital signs including blood pressure (systolic and diastolic pressures), pulse rate, body temperature, and respiration (frequency per minute) 
will be measured and recorded. Blood pressure and pulse rate will be recorded in a sitting position after the subject has rested comfortably for
at least 5 minutes(The blood pressure normal range is considered V 90 mmHg and W 139 mmHg for SBP; V 60 mmHg and W 90 mmHg for 
DBP). At Day 1and Day 8: Vital signs will be repeated prior to dosing and at 4 hours postdose. Vital signs will also be assessed at Day 10.
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h.
Electrocardiogram (12-lead ECG, including QTc evaluation) will be performed 4 hours postdose at Day 1 and Day 8. Electrocardiogram will 
also be performed at Day 10 before discharge from research unit.
i.
Adverse events will be collected starting from Day -1, the AEs since the date of first signature of informed consent will be recorded. The 
following visits will record any AEs since the last visit.
j.
Subjects will be discharged on Day 10, after final sample collection and safety examinations are completed (final examination).
k.
If subject has AE during trial and ongoing at discharge, the subject has to come back for the conditional follow-up visit. 
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2
Sponsor, Investigators, and Trial Administrative Structure
2.1
Trial Structure
The Sponsor’s legal representative is Sino-American Shanghai Squibb Pharmaceuticals Ltd.
(SASS). The study will be conducted by Contract research organization (
 and
).
The Sponsor will supply the medication used in the trial. The investigational medicinal products 
(IMPs), Glucophage Immediate Release (GIR) 500 mg tablets, will be produced under Good 
Manufacturing Practice (GMP) conditions by SASS in China and by Merck Santé s.a.s. in Semoy
(MSS) in France as test and reference IMPs respectively.
2.2
Trial Center/Country
The trial will be conducted in single center in China.
3
Background Information
3.1
Diabetes Mellitus and Treatment
Diabetes mellitus is a metabolic disorder categorized by chronic hyperglycemia resulting from 
insufficient insulin secretion, insulin resistance, or both. This in turn leads to disturbances of the 
carbohydrate, lipid, and protein metabolism. Diabetes mellitus is therefore often associated with 
hypertension, dyslipidemia and central obesity, and is part of the metabolic syndrome [1]. The 
disease has a long asymptomatic pre-clinical phase, but complications are usually present at the 
time of diagnosis [2].
Type 2 diabetes mellitus (T2DM) accounts for 90 to 95% of patients with diabetes [1]. It is usually 
acquired secondarily and during adulthood, with a tendency to earlier onset, especially in 
connection with obesity, even in adolescence and childhood [3]. The T2DM is a worldwide health 
concern, with the global prevalence estimated to be as high as 9% amongst adults aged 18+ years 
[4]. According to World Health Organization, the diagnosis of T2DM is based on a glycosylated 
hemoglobin type A1C (HbA1C) V 6.5%; or fasting plasma glucose (FPG) V 126 mg/dl (7.0 mmol/l); 
or 2-hour plasma glucose V 200mg/dl (11.1 mmol/l) in a 75 g oral glucose tolerance testing; or a 
random plasma glucose V 200 mg/dl (11.1 mmol/l) in a patient with classic symptoms of 
hyperglycemia or hyperglycemic crisis [1,2,4,5].
A prospective study in T2DM patients revealed that lacking glycemic control is correlated with 
the development of diabetic complications, even a small rise above the normal plasma glucose 
concentration range increases the risk of macrovascular and microvascular complications [6]. The 
primary effectiveness of T2DM treatment therapy in present time is determined by a surrogate 
outcome, ie, change in HbA1C [7,8]. The IDF recommends a general HbA1C target of 7% [2]. In 
patients with renal impairment, the HbA1C should be targeted between 7.0 and 8.5%, depending 
on patient characteristics, in order to delay or prevent progression of the microvascular 
complications, including diabetic kidney disease [9], but also not to risk hypoglycemia.
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Increasingly, additional surrogate parameters, such as the body mass index (BMI), are taken into 
account in order to apply a more patient-tailored approach [10].
To date, the first intervention in newly diagnosed diabetes is still a change in lifestyle together 
with weight loss and physical activity. Until 2015, there were 9 distinct oral pharmacologic classes 
and a variety of insulin and noninsulin injectable medications available for the treatment of T2DM
[11]. Metformin was established as first-line oral antidiabetic therapy in patients with T2DM by 
findings of the UKPDS study in 1998 and further confirmed in all internationally accepted 
guidelines [12,13] unless contraindicated or not tolerated.
3.2
Glucophage Immediate Release
Glucophage®
(Metformin 
hydrochloride: 
N,N-dimethylimidodicarbonimidic 
diamide 
hydrochloride; 1,1-dimethylbiguanide hydrochloride; N,N-dimethyldiguanide hydrochloride; N’-
dimethylguanylguanidine hydrochloride) is an oral antihyperglycemic drug belonging to the class 
of biguanides and is not chemically or pharmacologically related to any other class of oral 
antihyperglycemic agents. The active ingredient, metformin, is the main representative of the 
biguanide class antihyperglycemic drugs.
Glucophage Immediate Release (GIR) tablet contains metformin hydrochloride, a white to off-
white crystalline compound with a molecular formula of C4H11N5 • HCl and a molecular weight 
of 165.62. Metformin hydrochloride is freely soluble in water and is practically insoluble in 
acetone, ether, and chloroform. It is an antihyperglycemic agent, which improves glycemic control 
in patients with T2DM. It does not stimulate insulin secretion and therefore does not produce 
clinically significant hypoglycemia. Metformin targets insulin resistance at the liver by decreasing 
hepatic glucose production and in muscle by enhancing peripheral glucose uptake and utilization, 
furthermore, it also delays intestinal glucose absorption. Metformin has been used for clinical 
management of diet-failed T2DM patients since 1959. Over this time, extensive experience has 
been gathered relating to the clinical use and safety of metformin. Currently, there are different 
approved pharmaceutical forms of Glucophage®, which have been developed to offer patients 
options that may fit their lifestyle and thereby improve compliance. Refer to the Investigator’s 
Brochure (IB) [14] for further information about the nonclinical and clinical programs of GIR and 
Guidance for the Investigator.
3.3
Study Rationale
A bioequivalence (BE) study is proposed to support “Generics Quality Consistency Evaluation” 
in China, a campaign started by Chinese health authority since 2015 with the aim to improve the 
overall quality of generics-manufacture pharmaceutical industry.
The aim of a clinical BE trial is to investigate the BE of GIR 500 mg tablets manufactured by 
SASS in China (test product) and GIR 500 mg tablets manufactured by MSS in France (as 
reference product) as a key demonstration of quality of the test product being equal to the 
reference. The clinical BE result serves also as part of the supporting package along with additional 
necessary testing including Chemistry, Manufacturing, and Controls, in vitro dissolution, etc., to 
substantiate regulatory filing upon request.
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This clinical trial will be conducted in compliance with the clinical trial protocol, International 
Council for Harmonisation (ICH) good clinical practice (GCP), and any additional applicable
regulatory requirements.
4
Trial Objectives
4.1
Primary Objectives
The primary objective of this trial is:
To assess BE between the GIR formulation manufactured in China (test IMP) and that 
manufactured in France (reference IMP) following single oral dose administrations under fasting 
and fed conditions.
4.2
Secondary Objectives
The secondary objectives of this trial are:
1. To compare additional pharmacokinetic (PK) parameters of GIR after single dose 
administrations of test and reference products.
2. To examine the safety and tolerability of GIR after single dose administrations of test and 
reference products.
5
Investigational Plan
5.1
Overall Trial Design and Plan
This trial is designed as a Phase I, open-label, randomized, 2-period, 2-sequence, crossover trial to 
assess BE between single oral doses of GIR from different manufacturing facilities, each given 
concomitantly as a single dose in fasting or fed state. Subjects will be randomized to receive, in 
each period, either:
!
1 tablet of 500 mg test GIR (manufactured in SASS/China) or
!
1 tablet of 500 mg reference GIR (manufactured in MSS/France)
!
Drug administration will be done with or without food depending on group allocation to 
either fed or fasted condition.
The trial has a duration for each subject of approximately 4 weeks (as shown in Table 2), including:
!
A screening period within 2 weeks before the first GIR administration
!
First dosing/sampling period up to 2 days (48 hours) after dosing
!
A washout period of at least 7 days after the first GIR administration
!
Second dosing/sampling period up to 2 days (48 hours) after dosing
!
A conditional follow-up examination period (only for subjects who has AE during the trial
and ongoing at discharge) up to 7 days following the last drug administration.
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Table 2
Instruction of Trial Periods 
Screening Period
Treatment Period 1
Washout Period
Treatment Period 2
Conditional
follow-up 
visit 
(only for subject 
who has AE)
Day -14 – Day -1
Day 1 – Day 3
(inpatient)
7 days (inpatient)
Day 8 – Day 10
(inpatient)
Day 15
Given local health authority guidance and Investigator recommendation, a total of 44 healthy male 
or female Chinese subjects will be enrolled in the trial, with at least 7 subjects of each gender in 
the fasted group, and at least 5 subjects of each gender in the fed group, representing 1/4 of the 
total number. Subjects will be allocated to fasting vs. fed sub-group, ie, 26 subjects will be enrolled 
into the fasting group and 18 subjects in the fed group, respectively (Figure 1). The sample size 
provides sufficient power to demonstrate BE. Each subject will be administered both the test and 
reference products in this 2 × 2 crossover BE trial to minimize the effect of the individual 
difference and periodic difference of the testing results.
Figure 1
Schematic Chart of Trial Design
GIR= glucophage immediate release
5.2
Discussion of Trial Design
This is a single-center, open-label, 2-way crossover design. This trial has been designed 
considering the latest regulatory guidelines on BE design issued by Chinese Food and Drug 
Administration in March 2016 [15]. In this new guideline, it is recommended to design a clinical 
BE study in accordance with the intended clinical practice and label of the test and reference 
product.
According to these guidelines, it is justified to conduct the trial in a crossover design, allowing for 
each subject to serve as his/her own control. The trial will be performed in an open-label manner, 
which will not influence the outcome as the primary objectives and endpoints are related to PK 
parameters, which will be evaluated with validated methods. Bioanalysis will also be done with 
validated methods. Based on previous PK experience, the sample size of 26 subjects in the fasting 
group and 18 subjects in the fed group will provide sufficient PK information as well as safety and 
tolerability data without exposing too many subjects. Study healthy subject demographics will 
represent a broader population of age (18 to 55 years old) and BMI (18 to 30 kg/m2). The treatment 
Fasting (n= 26)
Test GIR (13)
Reference GIR (13)
Fasting (n= 26)
Test GIR (13)
Reference GIR (13)
Fed (n= 18)
Test GIR (9)
Reference GIR (9)
Fed (n= 18) 
Test GIR (9)
Reference GIR (9)
Approximately 7-day washout
Period 2 (Day 8)
Period 1 (Day 1)
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schedule and dose of metformin has been chosen according to the standard treatment regimen 
applied for subjects suffering from T2DM. In China, the recommended daily dose prescribed for 
metformin is 2000 mg, whereas the average daily dose is approximately 1500 mg. There are 3 
selections of strength for GIR tablets, 500, 850 and 1000 mg. Base on ethical consideration for the 
trial will be conducted on healthy subjects, and that the 500 mg GIR tablet is a commonly 
prescribed dose strength in China, the GIR 500 mg tablet is selected for this trial.
5.2.1
Inclusion of Special Populations
Not applicable.
5.3
Selection of Trial Population
5.3.1
Inclusion Criteria
Subjects meeting all of the following criteria will be considered for enrollment in the trial:
1. Subject has given written informed consent before any trial-related activities
2. Gender: Chinese male and female (at least 1/4 of each gender per trial group)
3. Age: between 18 and 55 years, inclusive
4. Weight: 50 to 80 kg; BMI: 18 to 30 kg/m2
5. Nonsmoker since at least 3 months
6. Good physical and mental health status, determined on the basis of the medical history 
and a physical examination
7. All values for biochemistry and hematology tests of blood and urine within the normal 
range or showing no clinically relevant deviation as judged by the Investigator
8. Electrocardiogram recording (12-lead ECG) without signs of clinically relevant 
pathology as judged by the Investigator
9. Vital signs (blood pressure, pulse, body temperature, and respiration) in sitting position 
within the normal range or showing no clinically relevant deviation as judged by the 
Investigator (The blood pressure normal range is considered V 90 mmHg and 
W 139 mmHg for systolic blood pressure [SBP]; V 60 mmHg and W 90 mmHg for 
diastolic blood pressure [DBP])
10. All women of childbearing potential (WOCBP) are not nursing, are not pregnant, and are 
using highly effective methods of birth control (defined as those, alone or in combination, 
that result in a low failure rate [ie, less than 1 percent per year] when used consistently 
and correctly) for a period of at least 1 month before and after last dosing. Standard birth 
control methods are considered to be implanted contraceptive therapy and intrauterine 
devices (oral contraceptive excluded). Female subjects may also be enrolled if they are 
postmenopausal (ie, at least 12 consecutive months of amenorrhea after the last menstrual 
period) or surgically sterilized/hysterectomized at least 6 months prior to trial
participation; WOCBP must have negative serum pregnancy tests at screening and on 
admission (Day -1) (see Appendix I for details)
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11. Negative screen for alcohol and drugs of abuse (cannabis, benzodiazepines, barbiturates, 
opiates, cocaine, and methyl amphetamine) at screening and on admission
12. Negative screen for hepatitis A virus (HAV) antibodies, hepatitis B surface antigen 
(HBsAg), hepatitis C virus (HCV) antibodies, human immunodeficiency virus (HIV) 
antibodies, and treponema pallidum (TP) antibodies.
5.3.2
Exclusion Criteria
Subjects presenting with any of the following will not be included in the trial:
1. Participation in a clinical trial within 90 days prior to first drug administration
2. Blood donation (equal or more than 500 mL) or significant blood loss within 90 days 
prior to first drug administration
3. Any surgical or medical condition, including findings in the medical history or in the 
pretrial assessments, or any other significant disease, that in the opinion of the 
Investigator, constitutes a risk or a contraindication for the participation of the subject in 
the trial or that could interfere with the trial objectives, conduct or evaluation
4. History of surgery of the gastrointestinal tract which could influence the gastrointestinal 
absorption and/or motility according to the Investigator’s opinion
5. History or presence of relevant liver diseases or hepatic dysfunction
6. Allergy: ascertained or presumptive hypersensitivity to the active drug substance and/or 
formulations’ ingredients; history of anaphylaxis to drugs or allergic reactions in general, 
which the Investigator considers may affect the outcome of the trial
7. Receipt of any prescription or nonprescription medication within 2 weeks before the first 
IMP administration, including multivitamins and herbal products (eg, St John’s Wort, or
traditional Chinese medicines), except paracetamol
8. Renal failure or renal dysfunction (creatinine clearance < 80 mL/min) as assessed by 
using the estimated measure with the Modification of Diet in Renal Disease (MDRD) 
equation
9. Known lack of subject compliance or inability to communicate or cooperate with the 
Investigator (eg, language problem and poor mental status)
10. Nonacceptance of trial high-fat breakfast (eg, vegetarians, vegans and subjects who 
follow special diets)
11. Consumption of large quantities of methyl xanthine-containing beverages (> 5 cups of 
coffee/day or equivalent)
12. Consumption of grapefruit, cranberry or juices of these fruits, from 14 days prior to drug 
administration until collection of the last PK sample in Period 2
13. Any contraindication to Glucophage
14. Abnormal and clinically significant chest X-ray finding at screening
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5.4
Criteria for Initiation of Trial Treatment
Not applicable.
5.5
Criteria for Subject Withdrawal
5.5.1
Withdrawal from Trial Therapy 
Subjects who withdraw from the trial will also be withdrawn from the IMP. A subject who drops 
out will not be replaced for this trial as long as the minimum sample size of evaluable subjects is 
met. The minimum requirement is 20 evaluable subjects in the fasting and 12 subjects in the fed 
group, which will provide adequate power to show BE in both groups.
5.5.2
Withdrawal from the Trial
Subjects are free to discontinue the trial at any time without giving their reasons. A subject must 
be withdrawn in the event of withdrawal of the subject’s consent. Furthermore, participation in 
this clinical trial can be discontinued by the Investigator for one of the following reasons:
1. Adverse events(AEs), as assessed by the Investigator to affect the subject safety or the
outcome of the trial endpoints
2. Significant protocol violation such as noncompliance with restrictions regarding alcohol 
and drug use, and nonadherence to the fasting or fed conditions
3. Difficulties with blood collection
4. Emesis experienced within 4 hours following drug administration because of possibly
incomplete absorption (this period of time corresponds also to 2 times the median time of 
maximum plasma concentration [tmax] of GIR). Subjects experiencing vomiting later than 
4 hours postdose will not be withdrawn unless otherwise decided by the Investigator in 
light of subject’s safety or trial integrity
5. Subject is uncooperative during the trial
6. Use of any ongoing or concomitant medication that is prohibited
Concomitant medication of any drug except pain relief medication (paracetamol) is prohibited, the 
administration of paracetamol should not exceed 1 g per day and not more than 3 consecutive days. 
Details of reasons for premature withdrawal of subjects will be recorded and documented in the 
final report.
5.6
Premature Termination of the Trial
This trial is to be conducted in healthy subjects using products in which the safety profile is well 
known and also proven in the population with the target disease. The conduct of this trial poses 
very little risk of premature withdrawal due to safety issues. However, in every case of (premature) 
withdrawal, the assessments scheduled for Premature Withdrawal visit must be conducted 
(Section 6.13).
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In addition, the clinical trial may be terminated prematurely or suspended at the request of Health 
Authorities or if new safety or efficacy information leads to an unfavorable risk benefit judgment 
for GIR. The Sponsor may discontinue the trial if it becomes unjustifiable for medical or ethical 
reasons, for poor enrollment, or because of discontinuation of clinical development of GIR or 
withdrawal of GIR or comparator from the market for safety reasons.
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs)
will be informed about the discontinuation of the trial in accordance with applicable regulations.
5.7
Definition of End-of-Trial
The End-of-Trail is defined as the last contact of the last subject (Day 10 or the conditional
follow-up visit/ [Day 15]/or any special day for Premature Withdrawal visit).
6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
6.1
Description of the Investigational Medicinal Products
All IMPs will be sourced from respective manufacturer as listed below (Table 3). The IMPs 
manufacturing process compliant with GMP requirements. The transportation and storage are to 
be tracked by temperature monitor to insure the medication quality and compliance to China 
regulation requirements.
Table 3
Information of Investigational Medicinal Products
Drug Treatment
Test IMP
Reference IMP
Formulation:
GIR 500 mg Tablet
GIR 500 mg Tablet
Manufacturer:
SASS., China
MSS, France
Expiry Date:
Refer to the label content
Refer to the label content
Storage Condition
According to medication label 
According to medication label
GIR 500 mg = Glucophage 500 mg Immediate Release; IMP = Investigational Medicinal Product; MSS = Merck Santé s.a.s. in 
Semoy; SASS = Sino-American Shanghai Squibb Pharmaceuticals Ltd.
6.2
Dosage and Administration
Potential trial subjects will be examined at a screening examination to determine their eligibility 
for participation. These tests are to be conducted within 14 days before the first trial administration 
(first IMP given on Day 1, Period 1).
On the evening before the dosing day in the first period, subjects will be admitted to the Clinical 
Research Unit (CRU) to fast prior to Day 1 dosing (administered the next morning). During the 
fast, subjects will refrain from all food and drinks except water from the evening after dinner of 
Day -1. Water will be provided until 2 hours predose; the drug will be given with 240 mL (8 oz) 
of water at room temperature; water will then be allowed ad libitum beginning 2 hours after the 
administration of the IMP.
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On Day 1 before IMP administration, ECG and vital signs will be assessed. If the subject does not 
meet all eligibility requirements, the subject cannot be randomized to the trial.
Eligible subjects will be randomly assigned to 1 of 2 sequences. Each subject will receive single 
dose GIR 500 mg (SASS/China manufactured) or single dose of GIR 500 mg (MSS/France
manufactured) separated by a Washout period of 7 days.
The subjects in the fasting group will have fasted for at least 10 hours by the time of predose blood 
sample collected after 07:00 on Day 1.
For the fed group, subjects will consume a standard breakfast around 30 minutes before dosing,
the breakfast should be finished by 10 minutes before dosing and subjects should have predose 
blood sample collected. The single dose of trial drug administration will occur 10 minutes after 
blood collection around 07:00 in the morning of the first day of each period. The content of the 
breakfast will match the high-fat, high-calorie recommendation based on the regulatory guideline
[16].
6.3
Assignment to Treatment Groups
Each eligible subject will receive his allocated treatment according to a computer-generated 
randomization schedule (Table 4).
Sequence A to B:
!
Day 1 (Period 1), Treatment A: the administration of a single dose of test GIR
!
Day 8 (Period 2), Treatment B: the administration of a single dose reference GIR.
Sequence B to A:
!
Day 1 (Period 1), Treatment B: the administration of a single dose reference GIR
!
Day 8 (Period 2), Treatment A: the administration of a single dose of test GIR.
The 2 doses will be separated by a Washout period of approximately 7 days (Table 2).
Table 4
Assignment to Administration Sequences
Day 1 of Period 1
Day 1 of Period 2
Sequence A to B
GIR 500 mg (SASS/China manufactured)
(Test IMP)
GIR 500 mg (MSS/France manufactured)
(Reference IMP)
Sequence B to A
GIR 500 mg (MSS/France manufactured)
(Reference IMP)
GIR 500 mg (SASS/China manufactured)
(Test IMP)
GIR = Glucophage Immediate Release; IMP = Investigational Medicinal Product; MSS = Merck Santé s.a.s. in Semoy; 
SASS = Sino-American Shanghai Squibb Pharmaceuticals Ltd.
This 2 × 2 crossover design for comparison of 2 treatments complies with the Chinese guideline 
for BE trials [15]. The guideline recommends 2 sequences in order to minimize the effect of 
individual and periodic differences. The guideline suggests that the duration of Washout period 
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should be at least 7 times t1/2. Therefore, 7 days have been assigned as the Washout period duration 
to assure that the main collection times in Period 2 can occur on a weekday.
6.4
Noninvestigational Medicinal Products to be Used
No other drugs are required by the protocol.
6.5
Concomitant Medications and Therapies
Concurrent administration of any medication including herbal medications and traditional Chinese 
medicines are prohibited during the trial (except paracetamol, see Section 6.5.1).
Any additional concomitant therapy that becomes necessary during the trial must be recorded in 
the corresponding section of the eCRF noting the name, dose, duration and indication of each drug. 
Upon use of any prohibited concomitant medication the subject shall then discontinue his/her 
participation in the trial treatment and be withdrawn from trial as described in Section 5.5.2.
Medications administered between dates of informed consent form (ICF) signed to first IMP 
dosing (Day 1) will be recognized as prior medication and used for eligibility check. After IMP 
dosing, any medication will be recorded as concomitant medication. The medication taken, if any,
shall be documented in the eCRF stating the international nonproprietary name and trade name of 
the medication, its dose, duration, galenic form, route of administration, date and time of all 
administrations and indication. The data recorded up to the time at which the subject in question 
was withdrawn shall be taken for the evaluation of the trial substance’s safety and tolerability.
6.5.1
Permitted Medicines
No concomitant medication except pain relief medication (paracetamol) is allowed during the trial.
The administration of paracetamol should not exceed 1 g per day and not more than 3 consecutive 
days, and should be documented in eCRF.
6.5.2
Prohibited Medicines
Concurrent administration of any medication except paracetamol is prohibited during the trial.
Subjects enrolled in this trial should be in good general health and therefore should not be taking 
any other medication.
Upon use of any prohibited concomitant medication the subject shall then discontinue his/her 
participation in the trial treatment.
6.5.3
Other Interventions
Not applicable.
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6.5.4
Special Precautions
6.5.4.1
Alcohol Prohibition
The subjects have to abstain from alcohol from 2.5 days (approximately 60 hours) prior to dosing 
and through the entire study period.
In case of any suspicion of alcohol consumption, an additional test for alcohol may be performed 
to confirm the Investigator's judgment.
6.5.4.2
Smoking Prohibition
Smoking is included as an exclusion criterion barring eligibility into the trial and smoking is also 
prohibited during the trial.
6.5.4.3
Food Restriction
Fluids
Subjects are not allowed to excessively consume beverages containing xanthine derivate (> 5 cups 
of coffee a day or equivalent) and need to stop caffeine consumption from 48 hours prior to drug 
administration until collection of the last PK sample in each period. Subjects also need to stop 
intake of grapefruit, cranberry or juices/beverages of these fruits, from 14 days prior to drug 
administration until collection of the last PK sample in Period 2.
Food and fasting
Subjects included in the fed group must agree to consume the trial high-fat breakfast. In the fed 
group, the breakfast should be similar in fat and caloric composition of the recommended high-fat 
(approximately 50% of total caloric content of the meal), high-calorie (approximately 800 to 1000 
calories) Chinese breakfast according to the standard of the trial center. During the hospitalization 
periods, subjects will receive breakfast, lunch, and dinner at regular times (as applicable).
Prior to each drug administration (ie, Day 1 or Day 8), subjects in both groups need to fast 
overnight for at least 10 hours.
All subjects will refrain from drinking water during the first 2 hours and fasted for the first 4 hours 
after drug administration. Standard diet for lunch and dinner will be served for both fasting and 
fed groups. Beverages should be controlled: fluid intake will be controlled for each inpatient period 
for all subjects. The subjects should drink approximately 2 L of water during the first 24 hours 
after each drug administration.
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions
Not applicable.
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6.6
Packaging and Labeling of the Investigational Medicinal 
Product
All IMPs will be packaged and labeled in accordance with all applicable regulatory requirements 
and to be GMP compliance, so that it shall be possible to retrace the composition and 
pharmaceutical quality.
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
All IMP treatment boxes supplied to the trial center must be stored carefully, safely, and separately 
from other drugs. The handling and storage of IMPs should follow the regulatory requirements 
from authorities. Sponsor must provide trial center enough drugs, including subject treatment and 
in additional at least 5 times full testing sample size for any requested testing in the inspection in 
the future. In terms of study IMP as well as reference IMP, the subject treatment using part and 
the extra 5 times of full testing samples will be from one identical batch and to be labeled equally
without any difference to fulfill the randomized treatment IMPs/retention sample selection 
requirement at trial center. This requirement is appropriate for both study drugs and reference 
drugs.
Trial medication must not be used for any purpose other than the trial. The administration of trial 
medication to subjects who have not been enrolled into the trial is not covered by the subject’s trial 
insurance.
Upon receipt of trial treatment boxes at the trial center, the following must be performed by the 
trial staff:
!
Check and insure the IMPs shipment period is under the controlled temperature by referring 
the temperature logger data.
The Investigator (or the pharmacist or another person who is designated by the Investigator) will 
maintain the following records for the trial medication:
!
Inventory at the center
!
Administration to each subject
!
Destruction of unused medication.
It must be ensured that the IMP is not used at the trial center:
!
After the expiry date
!
After the retest date unless the IMP is reanalyzed and its release date extended
!
Before to receive any written greenlight from Sponsor when temperature deviation 
occurred to IMPs during the trial center storage.
These procedures are to be closely monitored by the trial monitor and trial manager.
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The drugs for the subjects must be random drawing from all the study drugs and reference drugs 
provided by the Sponsor (it can reference to randomization list from statistics), the left drugs are 
as the retention samples for the inspection or testing in the future. Any temperature occurred during 
the trial center storage should report to CRA immediately. The responsible CRA report it to Merck 
immediately as well to collect Merck written decision to use or block the impacted IMPs.
6.8
Investigational Medicinal Product Accountability
The Investigator is responsible for ensuring accountability for IMPs, including reconciliation of 
drugs and maintenance of drug records. The details are:
!
Upon receipt of IMP, the Investigator (or designee) will check for accurate delivery and 
acknowledge receipt by signing (or initialing) and dating the documentation provided by the 
Sponsor and returning it to the Sponsor. A copy will be retained for the Investigator File
!
The dispensing of the IMP will be carefully recorded on the appropriate drug accountability 
forms provided by the Sponsor and an accurate accounting will be available for verification by 
the Sponsor Monitor at each monitoring visit
!
The IMP accountability records will include:
o
Confirmation of IMP receipt, in good condition and in the defined temperature range
o
The inventory of IMP provided for the clinical trial and prepared at the site
o
The use of each dose by each subject
o
The disposition (including return, if applicable) of any unused IMP
o
Dates, quantities, batch numbers, vial numbers, expiry dates, formulation (for IMP 
prepared at the site), and the individual subject trial numbers.
!
The Investigator should maintain records that adequately document:
o
That the subjects were provided the doses specified by the clinical trial 
protocol/amendment(s), and
o
That all IMP provided by the Sponsor was fully reconciled.
The retention samples should be stored at trial center or the third party under appropriate condition. 
It is the trial center to decide the retention sample storage place and the retention samples will not
be returned to Sponsor. The trial center must collect the Sponsor’s written confirmation before to 
proceed any retention sample destruction activity.
6.9
Assessment of Investigational Medicinal Product Compliance
The trial treatments will be administered either by the Investigator or under his or her direct 
supervision in a CRU.
Investigational medicinal product administration and any reason for noncompliance should be 
recorded in the eCRF.
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6.10
Blinding
Not applicable as this is an open-label trial.
6.11
Emergency Unblinding
Not applicable.
6.12
Treatment of Overdose
This is a trial where GIR (test or reference) will be administered once per period by the 
Investigator/Clinical Trial Coordinator. Therefore, the risk of overdose will be negligible. In case 
of unexpected events, the supervising physician is responsible for diagnosis and treatment of 
unexpected adverse reactions according to accepted standard medical care and full documentation.
6.13
Medical Care of Subjects after End-of-Trial
After a subject has completed the trial and has AE during the trial and ongoing at discharge or has 
withdrawn prematurely, a conditional follow-up visit (Day 15, if subject completed the trial on 
Day 10, or any specific day for premature withdrawal) will be conducted and safety assessments 
will be performed.
Upon the careful screening for healthy subjects such as detailed in the eligibility criteria for this 
trial, no serious AEs related to study treatment are expected during this trial. However, in case of 
any ongoing AE at the last visit, these AEs must be monitored until they have either returned to 
normal or are no longer considered as clinically relevant or can be explained. If necessary, other 
medical disciplines should be consulted.
7
Trial Procedures and Assessments
7.1
Schedule of Assessments
The schedule of assessments will include:
!
Screening (determining eligibility to the trial, including assessments during admission to 
CRU; Day -14 to Day -2)
!
Admission to the CRU before Period 1 (Day -1)
!
Period 1 (Day 1 to Day 3)
!
Washout Period
!
Period 2 (Day 8 to Day 10 Discharge Day)
!
Conditional follow-up (Day 15) only for subject who has AE during the trial and ongoing 
at discharge (Table 1).
Subject will participate in the clinical trial on an inpatient basis during Day -1 to Day 10.
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The description of these trial intervals are as follow.
7.1.1
Screening (Day -14 to Day -2)
The following assessments will be conducted during screening (between Day -14 and Day -2) to 
determine eligibility of the subject for randomization to the trial.
Informed Consent
Prior to performing any trial assessments, the Investigator will ensure that the subject or the 
subject’s legal representative has provided written informed consent according to the 
procedure described in Section 9.2. The ICF will be signed by the subject prior to the subject’s 
inclusion into the trial.
Inclusion/exclusion Criteria
Potential trial subjects will be examined at screening to determine their eligibility for clinical 
trial participation. The inclusion and exclusion criteria will be reviewed to determine 
eligibility for the trial while collecting the necessary information. All screening assessments 
are to be conducted within 14 days before the first trial administration (first IMP given on 
Day 1, Period 1). Renal failure will be assessed by using the estimated measure with MDRD 
equation [17].
Demographic Information
Demographic information will consist of data collected for date of birth, sex, race (Chinese, 
non-Chinese), height and weight. The BMI (kg/m2) will be calculated.
Other Baseline Information
Other Baseline information will include inquiry for the history of alcohol and nicotine 
consumption plus the Baseline assessments described in more detail below: physical 
examination, vital signs, ECG recordings, medical history, and laboratory tests.
Medical history will include screening for past illnesses associated with allergic disorders; 
eyes, ears, nose, and throat; and past illnesses describing the cardiac, vascular, pulmonary, 
musculoskeletal, gastrointestinal, genitourinary, neurological, endocrine, psychiatric, 
dermatological, hematological systems of the body, and previous treatments.
Prior medications within 30 days before the date of first signature of informed consent will 
be collected.
Physical Examination
A detailed physical examination will be performed. This examination includes assessments 
of the general appearance, skin and mucosa, superficial lymph nodes, head and neck, chest, 
abdomen, musculoskeletal, and neurological systems.
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Vital Signs
Blood pressure (systolic and diastolic pressures), pulse rate, body temperature, and respiration 
(frequency per minute) will be measured and recorded. Blood pressure and pulse rate will be 
recorded in a sitting position after the subject has rested comfortably for at least 5 minutes.
Electrocardiogram Recording
A 12-lead ECG (including QTc evaluation) will be performed. Results of the ECG recordings 
will be included in the subject's eCRF. Printouts for each ECG will include date, time, initials 
of the technician/nurse, and initials of the Investigator who reviewed the printout. (see 
Section 7.4.4 for specific ECG determinations and procedures).
Chest X-ray
A chest X-ray imaging will be performed to check for any clinical significant abnormalities.
Laboratory Tests
Laboratory tests include blood tests and urinalysis. Parameters of hematology assessments are 
tabulated in Table 5 and Table 6, biochemistry assessment parameters are tabulated in Table
7. All laboratory test sample should be collected under fasted condition if possible. There will 
also be serum pregnancy test for WOCBP.
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Table 5
Hematology Assessments
Parameter
Dimension/Unit
Erythrocytes
×1012/L
Hemoglobin 
g/L
Hematocrit 
%
Mean corpuscular volume
fL
Mean corpuscular hemoglobin
pg
Mean corpuscular hemoglobin concentration
g/L
Red blood cell distribution width
% 
Platelets
×109/L
Mean platelet volume
fL
Thrombocytocrit
%
Platelet distribution width
%
White blood cells
×109/L
Table 6
Hematology Assessments for Differential White Blood Cell Counts
Parameter
Dimension/Unit
Neutrophils
109/L and %
Monocytes
109/L and %
Lymphocytes
109/L and %
Table 7
Biochemistry Assessments
Parameter
Dimension/Unit
Alanine aminotransferase
IU/L
Aspartate aminotransferase
IU/L
Total bilirubin
amol/L
Direct bilirubin
amol/L
Indirect bilirubin
amol/L
Protein total
g/L
Albumin
g/L
Globulin
g/L
Albumin/globulin ratio
(Not applicable)
Alkaline phosphatase
IU/L
Glutamyl transpeptidase
IU/L
Urea nitrogen
mmol/L
Creatinine
amol/L
Cholesterol
mmol/L
Triglycerides
mmol/L
Glucose
mmol/L
Creatine kinasea
IU/L
Lactate dehydrogenase
IU/L
Calcium
mmol/L
Phosphorus
mmol/L
b-Amylase
U/L
Sodium
mmol/L
Potassium
mmol/L
Chloride
mmol/L
a.
If creatine kinase is above the upper limit of normal and evaluated as clinically relevant, a retest should be done and the 
creatine phosphokinase MB isoenzyme should be determined.
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Urinalysis
Appearance, blood, glucose, ketones, nitrite, pH, protein, and leukocytes will be assessed. 
Microscopic examination will be performed if dipstick test is positive for leukocytes, blood, 
nitrites, or proteins.
Serum pregnancy test
Pregnancy testing for females of childbearing potential only (human chorionic gonadotropin
in serum)
Other laboratory tests
Serology
The following test will be done for viral infection screening:
! HAV antibody
! HBsAg
! HCV antibody
! HIV antibody
! TP antibody
Urine screening of drugs of abuse
The following urine tests for drug abuse will be conducted: levels for other drugs of abuse 
(eg, cannabis, benzodiazepines, barbiturates, opiates, cocaine, and methyl amphetamine).
Breath test of alcohol
Concentration of alcohol in breath will be tested.
Urine nicotine
Concentration of nicotine in urine will be tested.
7.1.2
Admission to Clinical Research Unit (Day -1)
In the evening before the dosing day, subjects will be admitted in an inpatient status to the CRU 
at least 12 hours prior to Day 1 dosing for an overnight fast. Subjects will refrain from all food and 
drinks except water from the evening after dinner of Day -1. They will have fasted for at least 
10 hours by the time of drug administration (fasting group) or standard breakfast (fed group) next 
morning.
Trial eligibility assessments will be performed including: physical examination, vital signs, ECG, 
laboratory tests, and prior medications since screening visit, treatments and diseases (medical 
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history) as well as testing for alcohol and drug abuse. Female subjects with childbearing potential 
will have a serum pregnancy test.
If the subject is determined to be ineligible for the trial due to any of the above assessments, the 
subject will be considered a screening failure and will not continue to randomization to the trial.
Adverse events will be collected and recorded on the eCRF, AEs since the date of first signature 
of informed consent will be recorded.
Randomization
Eligible subjects will then be randomly assigned to 1 of 2 sequences (Table 4).
7.1.3
Period 1 
(Day 1
administration 
to
48 hours
post 
administration)
Day 1, IMP Administration
On Day 1, the following assessments will be conducted and/or collected and recorded on the eCRF.
Trial Eligibility Assessments
Subjects will be assessed for vital signs (blood pressure, pulse rate, temperature and 
respiration). Blood pressure assessments determine eligibility to be randomized to the trial. 
The blood pressure (measured in sitting position after at least 5 minutes rest) normal range 
is considered V 90 mmHg and W 139 mmHg for SBP; V 60 mmHg and W 90 mmHg for DBP.
Any concomitant medications, diseases and treatments should be documented. Concurrent 
administration of any medication will be prohibited during the trial (Section 6.5.2).
If the subject is determined to be ineligible for any of the above assessments, the subject will 
not receive randomized treatment.
Any AEs and serious adverse events (SAEs) should also be recorded.
Baseline Sampling
Eligible subjects will have their Baseline blood sample collected at 10 minutes before GIR
administration in Period 1 for both the fasting and fed group subjects.
Administration of IMP
As per randomization, each subject will receive a single dose of test GIR (Sequence A-B) or 
reference GIR (Sequence B-A) accordingly.
The single dose of GIR administration will occur after 07:00 in the morning of the first day 
of each period. A total volume of 240 mL water will be consumed with the medication. 
Following the administration of the drug, hands and mouth will be checked in order to 
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confirm the consumption of the medication. All subjects will refrain from drinking water 
during the first 2 hour after drug administration and refrain from eating during the first 
4 hours. Standard diet for lunch and dinner will be served for both fasting and fed groups. 
Beverages should be controlled: fluid intake will be controlled for each inpatient period for 
all subjects. The subjects should drink approximately 2 L of water during the first 24 hours 
after drug administration.
Fasting condition and Meal Information Recording
The subjects will have their meals at the research unit on Day 1. The fasting condition; time 
of breakfast uptake and corresponding time to IMP administration; the scheduled time and 
exact time of lunch and dinner, will be recorded.
Blood Sampling (Postdose)
Blood samples for the determination of metformin (active ingredient of GIR) will be taken 
at the specified times (Table 8). The complete schedule for each trial period is presented in 
the table. The clock time of all blood draws will be recorded and reported for each subject 
in the eCRF. The actual sampling times, if available, will always be used for calculation.
Pharmacokinetic Sampling procedure
For plasma metformin detection, blood samples will be collected by indwelling cannula 
(short-term peripheral catheter) for the first day and by direct venipuncture for the rest of the 
time. Blood samples should be processed within 30 minutes (centrifuge each tube for 
10 minutes at 2000 g) or otherwise should be kept in an ice water bath pending processing.
Plasma samples will be prepared, divided into 2 aliquots and stored at maximum 
(max) -20°C. Plasma concentration of metformin will be analyzed by validated bioanalytical 
method.
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Table 8
Sampling Collection Schedule
Trial Day
Period Day
Time of Blood Sample (hour)
Window 
Allowance 
(minute)
1
1 – Predose in Period 1
Baseline blood draw (10 minutes prior to drug 
administration)
±2
1
1 – Single dose administration 
and Washout begins
0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14
±2
2
2 
24, 36
±5
3
3
48
±5
8
1-Predose in Period 2
Baseline blood draw (10 minutes prior to drug 
administration)
±2
8
1 – Single dose administration 
and Washout begins
0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14
±2
9
2 
24, 36
±5
10
3
48
±5
Premature 
Withdrawal
1-sample at premature withdrawal
±30
Note: All blood samples should be processed within 30 minutes (centrifuge each tube for 10 minutes at 2000g) 
or otherwise should be kept in an ice water bath pending processing. There will be an extra PK sampling for 
subjects who has premature withdrawal. For subjects having conditional follow-up visit for safety, no PK 
sampling is required.
Safety Monitoring
Vital signs will be repeated prior to dosing and at 4 hours postdose.
A 12-lead ECG (including QTc evaluation) will be performed 4 hours postdose.
Any concomitant diseases and treatments should be documented. Any AEs and SAEs should 
also be recorded. Concurrent administration of any medication will be prohibited during the 
trial.
Day 2 to Day 3, Period 1
Pharmacokinetic Blood Sampling (Postdose, continued)
During the 2 days following Day 1, blood samples will be taken according to the trial 
schedule (Table 8). On Day 2, sampling will be conducted at 24 and 36 hours; on Day 3,
sampling will be conducted at 48 hours after GIR administration. 
Safety Monitoring
Any concomitant diseases and treatments have to be documented. Concurrent administration 
of any medication will be prohibited during the trial. Any AEs and SAEs should also be 
recorded. Physical examination will be performed on Day 3.
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7.1.4
Washout Period 
The 2 administrations of IMP are separated by a Washout of 7 days (inpatient). Washout begins 
postdose on Day 1 and continues for approximately 7 days.
7.1.5
Day 7
Subjects will refrain from all food and drinks except water from the evening after dinner of Day 7. 
They will have fasted for at least 10 hours at the time of drug administration (fasting group) or 
standard breakfast (fed group) next morning.
Trial eligibility assessments will include: physical examination and concomitant medications 
(Table 1). 
If the subject is determined to be ineligible for any of the above assessments, the subject will be 
dismissed from the CRU and will not continue with the trial.
Any AEs will be collected and recorded on the eCRF.
7.1.6
Period 2
(Day 8
administration 
to 
48 hours
post 
administration)
Day 8, IMP Administration
Procedures outlined on Day 1 in Period 1 will be repeated on Day 8 for continuing trial eligibility 
into Period 2.
Baseline Sampling
Eligible subjects will have their Baseline blood sample collected 10 minutes before IMP
administration in Period 2.
Administration of IMP
Each subject will receive the IMP according to the randomization plan (sequence of test and 
reference GIR).
The single dose of GIR administration will occur after 07:00 in the morning of Day 8
following the procedures described for Day 1 in Section 7.1.3.
Pharmacokinetic Blood Sampling (Postdose)
Blood samples for the determination of plasma metformin will be taken at the specified times: 
as shown in Table 8.
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Safety Monitoring
Any AEs and SAEs are also to be recorded. Any concomitant diseases and treatments have to 
be documented.
Vital signs will be taken prior to dosing and also at 4 hours postdose.
A 12-lead ECG (including QTc evaluation) will be performed 4 hours postdose.
Day 9 to Day 10
Pharmacokinetic Blood Sampling (Postdose, continued)
Blood samples for the determination of GIR will be taken at the specified times (Table 8).
On Day 9, sampling will be conducted at 24 and 36 hours; on Day 10, sampling will be 
conducted at 48 hours after GIR administration. The subject is allowed to leave the CRU on 
Day 10 after the morning blood sampling (48 hours sample).
Safety Monitoring
Any AEs and SAEs are also to be recorded. Any concomitant diseases and treatments have to 
be documented. Any AEs and SAEs are also to be recorded.
Vital signs will be assessed at Day 10.
A 12-lead ECG (including QTc evaluation) will be performed at Day 10 before discharge.
At the day of discharge (Day 10), physical examination will be performed. A blood sample 
for determination of hematology and biochemistry will be taken and a urinalysis will be 
performed. These investigations on the day of discharge represent the final examination.
On the morning of Day 10 in the clinic after the morning blood sampling collection (48-hours
sample), the Investigator will decide whether or not the subject needs to stay for any additional 
time in the clinic. If there are no safety concerns based on the assessment by the Investigator, 
the subject will be allowed to leave the clinic.
7.1.7
Conditional follow-up (Day 15)/Premature Withdrawal
Conditional follow-up visit (only for subject with AE during the trial and ongoing at 
discharge)
At conditional follow-up (Day 15) the assessments include: physical examination, vital signs, 
ECG, laboratory tests (hematology, biochemistry, and urinalysis), and AEs will be assessed. Any 
concomitant treatments have to be documented. The case conclusion has to be filled in for every 
subject who has received at least one dose of the IMPs.
If AEs or pathological findings, ie, clinically relevant deviations from Baseline findings are 
obtained during the final examination, these findings must be monitored until they have either 
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returned to normal or are no longer considered as clinically relevant or can be explained. If 
necessary, other medical disciplines should be consulted.
Premature Withdrawal
The assessments at Premature Withdrawal visit include: physical examination, vital signs, ECG, 
laboratory tests (hematology, biochemistry, and urinalysis), AEs, and concomitant treatments 
(Table 1). The case conclusion has to be filled in for every subject who has received at least one 
dose of the IMPs.
If AEs or pathological findings, ie, clinically relevant deviations from Baseline findings are 
obtained during the final examination, these findings must be monitored until they have either 
returned to normal or are no longer considered as clinically relevant or can be explained. If 
necessary, other medical disciplines should be consulted.
Pharmacokinetic Blood Sampling
Blood samples for the determination of GIR will be taken (Table 8).
7.1.8
Estimated Blood Sample Volumes per Subject
The blood sample volumes of each subject are estimated in Table 9.
Table 9
Estimated Blood Sample Volumes per Subject
Time Points
Evaluation Indexes
Total Blood Volume (mL)
Screening
Serum virology
4
Hematology
2
Biochemistry
4
Serum Pregnancy Test (if applicable)
4
Approximate Total
14 (10 for male)
Period 1
Hematology
2
Biochemistry
4
Serum Pregnancy Test (if applicable)
4
Pharmacokinetics
3*17
Approximate Total
61 (57 for male)
Period 2
Hematology
2
Biochemistry
4
Pharmacokinetics
3*17
Approximate Total
57
Conditional follow-up
Or
Premature Withdrawal
Hematology
2
Biochemistry
4
Approximate Total
6
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Pharmacokinetics (only for premature 
withdrawal)
3
Approximate Total of Each Subject
132(124 for male)
With conditional follow-up:
138 (130 for male)
7.2
Demographic and Other Baseline Characteristics
At screening, the following demographic data will be collected: date of birth, sex, race, and height 
and weight. The BMI (kg/m2) will be calculated.
7.3
Efficacy Assessments
Not applicable.
7.4
Assessment of Safety
The safety profile of GIR (test or reference) will be assessed through the recording, reporting and 
analyzing of baseline medical conditions, physical examination findings, vital signs (blood 
pressure, pulse rate, temperature and respiration), ECG, laboratory tests, and AEs.
Comprehensive assessment of any apparent toxicity experienced by the subject will be performed 
throughout the course of the trial, from the time of the subject’s signature of informed consent. 
Trial site personnel will report any AE, whether observed by the Investigator or reported by the 
subject (see Section 7.4.1.2).
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product, regardless of causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to Grade the severity or toxicity of each AE.
Investigators must assess the severity of AEs according to the Qualitative Toxicity Scale, as 
follows:
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Mild:
The subject is aware of the event or symptom, but the event or symptom is easily 
tolerated.
Moderate:
The subject experiences sufficient discomfort to interfere with or reduce his or her 
usual level of activity.
Severe:
Significant impairment of functioning: the subject is unable to carry out his or her
usual activities.
Investigators must also systematically assess the causal relationship of AEs to IMP using the 
following definitions. Decisive factors for the assessment of causal relationship of an AE to the 
IMP include, but may not be limited to, temporal relationship between the AE and the IMP, known 
side effects of IMP, medical history, concomitant medication, course of the underlying disease,
trial procedures.
Unrelated:
Not 
reasonably 
related 
to 
the 
IMP. 
AE 
could 
not 
medically 
(pharmacologically/clinically) be attributed to the IMP under study in this clinical 
trial protocol. A reasonable alternative explanation must be available.
Related:
Reasonably related to the IMP. AE could medically (pharmacologically/clinically)
be attributed to the IMP under study in this clinical trial protocol.
Adverse Drug Reaction
In accordance with GCP, adverse drug reaction (ADR) is an adverse event considered related to 
drug treatment.
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (eg, on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead to 
treatment discontinuation or are considered otherwise medically important by the Investigator. If 
a laboratory abnormality fulfills these criteria, the identified medical condition (eg, anemia, 
increased alanine aminotransferase) must be reported as the AE rather than the abnormal value 
itself.
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
! Results in death
! Is life-threatening. (Note: The term “life-threatening” refers to an event in which the subject is 
at risk of death at the time of the event, not an event that hypothetically might have caused death 
if it was more severe.)
! Requires inpatient hospitalization or prolongs an existing hospitalization
! Results in persistent or significant disability or incapacity
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! Is a congenital anomaly or birth defect
! Is otherwise considered to be medically important. (Note: Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered as SAEs 
when, based upon appropriate medical judgment, they may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above. Examples 
of such events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse).
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (eg, an
overnight stay to facilitate chemotherapy and related hydration therapy application) are not 
considered SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (eg, undesirable effects of any administered treatment) 
must be documented and reported as SAEs.
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial visit, the subject will be queried on changes in his condition. During the reporting 
period of the trial any unfavorable changes in the subject’s condition will be recorded as AEs, 
whether reported by the subject or observed by the Investigator.
All AEs must be documented in the appropriate section of the eCRF. Complete, accurate and 
consistent data on all AEs experienced for the duration of the reporting period (defined below) will 
be reported on an ongoing basis. Among these AEs, all serious AEs and nonserious ADRs must 
be additionally documented and reported using an SAE Report Form as described in 
Section 7.4.1.4.
The following aspects must be recorded for each AE in the eCRF:
1. Description of the AE in medical terms, not as reported by the subject
2. Date/time of onset (only in relation to administration of IMP: before, during, or after)
3. Severity Grade (Section 7.4.1.1), assessed by the Investigator according to the Qualitative 
Toxicity Scale
4. Causal relationship to the IMP applied per protocol, assessed by the Investigator
5. Action taken with regard to trial treatments
6. Concomitant medication
7. Outcome
8. Seriousness (appropriate criteria documented).
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates (and times when it is important to assess the time of AE onset relative to the 
recorded treatment administration time), its severity, its causal relationship with the trial treatment, 
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any other potential causal factors, any treatment given or other action taken, and its outcome. In 
addition, serious cases should be identified and the appropriate seriousness criteria documented.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is included into the trial 
(date of first signature of informed consent) and continues through the trial’s post treatment period. 
The complete trial duration for collecting AEs is defined as beginning with the date of the signing 
of the consent form (up to 14 days before Day 1 of trial Period 1), continuing during the IMP
administration, and collection continued until Day 10 or 7 days after the day of the last IMP
administration (conditional follow-up visit, Day 15, if subject has AE during the trial and ongoing 
at discharge). In case of early termination, AEs until Premature Withdrawal visit will be collected.
Any SAE assessed as related to the IMP must be reported whenever it occurs, irrespective of the 
time elapsed since the last administration of IMP.
7.4.1.4
Procedure for Reporting Serious Adverse Events
and 
Nonserious Adverse Drug Reactions
In the event of any SAE and nonserious ADR occurring during the reporting period, the 
Investigator must immediately (within a maximum 24 HOURS after becoming aware of the event) 
inform Global Drug Safety by telephone, by fax or by e-mail.
To do so, the Investigator/reporter must complete a Sponsor SAE report following specific 
instructions (SAE report Completion Instruction) and using preferably the electronic template, and 
send it directly to the Sponsor’s Global Drug Safety department by electronic mail or facsimile, 
using the dedicated e-mail address and facsimile numbers specified below.
E-mail:
Facsimile:
When an event (or follow-up information) is reported by telephone, a written report must be sent 
immediately thereafter by fax or e-mail. All written reports should be transmitted using the SAE 
Report Form (Clinical Trials), which must be completed by the Investigator following specific 
completion instructions.
Reporting procedures and timelines are reported in the same manner as for follow-up information 
for any new information for a subject as was collected on a previously reported SAE.
Specific guidance can be found in SAE Report Form Instructions provided by the Sponsor.
The Investigator/reporter must respond to any request for follow-up information (eg, additional 
information, outcome and final evaluation, specific records where needed) or to any question the 
Sponsor may have on the AE within the same timelines as described for initial reports. This is 
necessary to permit a prompt assessment of the event by the Sponsor and (as applicable) to allow 
the Company to meet strict regulatory timelines associated with expedited safety reporting 
obligations.
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Requests for follow-up will usually be made by the responsible Monitor, although in exceptional 
circumstances the Sponsor’s Drug Safety department or its designee may contact the Investigator 
directly to obtain clarification or to discuss a particularly critical event.
7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators
In the event of any SAE occurring during the reporting period, the Investigator must immediately 
(within 24 hours of becoming aware of the event) report to local regulatory authorities in 
accordance with applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (and in particular SAEs with outcome of death) involving his/her subjects to the 
IEC/IRB that approved the trial.
The Sponsor will send appropriate safety notifications to regulatory authorities in accordance with 
applicable laws and regulations.
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of “findings that 
could adversely affect the safety of subjects, impact the conduct of the trial or alter the IEC’s/IRB’s 
approval/favorable opinion to continue the trial.” In particular and in line with respective 
regulations, the Sponsor/designee will inform the Investigator of AEs that are both serious and 
unexpected and are considered to be related to the administered product (“suspected unexpected 
serious adverse reactions” or SUSARs). The Investigator should place copies of Safety Reports in 
the Investigator Site File. National regulations with regard to Safety Report notifications to 
Investigators will be taken into account.
When specifically required by regulations and guidelines, the Sponsor will provide appropriate 
Safety Reports directly to the concerned lead IEC/IRB and will maintain records of these 
notifications. When direct reporting by the Sponsor is not clearly defined by national or 
site-specific regulations, the Investigator will be responsible for promptly notifying the concerned 
IEC/IRB of any Safety Reports provided by the Sponsor and of filing copies of all related 
correspondence in the Investigator Site File.
7.4.1.6
Monitoring of Subjects with Adverse Events
Any AE that occurs during the course of the clinical trial and is considered to be related to the IMP
must be monitored and followed up until the outcome is known, unless the subject is documented 
as “lost to follow-up.” Reasonable attempts to obtain this information must be made and 
documented. It is the responsibility of the Investigator to ensure that any necessary additional 
therapeutic measures and follow-up procedures are performed.
7.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to trial treatment (eg, resulting from 
a drug interaction with a contraceptive medication) are considered to be AEs. However, all 
pregnancies with an estimated conception date during the period defined in Section 7.4.1.3 must 
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be recorded by convention in the AE page/section of the eCRF. The same rule applies to 
pregnancies in female subjects and to pregnancies in female partners of male subjects. The 
Investigator must notify the Sponsor/designee in an expedited manner of any pregnancy using the 
Pregnancy Report Form, which must be transmitted according to the same process as described 
for SAE reporting in Section 7.4.1.4.
Investigators must actively follow-up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial.
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the subject sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event.
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from trial medication immediately. The Sponsor/designee must be notified 
without delay and the subject must be followed as mentioned above.
7.4.3
Clinical Laboratory Assessments
Safety and tolerability will be assessed by monitoring laboratory measurements.
It is essential that the Sponsor be provided with a list of laboratory normal ranges before shipment 
of IMP. Any change in laboratory normal ranges during the trial will additionally be forwarded to 
the Sponsor.
7.4.4
Vital Signs, Physical Examinations, and Other Assessments
Safety and tolerability will also be assessed by monitoring of vital signs, physical examinations
and ECG as described in the following.
Vital signs
Blood pressure (systolic and diastolic pressures), pulse rate, body temperature, and respiration 
(frequency per minute) will be measured and recorded. Blood pressure and pulse rate will be 
recorded in a sitting position after the subject has rested comfortably for at least 5 minutes.
Physical examination
The examination includes assessments of the general appearance, skin and mucosa, superficial 
lymph nodes, head and neck, chest, abdomen, musculoskeletal, and neurological systems.
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Electrocardiogram
A 12-lead ECG (including QTc evaluation) will be performed.
After the subject has rested for at least 5 minutes in the supine position, a 12-lead ECG will be 
conducted by placing peripheral leads I, II, III, aVR, aVL, aVF followed by the precordial leads 
V1-V6 and all 12-leads recorded. At least 2 to 3 beats will be monitored at a speed of 25 mm/sec 
for each lead and a single lead (V2) run. Printouts for each ECG will include date, time, initials of 
the technician/nurse who performed the test and initials of the personnel who reviewed the printout 
(ie, a medical physician). Results of the ECG recordings will be included in the subject's eCRF.
The following parameters will be assessed:
!
RR-Interval [ms]
!
PR-Interval [ms]
!
QRS-Duration [ms]
!
QT-Interval [ms]
!
QTc (Bazett) [ms]
!
QTcF (Fridericia) [ms]
!
Heart Rate [beats per minute]
!
Rhythm (sinusal - other).
QT/QTc interval will be automatically computed using the Bazett correction formula (QTcB = 
QT/gRR) and the Fridericia correction formula (QTcF = QT/3gRR) according to the recently 
approved ICH guidance E1. 
7.5
Pharmacokinetics
For detection of metformin, the major active ingredient of GIR, blood samples will be collected as 
described in Section 7.1.
For every subject, during each treatment period, a total of 17 samples, approximately 3 mL each 
whole blood, will be collected at the following times:
!
at pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 24, 36, and 48 hours 
after dosing.
!
One sample will be collected at Premature Withdrawal if applicable.
The PK collection time is based on known single dose PK profiles of the immediate release
formulation and should be frequent and long enough to characterize the peak and extent of 
exposure. Plasma samples will be prepared, divided into 2 aliquots and stored at max -20°C. 
Subjects who complete both treatment periods will have a total of 34 samples (approximately 3 mL 
whole blood each sample) collected. Total PK blood volume collection is approximately 102 mL 
over 2 weeks.
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A validated bioanalytical method will be applied to analyze plasma concentration of metformin. 
The assay and all related procedure will be developed and cross-validated with previously 
established methods to ensure quality standard and technical specifications are met. Details of the 
assay will be provided in the Analytical plan separately.
The clock time of all blood draws will be recorded and reported for each subject in the eCRF. The 
actual sampling times, if available, will always be used for calculation.
The following PK parameters will be calculated from plasma concentrations of metformin by 
applying noncompartmental standard methods according respective Standard Operating 
Procedures.
Cmax
the maximum plasma concentration observed
tmax
time to reach the maximum plasma concentration
AUC0Nt
area under the plasma concentration-time curve from time zero to the last 
sampling time at which the concentration is at or above the lower limit of 
quantification, calculated using mixed log-linear trapezoidal rule
AUC0NO
area under the plasma concentration-time curve from time zero to infinity
AUCextra
extrapolated part of AUC0NO calculated by Clast calc/ Pz, expressed in 
percent
Pz
terminal elimination rate constant
t1/2 
apparent terminal half-life
CL/f 
total body clearance of drug from plasma following extravascular 
administration
Vss/f 
apparent volume of distribution at steady-state after extravascular 
administration
The PK parameter evaluation will be performed using the validated PK software tool 
Phoenix/WinNonlin.
7.6
Biomarkers
Not applicable.
7.7
Other Assessments
Not applicable.
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8
Statistics
8.1
Sample Size
The BE is declared if all comparisons in primary hypothesis achieve the criteria - the 90% 
confidence intervals for the ratios between test and reference of geometric means of both AUC0Nt
and Cmax for metformin in plasma are within 80.00% to 125.00% in both the fasted and fed group.
Based on the results of previously conducted BE trial PK data, (Iran BE 2013 [fasted] and 
EML056023-H105 [fed]) [18,19], Glucophage/metformin IR formulation has shown relatively 
low intraindividual Coefficient of Variation (CV), as shown below (Table 10 and Table 11).
IRAN BE-2013
!
Test: Single dose of metformin IR 500 mg tablets manufactured by
 
 (Iran) under fast condition
!
Reference: Single dose of metformin IR 500 mg tablets manufactured by Merck 
(Darmstadt) under fast condition
Table 10
Results from IRAN Bioequivalence Study-2013 Fasting (n= 21)
Parameter
Intra-Subject CV 
(%)
Geometric Mean
Ratioa (%)
90% Confidence Limitsa (%)
Test
Reference
Lower
Upper
Cmax
17.5
1404.5
1425.5
102
92.14
110.95
AUC0Nt
13.8
7946.5
8049.5
100
92.72
107.37
AUC0Nt = area under the plasma concentration-time curve from time 0 to time t; Cmax = the maximum plasma concentration 
observed; CV = Coefficient of Variation.
a Results from ANOVA Model
As shown in Table 12 and Table 13, if applying these CVs together with applicable BE criteria for 
AUC0Nt and Cmax [0.80 – 1.25],
 
 
 
 
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In total, 44 subjects should be included in the trial.
Table 12
Sample size and power – Assuming Coefficient of Variation = 17.5% for 
Cmax and 13.8% for AUC0It (Iran BE 2013 Fasting) and assume 5% 
variation for all ratios (95% to 105%)
Fasted Condition
Sample Size 
Power (%)
Joint Power
Cmax
AUC0Nt
18
88.2
97.4
> 85.9
20
91.3
98.4
> 89.9
22
93.6
99.0
> 92.7
AUC0Nt = area under the plasma concentration-time curve from time 0 to time t; Cmax = the maximum plasma concentration 
observed.
8.2
Randomization
Each eligible subject will be allocated to a treatment sequence according to a computer-generated 
randomization schedule. Subjects will be identified only by their assigned subject number. The 
subjects will receive consecutive subject numbers in the order of their enrollment into the trial.
A total of 44 eligible healthy male and female Chinese subjects (26 in fasting state and 18 in fed 
state, Table 14) who meet the eligibility criteria will be randomized (with at least 7 subjects of 
each gender in the fasted group, and at least 5 subjects of each gender in the fed group, representing 
1/4 of the total number within each group) on Day 1, in a 1:1 ratio to 1 of 2 treatment sequences: 
Sequence A-B or Sequence B-A as presented in Table 4.
In sequence A-B, subjects will receive test GIR tablets (Treatment A) in Period 1 and reference 
GIR tablets (Treatment B) in Period 2. In sequence B-A, subjects will receive reference GIR 
tablets in Period 1 and test GIR tablets in Period 2 after Washout.
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Table 14
Randomization Allocation
Day 1 of Period 1
Day 1 of Period 2
Fasting group (n= 26)
Treatment A (n= 13)
Treatment B (n= 13)
Treatment B (n= 13)
Treatment A (n= 13)
Fed group (n= 18)
Treatment A (n= 9)
Treatment B (n= 9)
Treatment B (n= 9)
Treatment A (n= 9)
Subjects will only be replaced if the number of subjects within each group falls below 20 (fasting) 
or 12 (fed). The subject who is replacing a discontinued subject will then be allocated to the 
treatment sequence of the subject who discontinued.
8.3
Endpoints
8.3.1
Primary Endpoints
The Primary Endpoints are the following PK parameters calculated from metformin plasma 
concentrations:
!
AUC0Nt of metformin
!
Cmax of metformin.
8.3.2
Secondary Endpoints
The Secondary Endpoints are the following PK parameters determined from plasma concentrations 
of metformin
!
tmax
!
t1/2
!
AUC0NO
!
AUCextra
!
Pz
!
CL/f
!
Vss/f
All PK parameters (Primary Endpoints and Secondary Endpoints) will be calculated from plasma 
concentrations of metformin by applying noncompartmental analysis methods according to 
respective Standard Operating Procedures (SOPs).
8.3.3
Safety Endpoints
Safety and tolerability will be assessed by monitoring of:
! Assessment of general safety and tolerability
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! Adverse Events
! Vital signs (blood pressure, pulse rate, temperature and respiration)
! Biochemistry, hematology, and urinalysis
! Computerized 12-lead ECG recordings (including QTc evaluation)
! Physical examination.
8.4
Analysis Sets
Safety Population
The Safety Population includes all subjects who received at least 1 dose of IMP. In general, clinical 
data will be analyzed for the Safety Population.
Pharmacokinetic Population
The PK parameters will be analyzed based on PK population. The PK population may include all 
subjects who completed the trial with adequate trial medication compliance, without any relevant 
protocol deviations with respect to factors likely to affect the comparability of PK results, and with 
sufficient evaluable data to determine Primary Endpoints (AUC0-t and Cmax) for both treatments in 
both groups. If subjects would receive concomitant medication for the treatment of an AE, their 
inclusion in the PK population will be decided on case-by-case basis.
8.5
Description of Statistical Analyses
8.5.1
General Considerations
Details of the statistical analysis will be presented in a statistical analysis plan prior to database 
lock.
The statistical analysis will not be started until all data have been corrected and checked for 
plausibility, and until all necessary coding and assessments have been completed.
All data recorded during the trial will be presented in individual data listings performed on the 
Safety Population. All data will be evaluated as observed values; no imputation method for missing 
values will be used. Methods for concentration data below the lower limit of quantification will be 
described in the statistical analysis plan. The consideration of covariates in the mixed effect model 
is not planned.
8.5.2
Analysis of Primary Endpoints
The null and alternative hypotheses are the following:
25
.1
/
8.0
/
25
.1
/
8.0
/
:
max
0
0

#

#

C
T
C
T
C
T
C
T
t
or
C
for
or
AUC
for
H
%
%
%
%
%
%
%
%
, for at least 1 Primary Endpoint
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25
.1
/
8.0
25
.1
/
8.0
:
max
0
1
&
&
&
&

C
T
C
T
t
C
for
AUC
for
H
%
%
%
%
, for both Primary Endpoints
Where
and 
are the means of Primary Endpoints following test IMP and reference IMP
(Treatment A and Treatment B), respectively.
The analysis of Primary Endpoints will be based on PK Population (Section 8.4)
The primary variable, Cmax and AUC0Nt in fasting and fed group will be log-transformed and mixed 
effect model will be applied. The model will include effects for sequence, treatment and period. 
Subject within sequence will be included as random effect. Bioequivalence will be assessed 
separately, in the fed and in the fasted group, and the trial will be successful only, if BE has been 
established in both groups.
Based on the residual (within-subject) variation, 90% CIs for the ratio of geometric means will be 
calculated. The BE can be established if the 90% Confidence Interval on the ratios between test 
and reference of the geometric means fall within 80.00% to 125.00%.
8.5.3
Analysis of Secondary Endpoints
For tmax, the Hodges-Lehmann estimates [20] for the pairwise treatment differences and the 
corresponding 90% CIs according to the Tukey method will be calculated.
The mixed model as described above will also be applied to AUC0NO. A 90% CI will be calculated 
for the ratios of geometric means of the test IMP and reference IMP.
Summaries using descriptive analyses for the remaining PK parameters and the safety variables 
will be performed as described in Section 8.5.4.
8.5.4
Analysis of Safety and Other Endpoints
All data recorded during the trial will be presented in individual data listings performed on the 
Safety Population.
All safety variables will be analyzed using descriptive statistics.
For the evaluation of safety parameters, the continuous variables will be summarized descriptively 
per treatment, period, time point, and overall by N, arithmetic mean, median, standard deviation 
(SD), standard error of the mean (SEM), and minimum and maximum values. Categorical 
variables will be presented in frequency tables with the counts of observations and corresponding 
percentages.
Blood pressures, pulse rate measurements and ECG recordings will be individually listed by 
treatment, subject number, period, and time point, and the abnormal values flagged according to 
reference laboratory ranges. All hematology and biochemistry parameters will be listed and 
summarized using descriptive statistics by treatment, period, and time point on observed values. 
Urinalysis will be summarized in frequency tables.
T
%
C
%
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After coding of AEs according to the Medical Dictionary for Regulatory Activity classification 
(current version) and assignment to a system organ class and preferred term, all AEs recorded 
during the course of the trial will be listed by treatment and subject number.
The AE listings will include the following items:
!
System organ class
!
Preferred term
!
Investigator’s description
!
Whether the event is treatment-emergent
!
Trial treatment at onset of event
!
Date and time of onset and resolution
!
Duration of the event
!
Date and time of last administration before AE
!
Intensity
!
Causality relationship to investigational product
!
Outcome
!
Action taken to investigational product
!
Other action
!
Seriousness.
Incidence of treatment-emergent adverse events (TEAEs) will be summarized using frequency of 
events and number of subjects experiencing these events per treatment, preferred term, and 
system/organ class.
In addition, all TEAEs will be tabulated by intensity and relationship to drug per treatment and 
group. An AE will be considered “treatment-emergent” if it occurred after the first investigational 
product administration or if it occurred before the first investigational product administration and 
worsened after.
Demographic parameters (age, height, and weight) will be summarized by means of tabulated 
descriptive statistics (the number of observations [N], arithmetic mean, median, SD, SEM, 
minimum and maximum) by treatment, group, and overall.
Results of physical examination will only be listed by treatment, subject, period, time point, and 
body system.
Other endpoints
Analyses described in this subsection will be performed in general for the PK population.
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Plasma concentrations below lower limit of quantitation will be analyzed as zero for descriptive 
statistics. Plasma concentration data will be summarized by treatment, analyte and scheduled time 
point showing the number of observations (N), arithmetic mean, SD, SEM, CV (%), minimum, 
median and maximum.
Mean plasma concentrations per treatment and analyte will be plotted (linear scale with SD, and 
semi-logarithmic scale) using scheduled time points for metformin.
Results of subjects not in the PK population will be annotated and listed together with the data of 
the other subjects, but will not be used for descriptive statistics and mean curves. Individual plasma 
concentrations (linear and semi-logarithmic scales) will be plotted by treatment (showing all 
subjects simultaneously) and by subject (showing all treatments simultaneously).
Handling of discontinued subjects and missing data
The first 6 (fasting) or 4 (fed) discontinued subjects of each group will not be replaced. Subjects 
will only be replaced if the number of subjects within each group falls below 20 (fasting) or 12 
(fed). The subject who is replacing a discontinued subject will then be allocated to the treatment 
sequence of the subject who discontinued.
8.6
Interim and Additional Planned Analyses
Not applicable
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the trial at his/her site. The Investigator will 
ensure that the trial is performed in accordance with the clinical trial protocol and with the ethical 
principles that have their origin in the Declaration of Helsinki, as well as with the ICH Note for 
Guidance on GCP (ICH Topic E6, 1996) and applicable regulatory requirements. In particular, the 
Investigator must ensure that only subjects who have given their informed consent are included 
into the trial.
9.2
Subject Information and Informed Consent
An unconditional prerequisite for a subject’s participation in the trial is his/her written informed 
consent. The subject’s written informed consent to participate in the trial must be given before any 
trial-related activities are carried out.
Adequate information must therefore be given to the subject by the Investigator before informed 
consent is obtained (a person designated by the Investigator may give the information, if permitted 
by local regulations). A subject information sheet in the local language and prepared in accordance 
with the Note for Guidance on GCP (ICH Topic E6, 1996) will be provided by the Sponsor for the 
purpose of obtaining informed consent. In addition to providing this written information to a 
potential subject, the Investigator or his/her designate will inform the subject verbally of all 
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pertinent aspects of the trial. The language used in doing so must be chosen so that the information 
can be fully and readily understood by lay persons.
Depending on national regulations, a person other than the Investigator may inform the subject 
and sign the ICF, as above.
Where the information is provided by the Investigator, the ICF must be signed and personally 
dated by the subject and the Investigator.
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived by the Investigator so that the forms can be retrieved at any time for 
monitoring, auditing and inspection purposes. A copy of the signed and dated information and ICF 
should be provided to the subject prior to participation.
Whenever important new information becomes available that may be relevant to the subject’s 
consent, the written subject information sheet and any other written information provided to 
subjects will be revised by the Sponsor and be submitted again to the IEC/IRB for review and 
favorable opinion. The agreed, revised information will be provided to each subject in the trial for 
signing and dating. The Investigator will explain the changes to the previous version.
9.3
Subject Identification and Privacy
Immediately after informed consent has been obtained, a unique subject number will be assigned 
to each subject at inclusion into the trial. This number will serve as the subject’s identifier in the 
trial as well as in the clinical trial database.
The subject’s data collected during the trial will be stored under this number. Only the Investigator 
will be able to link the subject’s trial data to the subject via an identification list kept at the site. 
The subject’s original medical data that are reviewed at the site during source data verification by 
the Monitor, audits and Health Authority inspections will be kept strictly confidential.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing subject data. Subjects will be informed accordingly, and will be requested to give their 
consent on data handling procedures in accordance with national regulations.
9.4
Emergency Medical Support and Subject Card
Subjects enrolled in this clinical trial will be provided with Emergency Medical Support cards 
during their trial participation, which will be furnished by the Sponsor. The Emergency Medical 
Support card is based on the need to provide clinical trial subjects with a way of identifying 
themselves as participating in a clinical trial, and subsequently to give health care providers access 
to the information about this participation that may be needed to determine the course of the 
subject’s medical treatment.
This service is designed to provide information to health care providers who are not part of the 
clinical trial.
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Clinical trial Investigators, who are already aware of the clinical trial protocol and treatment, have 
other means of accessing the necessary medical information for the management of emergencies 
occurring in their subjects.
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected subject. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose and to answer any questions. Any subsequent action will follow the 
standard processes established for the Investigators.
The Sponsor will provide the appropriate information to contact a physician. This includes the 
provision of a 24 hour contact number at the facility, whereby the health care providers will be 
given access to an appropriate physician to assist with the medical emergency.
9.5
Clinical Trial Insurance and Compensation to Subjects
Insurance coverage will be provided for each subject participating to the trial. Insurance conditions 
will meet good local standards, as applicable.
9.6
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the trial at a given site, the clinical trial protocol will be submitted 
together with the ICF to the responsible IEC/IRB for its favorable opinion/approval. The written 
favorable opinion/approval of the IEC/IRB will be filed in the Investigator Site File, and a copy 
will be filed in the Trial Master File by the Sponsor.
The trial must not start before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IEC/IRB. The IEC/IRB will be asked to provide 
documentation of the date of the meeting at which the favorable opinion/approval was given, and 
of the members and voting members present at the meeting. Written evidence of favorable 
opinion/approval that clearly identifies the trial, the clinical trial protocol version and the Subject 
Information and ICF version reviewed should be provided. Where possible, copies of the meeting 
minutes should be obtained.
Amendments to the clinical trial will also be submitted to the concerned IEC/IRB, before 
implementation in case of substantial changes (Section 10.5). Relevant safety information will be 
submitted to the IEC/IRB during the course of the trial in accordance with national regulations and 
requirements.
9.7
Health Authorities
The clinical trial protocol and any applicable documentation (eg, Investigational Medicinal 
Product Dossier, Subject Information and ICF) will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site.
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10
Trial Management
10.1
Case Report Form Handling
The main purpose of the eCRF is to obtain data required by the clinical trial protocol in a complete, 
accurate, legible and timely. The data in the eCRF should be consistent with the relevant source 
documents.
The Investigator or designee will be responsible for entering trial data in the eCRF provided by 
the designated Contracted Research Organization. It is the Investigator’s responsibility to ensure 
the accuracy of the data entered in the eCRFs.
The data will be entered into a validated database. The data management department of the 
designated Contracted Research Organization will be responsible for data processing, in 
accordance with the defined data management procedures under the supervision of the Sponsor. 
Database lock will occur once quality control procedure, and Quality Assurance procedures (if 
applicable) have been completed. Portable document format files of the eCRFs will be provided 
to the Investigators at the completion of the trial.
10.2
Source Data and Subject Files
The Investigator must keep a file (medical file, original medical records) on paper or electronically 
for every subject in the trial. It must be possible to identify each subject by using this subject file. 
This file will contain the demographic and medical information for the subject listed below and 
should be as complete as possible:
!
Subject’s full name
!
Date of birth
!
Sex
!
Height
!
Weight
!
Medical history and concomitant diseases
!
Prior and concomitant therapies (including changes during the trial)
!
Trial identification
!
Date of subject’s inclusion into the trial (ie, date of giving informed consent)
!
Subject number in the trial
!
Dates of the subject’s visits to the site
!
Any medical examinations and clinical findings predefined in the clinical trial protocol
!
All AEs observed in the subject
!
Date of subject’s last visit, or
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!
Date of premature withdrawal and reason for premature withdrawal of the subject from the 
trial or from IMP, if applicable.
Additionally, any other documents containing source data must be filed. Such documents must 
bear at least the subject number and the date when the procedure was performed. Information 
should be printed by the instrument used to perform the assessment or measurement, if possible. 
Information that cannot be printed by an automated instrument will be entered manually. Medical 
evaluation of such records should be documented as necessary and the documentation signed and 
dated by the Investigator.
Electronic subject files (if applicable) will be printed whenever the Monitor performs source data 
verification. Printouts must be signed and dated by the Investigator, countersigned by the Monitor 
and kept in a safe place at the site.
10.3
Investigator Site File and Archiving
Upon initiation of the trial, the Investigator will be provided with an Investigator Site File 
containing all necessary trial documents, which will be completed throughout the trial and updated 
as necessary. The file must be available for review by the Monitor, during Sponsor audits and for 
inspection by Health Authorities during and after the trial, and must be safely archived for at least 
5 years (or longer, per local requirements or as otherwise notified by the Sponsor) after the end of 
the trial. The documents to be archived include the Subject Identification List and the signed 
subject ICFs. If archiving of the Investigator Site File is no longer possible at the site, the 
Investigator must notify the Sponsor/designee.
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per ICH 
GCP guidelines, whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH GCP, and any other applicable regulations. 
The site Monitor will perform visits to the trial site at regular intervals.
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance activities. 
Audits may be conducted at any time during or after the trial to ensure the validity and integrity of 
the trial data. Representatives of the Quality Assurance unit from the Sponsor or a designated 
organization, as well as Health Authorities, must be permitted to access all trial documents and 
other materials at the site, including the Investigator Site File, the completed eCRFs, all IMP and
IMP accountability records, and the original medical records or files for each subject.
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10.5
Changes to the Clinical Trial Protocol
Changes to the clinical trial protocol will be documented in writing. Substantive amendments will 
usually require submission to the Health Authorities and to the relevant IEC/IRB for approval or 
favorable opinion. In such cases, the amendment will be implemented only after approval or 
favorable opinion has been obtained.
Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC/IRB or to Health Authorities 
only where requested by pertinent regulations. Any amendment that could affect the subject’s 
agreement to participate in the trial requires additional informed consent prior to implementation 
following the process as described in Section 9.2.
10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After completion of the trial, a clinical trial report according to ICH Topic E3 will be written by 
the Sponsor/designee in consultation with the Principal Investigator and other relevant committees 
or cohorts.
10.6.2
Publication
The Investigator will inform the Sponsor in advance about any plans to publish or present data 
from the trial. Any publications and presentations of the results (abstracts in journals or 
newspapers, oral presentations, etc.), either in whole or in part, by Investigators or their 
representatives will require presubmission review by the Sponsor.
The Sponsor will not suppress or veto publications, but maintains the right to delay publication in 
order to protect intellectual property rights. Any publications of the results, either in part or in total 
(abstracts in journals or newspapers, oral presentations, etc.) by Investigators or their 
representatives will require presubmission review by the Sponsor. The Sponsor is entitled to delay 
publication in order to obtain patent protection.
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11
References 
1. American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes Care. 
2014; 37 Suppl 1:S81-90.
2. International Diabetes Federation (IDF). E-Atlas of diabetes
seventh edition.
http://www.idf.org/diabetesatlas 
3. Copeland KC, Silverstein J, Moore KR, et al. Management of newly diagnosed type 2 
Diabetes Mellitus (T2DM) in children and adolescents. Pediatrics. 2013; 131(2):364-82.
4. World Health Organization (WHO). Definition and diagnosis of diabetes mellitus and 
intermediate hyperglycemia. Report of a WHO/IDF Consultation. 2006
5. Colagiuri S. Epidemiology of prediabetes. Med Clin North Am. 2011; 95(2):299-307, vii.
6. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and 
microvascular complications of type 2 diabetes (UKPDS 35): prospective observational 
study. BMJ. 2000; 321(7258):405-12.
7. Stein SA, Lamos EM, Davis SN. A review of the efficacy and safety of oral antidiabetic 
drugs. Expert Opin Drug Saf. 2013; 12(2):153-75.
8. Singh S. Type 2 diabetes pharmacoepidemiology update 2014: safety versus efficacy. Curr 
Diab Rep. 2014; 14(12):563.
9. Akbari A, Clase CM, Acott P, et al. Canadian Society of Nephrology commentary on the 
KDIGO clinical practice guideline for CKD evaluation and management. Am J Kidney 
Dis. 2015; 65(2):177-205.
10. Wilke T, Groth A, Fuchs A, et al. Real life treatment of diabetes mellitus type 2 patients: 
an analysis based on a large sample of 394,828 German patients. Diabetes Res Clin Pract. 
2014; 106(2):275-85.
11. Tran L, Zielinski A, Roach AH, et al. Pharmacologic treatment of type 2 diabetes: oral 
medications. Ann Pharmacother. 2015; 49(5):540-56.
12. Effect of intensive blood-glucose control with metformin on complications in overweight 
patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) 
Group. Lancet. 1998; 352(9131):854-65.
13. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 
2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus 
statement of the American Diabetes Association and the European Association for the 
Study of Diabetes. Diabetes Care. 2009; 32(1):193-203.
14. Investigator Brochure of Glucophage Immediate Release (GIR). Version 2017.
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15. Chinese Food and Drug Administration Guideline: “Technical Guidelines for Human 
Bioequivalence Studies with Pharmacokinetic Endpoints for Chemical Generic Drugs” 
Released March 2016.
16. USA Food and Drug Administration Guidance “Food-Effect Bioavailability and Fed 
Bioequivalence Studies”. 2002.
17. Zhang L, Wang F, Wang L, et al. Prevalence of chronic kidney disease in China: a cross-
sectional survey. Lancet. 2012; 379(9818):815-22.
18. Valizadeh H, Nayyeri-Maleki P, Ghanbarzadeh S, et al. Pharmacokinetics and 
bioequivalence of two brands of metformin 500 mg tablets in Iranian healthy volunteers. J 
Pharmaceutical Investigation. 2014; 44(1):61-68.
19. Clinical Study Report EML056023-H105. “Randomized, open-label, 2-way, crossover, 
single oral-dose, fed, bioequivalence study between 500 mg Glucophage LCM 004 and 
500 mg Glucophage® in healthy subjects”. 2006.
20. Lehmann, Erich L. Nonparametrics: Statistical methods based on ranks (Reprinting of 1988 
revision of 1975 Holden-Day ed.). New York: Springer 2006. pp.xvi+463. ISBN978-0-
387-35212-1.
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12
Appendices
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Appendix I:
Contraceptive Guidance and Woman of Childbearing Potential
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
1. Premenopausal female with 1 of the following:
! Documented hysterectomy
! Documented bilateral salpingectomy
! Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of participant’s medical 
records, medical examination, or medical history interview.
2. Premenarchal
3. Postmenopausal female
! Females who are postmenopausal (age-related amenorrhea + 12 consecutive months and 
increased follicle-stimulating hormone [FSH] > 40 mIU/mL), or who have undergone 
hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary to 
confirm postmenopausal status, an FSH will be drawn at screening.
! Females on HRT and whose menopausal status is in doubt will be required to use one of the 
nonhormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
Contraceptive Guidance
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of < 1% per year when used consistently and correctly. 
!
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationb
!
oral 
!
intravaginal 
!
transdermal 
!
Progestogen-only hormonal contraception associated with inhibition of ovulationb
!
oral 
!
injectable
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Highly Effective Methods That Are User Independent 
!
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb
!
Intrauterine device (IUD)
!
Intrauterine hormone-releasing system (IUS)
!
bilateral tubal occlusion
!
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used). 
!
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant).
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants participating in clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case 2 highly effective methods of contraception should be utilized during the 
treatment period and for at least 14 days after the last dose of study treatment 
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Appendix II:
Signature Pages and Responsible Persons for the Trial
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Signature Page – Protocol Lead
Trial Title:
A Randomized, Open-label, 2-Way-Crossover Study 
Assessing the Bioequivalence between Single Doses 
of 500 mg Glucophage Immediate Release (GIR) 
Tablets 
(Sino-American 
Shanghai 
Squibb 
Pharmaceuticals Ltd./ Manufactured in China) and 
500 mg GIR Tablets (Merck Santé s.a.s. in Semoy/ 
Manufactured in France) under Fed and Fasted State 
in Two Groups of Healthy Subjects
Clinical Trial Protocol 
Date/Version:
20 Nov 2017/Version 2.0
Protocol Lead:
I approve the design of the clinical trial:
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Institution:
Merck Serono Co., Ltd.
Address:
25F, NUO Center Office, No. 2A Jiangtai Road, Chaoyang District, 
Beijing 100016, P. R. China
Telephone number:
Fax number:
E-mail address:
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Signature Page – Principal Investigator
Trial Title
A Randomized, Open-label, 2-Way-Crossover Study 
Assessing the Bioequivalence between Single Doses 
of 500 mg Glucophage Immediate Release (GIR) 
Tablets 
(Sino-American 
Shanghai 
Squibb 
Pharmaceuticals Ltd./ Manufactured in China) and 
500 mg GIR Tablets (Merck Santé s.a.s. in Semoy/ 
Manufactured in France) under Fed and Fasted State 
in Two Groups of Healthy Subjects
Clinical Trial Protocol Date/Version
20 Nov 2017/Version 2.0
Center Number
Principal Investigator
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that I 
understand and will conduct the trial according to the clinical trial protocol, any approved protocol 
amendments, International Council for Harmonisation Good Clinical Practice (Topic E6) and all 
applicable Health Authority requirements and national laws.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Principle Investigator
Institution:
Address:
 
Telephone number:
Fax number:
E-mail address:
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Sponsor Responsible Persons not Named on the Cover Page
Name, academic degree:
Function/Title:
Biostatistician
Institution:
Merck Serono (Beijing) Pharmaceutical R&D Co., Ltd.
Address:
Merck Serono Co., Ltd.
25F, NUO Center Office
No. 2A Jiangtai Road, Chaoyang District
Beijing 100016
P. R. China
Telephone number:
Fax number:
E-mail address:
Name, academic degree:
Function/Title:
Institution:
Merck Serono (Beijing) Pharmaceutical R&D Co., Ltd.
Address:
Merck Serono Co., Ltd.
25F, NUO Center Office
No. 2A Jiangtai Road, Chaoyang District
Beijing 100016
P. R. China
Telephone number:
Fax number:
E-mail address:
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Appendix III:
Protocol Amendments and List of Changes
Amendment 1.0
Previous Protocol Amendments
None.
Table of Amendments
Amendment Number
Substantial
(Y/N)
Date
Region or Country
Included in the 
current document
(Y/N)
1.0
Y
20 November 2017
China
Y
Rationale
The amendment of protocol version 1.0 is based on consideration from study team and study center
of the feasibility of study, and additionally to simplify the study procedure in order to prevent 
noncompliance of subjects. The inpatient time was revised from twice to once through the study 
period. Instead of being hospitalized twice for each 3 days, the subjects are now staying at study 
center for 10 days during the study period. The demographics of subject will be adjusted to 
represent a population of weight that is more feasible, and also the ratio of genders are modified 
from 1/3 to 1/4 of total subject number. Furthermore, the blood pressure check for eligibility on 
Day 1 was modified to a wider range.
According to the evaluation by clinical pharmacologist, sampling time point is also adjusted.
Major Scientific Changes
The major scientific changes of this protocol amendment (Amendment No.1.0) are:
!
The change of hospitalization from twice to once during the trial sampling period, subject 
will be hospitalized from Day -1 to Day 10
!
Change descriptions regarding the inpatient period
!
Revise “End-of-Trial visit” to “conditional follow-up visit, define as only for subjects who 
has AE during the trial and ongoing at discharge”
!
Update of inclusion and exclusion criteria:
1. Change inclusion criteria 2: proportion of subject genders from 1/3 to 1/4 of total 
subject number
2. Change inclusion criteria 4: weight range from 55 – 95 kg to 50 – 80 kg
3. Change inclusion criteria 8: revise ECG assessment result to be judged by 
Investigator
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4. Revise inclusion criteria 9: Blood pressure normal range defined as V 90 mmHg and 
W 139 mmHg for SBP; V 60 mmHg and W 90 mmHg for DBP
5. Change inclusion criteria 10: reword conditions for WOCBP according to admission 
period change, revise all pregnancy study to be test by serum
6. Change inclusion criteria 11: revise the drug abuse list
7. Change exclusion criteria 7: revise the receipt of medication before study drug 
administration, remove hormonal contraceptives
8. Change exclusion criteria 12: revised wording for the time period that grapefruit, 
cranberry or juices of these fruits are restricted
!
Update on IMP information and handling, drug accountability
!
Correct the serum pregnancy test on screening 
!
Move randomization to Day -1
!
PK sampling: remove end-of-trial sample, but keep PK sampling on Premature Withdrawal
visit
!
Changes on study assessments:
1. Remove 8 hour postdose vital sign assessment on Day 1 and Day 8
2. Remove vital sign assessments on Day 2, Day 3, Day 7 and Day 9
3. Remove ECG on Day 3 (48 hour postdose) and Day 7
4. Remove laboratory test on Day 3 and Day 7, recalculate blood sample requirement 
according to this change
5. Remove alcohol, drug abuse test on Day 7 
6. Remove pregnancy test on Day 7 and Premature Withdrawal visit
!
Recalculate sample numbers and required blood for PK and laboratory tests
Correct minor errors
Administrative and Editorial Changes
Correction of administrative (change of Investigator and manufacturer name), minor editorial 
changes and inconsistencies throughout the document that have been identified since the 
finalization of the clinical trial protocol.
Changes to the clinical trial protocol text are presented in the table below. Additions and amended 
text are shown in bold. If the original clinical trial protocol text was already bold, changes are 
shown in bold and underlined, deletions are marked using strike through.
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Comparison with Clinical Trial Protocol Version 1.0, 21 July 2017 
Change
Section
Page
Previous Wording
New Wording
Update the 
information 
of reference 
manufacturer
Title page
List of 
abbreviation 
Synopsis
Section 2.1
Section 6.1 
Table 3
Signature 
page
1
8
10
17
24
67-68
Merck Santé in Semoy
Merck Santé s.a.s. in Semoy
Updated the 
information 
of the 
Principal 
Investigator
Title page
Synopsis-
Principal 
Investigator
Signature 
Page-
Principal 
Investigator
1
10
68
. 
 
Update of 
protocol 
version and 
date
Title page
Signature 
Page
1
67-68
21 Jul 2017/ Version 1.0
21 Jul20 Nov 2017/ Version 12.0 including amendment 1.0
Reword 
secondary 
objective
Synopsis, 
Section 4.2
10
19
1. To compare pharmacokinetic (PK) parameters of GIR after 
single dose administrations of test and reference products.
1. To compare additional pharmacokinetic (PK) parameters of GIR 
after single dose administrations of test and reference products.
Update for 
methodology 
wording and 
the term of 
End-of-Trial 
examination 
period to 
conditional 
follow-up 
visit 
Synopsis, 
Section 5.1
11
19
This trial is designed as a Phase I, open-label, randomized, 2-
period, 2-sequence, crossover trial to assess BE between a single 
oral dose of GIR from different manufacturing facilities, each 
given concomitantly as a single dose in fasting or fed state. 
Subjects will be randomized to receive, in each period, either:
!
1 tablet of 500 mg GIR (manufactured in Sino-
American Shanghai Squibb Pharmaceuticals Ltd. 
[SASS]/China) or
!
1 tablet of 500 mg GIR (manufactured in Merck Santé 
s.a.s. in Semoy [MSS]/ France).
This trial is designed as a Phase I, open-label, randomized, 2-
period, 2-sequence, crossover trial to assess BE between a single 
oral doses of GIR from different manufacturing facilities, each 
given concomitantly as a single dose in fasting or fed state. 
Subjects will be randomized to receive, in each period, either:
!
1 tablet of 500 mg test GIR (manufactured in Sino-
American Shanghai Squibb Pharmaceuticals Ltd. 
[SASS]/China) or
!
1 tablet of 500 mg reference GIR (manufactured in 
Merck Santé s.a.s. in Semoy [MSS]/ France).
'RFXPHQW1R
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2EMHFW1R
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33'
33'
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33'
33'
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33'


GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
74/92
Change
Section
Page
Previous Wording
New Wording
!
Drug administration will be done with or without food 
depending on group allocation to either fed or fasted 
condition.
The trial has a duration of approximately 4 weeks including:
!
A screening period within 2 weeks before the first GIR 
administration
!
First dosing/sampling period up to 2 days (48 hours) 
after dosing
!
A washout period of approximately 7 days after the first 
GIR administration
!
Second dosing/sampling period up to 2 days (48 hours) 
after dosing 
!
An End-of-Trial examination period up to 7 days 
following the last drug administration.
!
Drug administration will be done with or without food
depending on group allocation to either fed or fasted 
condition.
The trial has a duration for each subject of approximately 4 weeks 
including:
!
A screening period within 2 weeks before the first GIR 
administration
!
First dosing/sampling period up to 2 days (48 hours) 
after dosing
!
A washout period of approximately 7 days after the first 
GIR administration
!
Second dosing/sampling period up to 2 days (48 hours) 
after dosing 
!
An End-of-Trial examination period up to 7 days 
following the last drug administration. A conditional 
follow-up examination period (only for subjects who 
has AE during the trial and ongoing at discharge) up 
to 7 days following the last GIR administration
Updated PK 
section 
description
Synopsis
11
The plasma concentrations of metformin will be determined by a 
validated analytical method. Pharmacokinetic parameters (Primary 
and Secondary Endpoints) will be calculated according to 
noncompartmental analysis methods. The mixed trapezoidal rule 
will be used to calculate the area under the plasma concentration 
curve.
The plasma concentrations of metformin will be determined by a 
validated LC/MS analytical method. Pharmacokinetic parameters 
(Primary and Secondary Endpoints) will be calculated according to 
noncompartmental analysis methods. The mixed trapezoidal rule 
will be used to calculate the area under the plasma concentration 
curve.
Updated the 
planned 
proportion of 
gender of 
subjects
Synopsis
Section 8.2
11
50
A total of 44 healthy male and female Chinese subjects will be 
enrolled in the trial, with each gender representing no less than 1/3 
of the total number (also evenly allocated to fasting vs. fed group), 
and are statistically powered to provide adequate sample size for 
BE testing
A total of 44 healthy male and female Chinese subjects will be 
enrolled in the trial, with at least 7 subjects of each gender in the 
fasted group, and at least 5 subjects of each gender in the fed 
group, representing 1/34 of the total number The sample size 
provides sufficient power to demonstrate BE.
Updated the 
inclusion 
criterion on
Description 
of gender 
proportion
Synopsis
Section 5.3.1
12
21
Gender: Chinese male and female (at least 1/3 of each gender per 
trial group)
Gender: Chinese male and female (at least 1/34 of each gender per 
trial group)
'RFXPHQW1R
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GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
75/92
Change
Section
Page
Previous Wording
New Wording
Updated the 
inclusion 
criterion on 
weight
Synopsis
Section 5.3.1
12
21
Weight: 50 to 80 kg; Body mass index (BMI): 18 to 30 kg/m2
Weight: 5550 to 9580 kg; Body mass index (BMI): 18 to 30 kg/m2
Updated the 
inclusion 
criterion of 
ECG 
assessment 
Synopsis
Section 5.3.1
12
21
Electrocardiogram recording (12-lead ECG) without signs of 
clinically relevant pathology in particular QTc (Bazett) < 450 ms.
Electrocardiogram recording (12-lead ECG) without signs of 
clinically relevant pathology as judged by the Investigator in 
particular QTc (Bazett) < 450 ms.
Updated the 
inclusion 
criterion of 
blood 
pressure 
normal range 
Synopsis
Section 5.3.1
12
21
Vital signs (blood pressure, pulse, body temperature, and 
respiration) in sitting position within the normal range or showing 
no clinically relevant deviation as judged by the Investigator
Vital signs (blood pressure, pulse, body temperature, and 
respiration) in sitting position within the normal range or showing 
no clinically relevant deviation as judged by the Investigator (The 
blood pressure normal range is considered O 90 mmHg and 
P 139 mmHg for systolic blood pressure [SBP]; O 60 mmHg 
and P 90 mmHg for diastolic blood pressure [DBP])
Updated and 
corrected the 
inclusion 
criterion on 
women of 
childbearing 
potential 
condition
Synopsis
Section 5.3.1
12
21
All women of childbearing potential (WOCBP) are not nursing, 
are not pregnant, and are using highly effective methods of birth 
control (defined as those, alone or in combination, that result in a 
low failure rate (ie, less than 1 percent per year) when used 
consistently and correctly) for a period of at least 1 month before 
and after dosing. Standard birth control methods are considered to 
be implanted contraceptive therapy and intrauterine devices (oral 
contraceptive excluded). Female subjects may also be enrolled if 
they are postmenopausal (ie, at least 12 consecutive months of 
amenorrhea after the last menstrual period) or surgically sterilized/ 
hysterectomized at least 6 months prior to trial participation; 
WOCBP must have a negative urine pregnancy test at screening 
and a negative serum pregnancy test on each admission (Day -1 of 
each treatment period)
All women of childbearing potential (WOCBP) are not nursing, 
are not pregnant, and are using highly effective methods of birth 
control (defined as those, alone or in combination, that result in a 
low failure rate (ie, less than 1 percent per year) when used 
consistently and correctly) for a period of at least 1 month before 
and after last dosing. Standard birth control methods are 
considered to be implanted contraceptive therapy and intrauterine 
devices (oral contraceptive excluded). Female subjects may also be 
enrolled if they are postmenopausal (ie, at least 12 consecutive 
months of amenorrhea after the last menstrual period) or surgically 
sterilized/ hysterectomized at least 6 months prior to trial 
participation; WOCBP must have a negative urine serum
pregnancy tests at screening and a negative serum pregnancy test
on each admission (Day -1 of each treatment period)
Updated the 
inclusion 
criterion on 
alcohol and 
drug abuse
Synopsis
Section 5.3.1
12
21
Negative screen for alcohol and drugs of abuse (opiate class, 
barbiturates, cocaine and metabolites, amphetamines, 
cannabinoids, benzodiazepines and tricyclic antidepressants) at 
screening and on each admission
Negative screen for alcohol and drugs of abuse (opiate class, 
barbiturates, cocaine and metabolites, amphetamines, 
cannabinoids, benzodiazepines and tricyclic antidepressants
cannabis, benzodiazepines, barbiturates, opiates, cocaine, and 
methyl amphetamine) at screening and on each admission
Updated the 
exclusion 
criterion on 
receipt of 
medications
Synopsis
Section 5.3.2
13
22
Receipt of any prescription or nonprescription medication within 
2 weeks before the first IMP administration, including 
multivitamins and herbal products (eg, St John’s Wort, or 
traditional Chinese medicines), except hormonal contraceptives in 
females and/or paracetamol
Receipt of any prescription or nonprescription medication within 
2 weeks before the first IMP administration, including 
multivitamins and herbal products (eg, St John’s Wort, or 
traditional Chinese medicines), except hormonal contraceptives in 
females and/or paracetamol
'RFXPHQW1R
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&&,


GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
76/92
Change
Section
Page
Previous Wording
New Wording
Updated the 
exclusion 
criterion on 
receipt of 
medications
Synopsis
Section 5.3.2
13
22
Consumption of grapefruit, cranberry or juices of these fruits,
14 days prior to drug administration.
Consumption of grapefruit, cranberry or juices of these fruits, 
from 14 days prior to drug administration until collection of the 
last PK sample in Period 2.
Updated the 
description in 
planned trial 
and treatment 
duration per 
subject
Synopsis
13
The planned treatment consists of initial screening assessments 
(within 14 days prior to the  first IMP administration) followed by 
2 trial periods (consisting of IMP administration following 2 days 
of blood sampling) in a crossover trial design. Each trial period 
includes a single dose of IMP administration and the doses are 
separated by approximately a 7-day Washout period. An End-of-
Trial visit (Day 15) will be conducted 7 days after administration 
in Period 2. The overall trial duration for each subject is 
approximately 4 weeks (or approximately 28 days) including the 
screening and End-of-Trial visit.
The planned treatment consists of initial screening assessments 
(within 14 days prior to the  first IMP administration on Day 1) 
followed by 2 trial periods (consisting of IMP administration 
following 2 days of blood sampling) in a crossover trial design. 
Each trial period includes a single dose of IMP administration and 
the doses are separated by approximately a 7-day Washout period. 
An End-of-Trial conditional follow-up visit (Day 15) will be 
conducted 7 days after administration in Period 2 (only for 
subjects who has AE during the trial and ongoing at 
discharge). The overall trial duration for each subject is 
approximately 4 weeks (or approximately 28 days) including the 
screening and End-of-Trial conditional follow-up visit.
Update 
wording of 
background-
Diabetes 
Mellitus and 
treatment
Section 3.1
17-18
A prospective study in T2DM patients revealed that lacking of 
glycemic control is correlated with the development of diabetic 
complications, even a small rise above the normal plasma glucose 
concentration range increases the risk of macrovascular and 
microvascular complications [6]. The primary effectiveness of 
T2DM treatment therapy in present time is determined by a 
surrogate outcome, ie, change in HbA1C [7,8]. The IDF 
recommends a general HbA1C target of 7% [2]. In patients with 
renal impairment, the HbA1C should be targeted between 7.0 and 
8.5%, depending on patient characteristics, in order to delay or 
prevent progression of the microvascular complications, including 
diabetic kidney disease [9], but also not to risk hypoglycemia. 
Increasingly, additional surrogate parameters, such as the body 
mass index (BMI), are taken into account in order to apply a more 
patient-tailored approach [10].
A prospective study in T2DM patients revealed that lacking of
glycemic control is correlated with the development of diabetic 
complications, even a small rise above the normal plasma glucose 
concentration range increases the risk of macrovascular and 
microvascular complications [6]. The primary effectiveness of 
T2DM treatment therapy in present time is determined by a 
surrogate outcome, ie, change in HbA1C [7,8]. The IDF 
recommends a general HbA1C target of 7% [2]. In patients with 
renal impairment, the HbA1C should be targeted between 7.0 and 
8.5%, depending on patient characteristics, in order to delay or 
prevent progression of the microvascular complications, including 
diabetic kidney disease [9], but also not to risk hypoglycemia. 
Increasingly, additional surrogate parameters, such as the body 
mass index (BMI), are taken into account in order to apply a more 
patient-tailored approach [10].
'RFXPHQW1R
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&&,


GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
77/92
Change
Section
Page
Previous Wording
New Wording
Updated the 
description of 
subject 
number 
Section 5.1
20
A total of 44 healthy male or female Chinese subjects will be 
enrolled in the trial, with each gender representing no less than 1/3 
of the total number (also evenly allocated to fasting vs. fed group). 
Subjects will also be allocated to fasting vs. fed sub-group, ie, 26 
subjects will be enrolled into the fasting group and 18 subjects in 
the fed group, respectively (Figure 1), and are statistically powered 
to provide adequate sample size for BE evaluation.
Given local health authority guidance and Investigator 
recommendation, A a total of 44 healthy male or female Chinese 
subjects will be enrolled in the trial, with at least 7 subjects of
each gender in the fasted group, and at least 5 subjects of each 
gender in the fed group, representing no less than 1/34 of the 
total number (also evenly allocated to fasting vs. fed group). 
Subjects will also be allocated to fasting vs. fed sub-group, ie, 26 
subjects will be enrolled into the fasting group and 18 subjects in 
the fed group, respectively (Figure 1). The sample size provides 
sufficient power to demonstrate BE., and are statistically 
powered to provide adequate sample size for BE evaluation.
Updated the 
term of End-
of-Trial 
examination 
period to 
conditional
follow-up 
visit
Section 5.1
Table 2 head 
row
20
End-of-Trial
End-of-Trial Conditional follow-up visit (only for subject who 
has AE)
Updated the 
instruction of 
trial periods
Section 5.1
Table 2 
20
Day -14 –
Day -1
Day 1 
(approximat
ely 60 hours 
inpatient 
starting 
from the day 
prior 
to 
dosing)
7 days
Day 8 
(approximat
ely 60 hours 
inpatient 
starting 
from the day 
prior 
to 
dosing)
Day 15
Day -14 –
Day -1
Day 1 
to 
Day 3
(approximat
ely 60 hours
inpatient 
starting 
from the day 
prior 
to 
dosing)
(inpatient)
7 days
(inpatien
t)
Day 8 
to 
Day 10
(approximat
ely 60 hours
inpatient 
starting 
from the day 
prior 
to 
dosing)
(inpatient)
Day 15
Updated the 
wording of 
withdrawal 
from trial 
therapy
Section 5.5.1
23
Subjects who withdraw from the trial will also be withdrawn from 
the IMP. A subject who drops out will not be replaced for this trial 
as long as the minimum sample size of evaluable subjects is met.
Subjects who withdraw from the trial will also be withdrawn from 
the IMP. A subject who drops out will not be replaced for this trial 
as long as the minimum sample size of evaluable subjects is met. 
The minimum requirement is 20 evaluable subjects in the 
fasting and 12 subjects in the fed group, which will provide 
adequate power to show BE in both groups.
Updated the 
wording of 
withdrawal 
from trial 
Section 5.5.2
23
4. Emesis experienced within 4 hours following drug 
administration because of incomplete absorption (this period of 
time corresponds also to 2 times the median time of maximum 
plasma concentration [tmax] of GIR). Subjects experiencing 
vomiting later than 4 hours postdose will not be withdrawn unless 
otherwise decided by the Investigator in light of subject’s safety or 
trial integrity
4. Emesis experienced within 4 hours following drug 
administration because of possibly incomplete absorption (this 
period of time corresponds also to 2 times the median time of 
maximum plasma concentration [tmax] of GIR). Subjects 
experiencing vomiting later than 4 hours postdose will not be 
withdrawn unless otherwise decided by the Investigator in light of 
subject’s safety or trial integrity
'RFXPHQW1R
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&&,


GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
78/92
Change
Section
Page
Previous Wording
New Wording
Updated the 
wording of 
withdrawal 
from trial 
regarding 
concomitant 
medication
Section 5.5.2
23
Concomitant medication of any drug except pain relief medication 
(paracetamol) is prohibited, the administration of paracetamol 
should not exceed 1 g per day. Details of reasons for premature 
withdrawal of subjects will be recorded and documented in the 
final report.
Concomitant medication of any drug except pain relief medication 
(paracetamol) is prohibited, the administration of paracetamol 
should not exceed 1 g per day and not more than 3 consecutive 
days. Details of reasons for premature withdrawal of subjects will 
be recorded and documented in the final report.
Updated the 
definition of 
End-of-Trial 
Section 5.7
24
The End-of-Trail is defined as the last contact of the last subject 
(usually the End-of-Trial visit [Day 15], which is scheduled for 
7 days after the administration day in Period 2 [Day 8]).
The End-of-Trail is defined as the last contact of the last subject 
(usually the End-of-Trial visit [Day 15], which is scheduled for 
7 days after the administration day in Period 2 [Day 8].Day 10 or 
the conditional follow-up visit/ [Day 15]/ or any special day for 
Premature Withdrawal visit).
Updated 
description of 
IMP
Section 6.1
24
All IMPs will be sourced from respective manufacturer as listed 
below (Table 3).
GIR= glucophage 
immediate 
release;
IMP= investigational 
medicinal product
All IMPs will be sourced from respective manufacturer as listed 
below (Table 3). The IMPs manufacturing process compliant 
with GMP requirements. The transportation and storage are 
to be tracked by temperature monitor to insure the medication 
quality and compliance to China regulation requirements.
GIR 
500 mg = Glucophage 
500 mg 
Immediate 
Release;
IMP = Investigational Medicinal Product; MSS = Merck Santé 
s.a.s. in Semoy; SASS = Sino-American Shanghai Squibb 
Pharmaceuticals Ltd.
Update 
dosage and 
administratio
n information
Section 6.2
24
Potential trial subjects will be examined at a screening 
examination to determine their eligibility for participation. These 
tests are to be conducted within 14 days before the first trial 
administration (Day 1, Period 1).
On the evening before the dosing day in each period, subjects will 
be admitted to the Clinical Research Unit (CRU) to fast prior to 
Day 1 dosing (administered the next morning).
Potential trial subjects will be examined at a screening 
examination to determine their eligibility for participation. These 
tests are to be conducted within 14 days before the first trial 
administration (first IMP given on Day 1, Period 1).
On the evening before the dosing day in each the first period, 
subjects will be admitted to the Clinical Research Unit (CRU) to 
fast prior to Day 1 dosing (administered the next morning).
Revise Table 
4 footnote
Section 6.3
25
GIR= Glucophage immediate release IMP= investigational 
medicinal product; SASS= Sino-American Shanghai Squibb 
Pharmaceuticals Ltd.
GIR= Glucophage iImmediate rReleaseImmediate Release; 
IMP= iInvestigational mMedicinal pProduct; MSS= Merck Santé 
s.a.s. in Semoy; SASS= Sino-American Shanghai Squibb 
Pharmaceuticals Ltd.
'RFXPHQW1R
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&&,


GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
79/92
Change
Section
Page
Previous Wording
New Wording
Update 
description 
regarding 
Concomitant 
Medications 
and Therapies
Section 6.5
26
Medications administered between enroll (date of informed 
consent form [ICF] signed) to first IMP dosing (Day 1) will be 
recognized as prior medication and used for eligibility check. After 
IMP dosing, any medication will be recorded as concomitant 
medication. The medication taken after subject enroll, if any, shall 
be documented in the eCRF stating the international 
nonproprietary name and trade name of the medication, its dose, 
duration, galenic form, route of administration, date and time of all 
administrations and indication. The data recorded up to the time at 
which the subject in question was withdrawn shall be taken for the 
evaluation of the trial substance’s safety and tolerability.
Medications administered between enroll (date of informed 
consent form ([ICF]) signed) to first IMP dosing (Day 1) will be 
recognized as prior medication and used for eligibility check. After 
IMP dosing, any medication will be recorded as concomitant 
medication. The medication taken after subject enroll, if any, shall 
be documented in the eCRF stating the international 
nonproprietary name and trade name of the medication, its dose, 
duration, galenic form, route of administration, date and time of all 
administrations and indication. The data recorded up to the time at 
which the subject in question was withdrawn shall be taken for the 
evaluation of the trial substance’s safety and tolerability.
Updated 
restriction of 
allowed pain 
relief 
medication
Section 6.5.1
26
No concomitant medication except pain relief medication 
(paracetamol) is allowed during the trial. The administration of 
paracetamol should not exceed 1 g per day and should be 
documented in eCRF.
No concomitant medication except pain relief medication 
(paracetamol) is allowed during the trial. The administration of 
paracetamol should not exceed 1 g per day and not more than 3 
consecutive days, and should be documented in eCRF.
Updated the 
special 
precaution of 
alcohol 
prohibition 
period
Section 
6.5.4.1
26-27
The subjects have to abstain from alcohol from 2.5 days 
(approximately 60 hours) prior to dosing and through the End-of-
Trial visit.
In case of any suspicion of alcohol consumption, a test for alcohol 
may be performed to confirm the Investigator's judgment.
The subjects have to abstain from alcohol from 2.5 days 
(approximately 60 hours) prior to dosing and through the End-of-
Trial visit entire study period.
In case of any suspicion of alcohol consumption, an additional 
test for alcohol may be performed to confirm the Investigator's 
judgment.
Updated the 
special 
precaution of 
food 
restriction
Section 
6.5.4.3
27
Fluids
Subjects are not allowed to excessively consume beverages 
containing xanthine (> 5 cups of coffee a day or equivalent) and 
need to stop caffeine consumption from 48 hours prior to drug 
administration until collection of the last PK sample in each 
period. Subjects also need to stop intake of grapefruit, cranberry or 
juices/beverages of these fruits, from 14 days prior to drug 
administration until collection of the last PK sample in Period 2.
Fluids
Subjects are not allowed to excessively consume beverages 
containing xanthine derivate (> 5 cups of coffee a day or 
equivalent) and need to stop caffeine consumption from 48 hours 
prior to drug administration until collection of the last PK sample 
in each period. Subjects also need to stop intake of grapefruit, 
cranberry or juices/beverages of these fruits, from 14 days prior to 
drug administration until collection of the last PK sample in 
Period 2.
'RFXPHQW1R
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&&,


GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
80/92
Change
Section
Page
Previous Wording
New Wording
Added the 
instruction of 
IMP 
preparation
Section 6.7
28
All IMP treatment boxes supplied to the trial center must be stored 
carefully, safely, and separately from other drugs. The handling 
and storage of IMPs should follow the regulatory requirements 
from authorities.
All IMP treatment boxes supplied to the trial center must be stored 
carefully, safely, and separately from other drugs. The handling 
and storage of IMPs should follow the regulatory requirements 
from authorities. Sponsor must provide trial center enough 
drugs, including subject treatment and in additional at least 5 
times full testing sample size for any requested testing in the 
inspection in the future. In terms of study IMP as well as 
reference IMP, the subject treatment using part and the extra 
5 times of full testing samples will be from one identical batch 
and to be labeled equally without any difference to fulfill the 
randomized treatment IMPs/retention sample selection 
requirement at trial center. This requirement is appropriate 
for both study drugs and reference drugs.
Updated the 
instruction of 
IMP handling
Section 6.7
28
The Investigator (or the pharmacist or another person who is 
designated by the Investigator) will maintain the following records 
for the trial medication:
Upon receipt of trial treatment boxes at the trial center, the 
following must be performed by the trial staff:
!
Inventory at the center
!
Administration to each subject
!
Destruction of unused medication.
It must be ensured that the IMP is not used at the trial site:
!
After the expiry date or
!
After the retest date unless the IMP is reanalyzed and its 
release date extended.
The Investigator (or the pharmacist or another person who is 
designated by the Investigator) will maintain the following records 
for the trial medication:
Upon receipt of trial treatment boxes at the trial center, the 
following must be performed by the trial staff:
!
Check and insure the IMPs shipment period is under 
the controlled temperature by referring the 
temperature logger data
The Investigator (or the pharmacist or another person who is 
designated by the Investigator) will maintain the following 
records for the trial medication:
!
Inventory at the center
!
Administration to each subject
!
Destruction of unused medication.
It must be ensured that the IMP is not used at the trial site center:
!
After the expiry date or
!
After the retest date unless the IMP is reanalyzed and its 
release date extended
!
Before to receive any written greenlight from 
Sponsor when temperature deviation occurred to 
IMPs during the trial center storage
Removed the 
instruction of 
destroying 
IMP 
Section 6.7
28
The unused and remained trial medication and the expired testing 
sample has to be destroyed under Sponsor’s agreement.
The unused and remained trial medication and the expired testing 
sample has to be destroyed under Sponsor’s agreement.
'RFXPHQW1R
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GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
81/92
Change
Section
Page
Previous Wording
New Wording
Added the 
instruction of 
IMP 
dispensing
Section 6.7
28
-
The drugs for the subjects must be random drawing from all 
the study drugs and reference drugs provided by the Sponsor 
(it can reference to randomization list from statistics), the left 
drugs are as the retention samples for the inspection or testing 
in the future.
Any temperature occurred during the site storage should 
report to CRA immediately. The responsible CRA report it to 
Merck immediately as well to collect Merck written decision to 
use or block the impacted IMPs.
Updated the 
instruction 
for drug 
accountability
Section 6.8
29
Unused IMP must not be discarded or used for any purpose other 
than the present trial. The unused IMP to be returned back or to be 
destroyed at site will be on sponsor’s e-mail notice and greenlight 
to proceed. Investigational medicinal product that has been 
dispensed to a subject must not be re-dispensed to a different 
subject.
The monitor will periodically collect the IMP accountability forms 
and will check all returns (both unused and used containers) before 
arranging for their return to the Sponsor or authorizing their 
destruction by the trial site.
Unused IMP must not be discarded or used for any purpose other 
than the present trial. The unused IMP to be returned back or to be 
destroyed at site will be on sponsor’s e-mail notice and greenlight 
to proceed. Investigational medicinal product that has been 
dispensed to a subject must not be re-dispensed to a different 
subject.
The monitor will periodically collect the IMP accountability forms 
and will check all returns (both unused and used containers) before 
arranging for their return to the Sponsor or authorizing their 
destruction by the trial site.
The retention samples should be stored at trial center or the 
third party under appropriate condition. It is the trial center 
to decide the retention sample storage place and the retention 
samples will not be returned to Sponsor. The trial center must 
collect the Sponsor’s written confirmation before to proceed 
any retention sample destruction activity.
Updated the 
instruction 
for Medical 
Care of 
Subjects after 
End-of-Trial
Section 6.13
30
After a subject has completed the trial or has withdrawn 
prematurely, an End-of-Trial visit (Day 15, if subject completed 
the trial) will be conducted and safety assessments will be 
performed.
Upon the careful screening for healthy subjects such as detailed in 
the eligibility criteria for this trial, no serious AEs related to study 
treatment are expected during this trial. However, in case of any 
ongoing AE at the End-of-Trial visit, these AEs must be monitored 
until they have either returned to normal or are no longer 
considered as clinically relevant or can be explained. If necessary, 
other medical disciplines should be consulted.
After a subject has completed the trial and has AE during the 
trial and ongoing at discharge or has withdrawn prematurely, 
aEnd-of-Trial conditional follow-up visit (Day 15, if subject 
completed the trial on Day 10, or any specific day for premature 
withdrawal) will be conducted and safety assessments will be 
performed.
Upon the careful screening for healthy subjects such as detailed in 
the eligibility criteria for this trial, no serious AEs related to study 
treatment are expected during this trial. However, in case of any 
ongoing AE at the End-of-Trial last visit, these AEs must be 
monitored until they have either returned to normal or are no 
longer considered as clinically relevant or can be explained. If 
necessary, other medical disciplines should be consulted.
'RFXPHQW1R
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&&,


GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
82/92
Change
Section
Page
Previous Wording
New Wording
Updated the 
schedule of 
assessments
Section 7.1
30
The schedule of assessments will include:
!
Screening (determining eligibility to the trial, including 
assessments during admission to CRU; Day -14 to Day -
2)
!
Admission to the CRU before Period 1 (Day -1)
!
Period 1 (Day 1 to Day 3)
!
Washout Period
!
Admission to the CRU before Period 2 (Day 7)
!
Period 2 (Day 8 to Day 10)
!
End-of-Trial (Day 15)/Premature Withdrawal (Table 1).
Subject will participate in the clinical trial on an inpatient basis 
during Day -1 to Day 3 and also during Days 7 to 10.
The schedule of assessments will include:
!
Screening (determining eligibility to the trial, including 
assessments during admission to CRU; Day -14 to Day -
2)
!
Admission to the CRU before Period 1 (Day -1)
!
Period 1 (Day 1 to Day 3)
!
Washout Period
!
Admission to the CRU before Period 2 (Day 7)
!
Period 2 (Day 8 to Day 10 Discharge day)
!
End-of-Trial Conditional follow-up (Day 15) only for 
subject who has AE during the trial and ongoing at 
discharge/Premature Withdrawal (Table 1).
Subject will participate in the clinical trial on an inpatient basis 
during Day -1 to Day3 and also during Days 7 to 10.
Revises 
Inclusion/Exc
lusion criteria 
checking 
statements
Section 7.1.1
31
Potential trial subjects will be examined at screening to determine 
their eligibility for clinical trial participation. The inclusion and 
exclusion criteria will be reviewed to determine eligibility for the 
trial while collecting the necessary information. All screening 
assessments are to be conducted within 14 days before the start of 
the trial. Renal failure will be assessed by using the estimated 
measure with MDRD equation
Potential trial subjects will be examined at screening to determine 
their eligibility for clinical trial participation. The inclusion and 
exclusion criteria will be reviewed to determine eligibility for the 
trial while collecting the necessary information. All screening 
assessments are to be conducted within 14 days before the start of 
the trial first trial administration (first IMP given on Day 1, 
Period 1). Renal failure will be assessed by using the estimated 
measure with MDRD equation
Revised ECG 
description 
due to 
redundant to 
7.4.4 
Section 7.1.1
31-32
A 12-lead ECG (including QTc evaluation) will be performed. 
Results of the ECG recordings will be included in the subject's 
eCRF. Printouts for each ECG will include date, time, initials of 
the technician/nurse, and initials of the Investigator who reviewed 
the printout. At least 5 to 7 beats will be monitored at a speed of 
25 mm/sec for each lead and a single lead (V2) run (see Section 
7.4.4 for specific ECG determinations and procedures).
A 12-lead ECG (including QTc evaluation) will be performed. 
Results of the ECG recordings will be included in the subject's 
eCRF. Printouts for each ECG will include date, time, initials of 
the technician/nurse, and initials of the Investigator who reviewed 
the printout. At least 5 to 7 beats will be monitored at a speed of 
25 mm/sec for each lead and a single lead (V2) run (see Section 
7.4.4 for specific ECG determinations and procedures).
Updated 
laboratory 
tests 
description
Section 7.1.1
34
Urinalysis
Appearance, blood, glucose, ketones, nitrite, pH, protein, and 
leukocytes will be assessed. Microscopic examination will only be 
performed if dipstick test is positive for leukocytes, blood, nitrites, 
or proteins.
Urinalysis
Appearance, blood, glucose, ketones, nitrite, pH, protein, and 
leukocytes will be assessed. Microscopic examination will only be 
performed if dipstick test is positive for leukocytes, blood, nitrites, 
or proteins.
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GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
83/92
Change
Section
Page
Previous Wording
New Wording
Updated Day 
1 procedure
Section 7.1.2
34
Trial eligibility assessments will be performed including: physical 
examination, vital signs, ECG and prior medications since 
screening visit, treatments and diseases as well as testing for 
alcohol and drug abuse. Female subjects with childbearing 
potential will have a serum pregnancy test.
Trial eligibility assessments will be performed including: physical 
examination, vital signs, ECG, laboratory tests, and prior 
medications since screening visit, treatments and diseases
(medical history) as well as testing for alcohol and drug abuse. 
Female subjects with childbearing potential will have a serum 
pregnancy test.
Added 
randomizatio
n to Day -1
Section 7.1.2
34
-
Randomization
Eligible subjects will then be randomly assigned to 1 of 2 
sequences (Table 4).
Updated Day 
1 procedure 
on blood 
pressure 
check
Section 7.1.3
35
Subjects will be assessed for vital signs (blood pressure, pulse rate, 
temperature and respiration). Blood pressure assessments 
determine eligibility to be randomized to the trial. The blood 
pressure (measured in sitting position after at least 5 minutes rest) 
must not be below 100 mmHg and/or 65 mmHg or above 139 
mmHg and/or 90 mmHg.
Subjects will be assessed for vital signs (blood pressure, pulse rate, 
temperature and respiration). Blood pressure assessments determine 
eligibility to be randomized to the trial. The blood pressure 
(measured in sitting position after at least 5 minutes rest) must not 
be below 100 mmHg and/or 65 mmHg or above 139 mmHg and/or 
90 mmHg.
normal range is considered O 90 mmHg and 
P 139 mmHg for SBP; O 60 mmHg and P 90 mmHg for DBP.
Updated Day 
1 procedure
Section 7.1.3
35
If the subject is determined to be ineligible for any of the above 
assessments, the subject will not be randomized to the trial.
If the subject is determined to be ineligible for any of the above 
assessments, the subject will not receive randomized treatment be 
randomized to the trial.
Removed 
randomizatio
n from Day 1
Section 7.1.3
35
Randomization
Eligible subjects will then be randomly assigned to one of 2 
sequences (Table 4).
Randomization
Eligible subjects will then be randomly assigned to one of 2 
sequences (Table 4).
Updated PK 
sampling 
procedure
Section 7.1.3
36
For plasma metformin detection, blood samples will be collected 
by indwelling cannula (short-term peripheral catheter) for the first 
day and by direct venipuncture for the rest of the time. Blood 
samples should be processed within 30 minutes or otherwise 
should be kept in an ice water bath pending processing. Plasma 
samples will be prepared, divided into 2 aliquots and stored at max 
-20°C. Plasma concentration of metformin will be analyzed by 
validated bioanalytical method.
For plasma metformin detection, blood samples will be collected 
by indwelling cannula (short-term peripheral catheter) for the first 
day and by direct venipuncture for the rest of the time. Blood 
samples should be processed within 30 minutes (centrifuge each 
tube for 10 minutes at 2000g) or otherwise should be kept in an 
ice water bath pending processing. Plasma samples will be 
prepared, divided into 2 aliquots and stored at max -20°C. Plasma 
concentration of metformin will be analyzed by validated 
bioanalytical method.
Updated PK 
sampling 
collection 
schedule
Section 7.1.3
End-of-Trial 
(Day 15)/Prematu
re Withdrawal
1-sample at End-of-Trial 
visit
±30
End-of-Trial 
(Day 15)/Prem
ature 
Withdrawal
1-sample at End-of-Trial 
visit premature 
withdrawal
±30
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GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
84/92
Change
Section
Page
Previous Wording
New Wording
Added note 
for blood 
sample 
processing
Section 7.1.3
Table 8 
footnote
36
-
Note: All blood samples should be processed within 30 minutes 
(centrifuge each tube for 10 minutes at 2000 g) or otherwise 
should be kept in an ice water bath pending processing. There 
will be an extra PK sampling for subjects who has premature
withdrawal. For subjects having conditional follow-up visit for 
safety, no PK sampling is required.
Updated Vital 
sign
assessment at 
Period 1
Section 7.1.3
37
Vital signs will be repeated prior to dosing and at 4 and 8 hours 
postdose.
Vital signs will be repeated prior to dosing and at 4 and 8 hours 
postdose.
Updated 
assessment 
procedure on 
Day 2 to Day 
3
Section 7.1.3
37
Pharmacokinetic Blood Sampling (Postdose, continued)
During the 2 days following Day 1, blood samples will be taken 
according to the trial schedule (Table 8). On Day 2, sampling 
will be conducted at 24 and 36 hours; on Day 3, sampling 
will be conducted at 48 hours after GIR administration. 
Subjects will be allowed to leave the CRU on Day 3 after the 
morning blood sampling collection (48-hour sample).
Pharmacokinetic Blood Sampling (Postdose, continued)
During the 2 days following Day 1, blood samples will be taken 
according to the trial schedule (Table 8). On Day 2, sampling 
will be conducted at 24 and 36 hours; on Day 3, sampling 
will be conducted at 48 hours after GIR administration. 
Subjects will be allowed to leave the CRU on Day 3 after the 
morning blood sampling collection (48-hour sample).
Updated 
assessment 
procedure on 
Day 2 to Day 
3
Section 7.1.3
37
Safety Monitoring
Any concomitant diseases and treatments have to be documented. 
Concurrent administration of any medication will be prohibited 
during the trial. Any AEs and SAEs should also be recorded.
Vital signs will be assessed before blood sampling from Day 2 to 
Day 3.
A 12-lead ECG (including QTc evaluation) will be performed 
48 hours postdose at Day 3.
At the day of discharge, a blood sample for determination of 
hematology and biochemistry will be taken and a urinalysis will be 
performed. Physical examination will also be performed.
On the morning of Day 3 in the CRU after the blood sampling 
collection (48-hour sample), the Investigator will decide whether 
or not the subject needs to stay for any additional time in the 
clinic. If there are no safety concerns based on the assessment by 
the Investigator, the subject will be allowed to leave the CRU.
Safety Monitoring
Any concomitant diseases and treatments have to be documented. 
Concurrent administration of any medication will be prohibited 
during the trial. Any AEs and SAEs should also be recorded.
Physical examination will also be performed on Day 3.
Vital signs will be assessed before blood sampling from Day 2 to 
Day 3.
A 12-lead ECG (including QTc evaluation) will be performed 
48 hours postdose at Day 3.
At the day of discharge, a blood sample for determination of 
hematology and biochemistry will be taken and a urinalysis will be 
performed. Physical examination will also be performed.
On the morning of Day 3 in the CRU after the blood sampling 
collection (48-hour sample), the Investigator will decide whether 
or not the subject needs to stay for any additional time in the 
clinic. If there are no safety concerns based on the assessment by 
the Investigator, the subject will be allowed to leave the CRU.
Updated 
description of 
washout 
period
Section 7.1.4
37
The 2 administrations of IMP are separated by a Washout of 
7 days. Washout begins postdose on Day 1 and continues for 
approximately 7 days.
The 2 administrations of IMP are separated by a Washout of 
7 days (inpatient). Washout begins postdose on Day 1 and 
continues for approximately 7 days.
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GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
85/92
Change
Section
Page
Previous Wording
New Wording
Updated 
assessment 
procedure on 
Day 7
Section 7.1.5
37-38
7.1.5 Admission to Clinical Research Unit (Day 7)
In the evening before the dosing day, subjects will be admitted to 
the CRU at least 12 hours prior to Day 8 dosing for an overnight 
fast. 
Subjects will refrain from all food and drinks except water from 
the evening after dinner of Day 7. They will have fasted for at least 
10 hours at the time of drug administration (fasting group) or 
standard breakfast (fed group) next morning.
Trial eligibility assessments will include: physical examination, 
vital signs, ECG, and concomitant medications (Table 1). Testing 
for alcohol and drug abuse will be performed. In addition, a blood 
sample for determination of hematology and biochemistry will be 
taken and a urinalysis will be performed. Serum pregnancy test 
will be performed for females of childbearing potential only.
7.1.5 Admission to Clinical Research Unit (Day 7
In the evening before the dosing day, subjects will be admitted to 
the CRU at least 12 hours prior to Day 8 dosing for an overnight 
fast. 
Subjects will refrain from all food and drinks except water from 
the evening after dinner of Day 7. They will have fasted for at least 
10 hours at the time of drug administration (fasting group) or 
standard breakfast (fed group) next morning.
Trial eligibility assessments will include: physical examination, 
vital signs, ECG and concomitant medications (Table 1). Testing 
for alcohol and drug abuse will be performed. In addition, a blood 
sample for determination of hematology and biochemistry will be 
taken and a urinalysis will be performed. Serum pregnancy test 
will be performed for females of childbearing potential only.
Updated Day 
8 procedure
Section 7.1.6
38
Procedures outlined on Day 1 in Period 1 will be repeated on 
Day 8 for continuing trial eligibility into Period 2 (except for 
randomization).
Procedures outlined on Day 1 in Period 1 will be repeated on 
Day 8 for continuing trial eligibility into Period 2 (except for 
randomization).
Updated Vital 
sign 
assessment at 
Period 2
Section 7.1.6
38
Vital signs will be repeated prior to dosing and at 4 and 8 hours 
postdose.
Vital signs will be repeated prior to dosing and at 4 and 8 hours 
postdose.
Updated ECG 
procedures
Section 7.1.6
39
Day 9 to Day 10
A 12-lead ECG (including QTc evaluation) will be performed 
48 hours postdose at Day 10.
At the day of discharge, physical examination will be performed. 
A blood sample for determination of hematology and biochemistry 
will be taken and a urinalysis will be performed.
Day 9 to Day 10
A 12-lead ECG (including QTc evaluation) will be performed 
48 hours postdose at Day 10 before discharge.
At the day of discharge (Day 10), physical examination will be 
performed. A blood sample for determination of hematology and 
biochemistry will be taken and a urinalysis will be performed.
These investigations on the day of discharge represent the final 
examination.
Update End-
of-Trial visit
Section 7.1.7
39
7.1.7 End-of-Trial (Day 15)/Premature Withdrawal
End-of-Trial
At End-of-Trial (Day 15) the assessments include: physical 
examination, vital signs, ECG, laboratory tests (hematology, 
biochemistry, and urinalysis), and AEs will be assessed. Any 
concomitant treatments have to be documented. The case 
conclusion has to be filled in. Serum pregnancy test will be
performed for females of childbearing potential only.
7.1.7 End-of-Trial Conditional follow-up (Day 15)/Premature 
Withdrawal
End-of-Trial
Conditional follow-up visit (only for subject with AE during 
the trial and ongoing at discharge)
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GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
86/92
Change
Section
Page
Previous Wording
New Wording
If AEs or pathological findings, ie, clinically relevant deviations 
from Baseline findings are obtained during the final examination, 
these findings must be monitored until they have either returned to
normal or are no longer considered as clinically relevant or can be 
explained. If necessary, other medical disciplines should be 
consulted.
Pharmacokinetic Blood Sampling
Blood samples for the determination of GIR will be taken once 
(Table 8).
Premature Withdrawal
The assessments at Premature Withdrawal visit include: physical 
examination, vital signs, ECG, laboratory tests (hematology, 
biochemistry, and urinalysis), AEs, and concomitant treatments 
(Table 1). The case conclusion has to be filled in. Serum
pregnancy test will be performed for females of childbearing 
potential only.
At End-of-Trial conditional follow-up (Day 15) the assessments 
include: physical examination, vital signs, ECG, laboratory tests 
(hematology, biochemistry, and urinalysis), and AEs will be 
assessed. Any concomitant treatments have to be documented. The 
case conclusion has to be filled in for every subject who has 
received at least one dose of the IMPs. Serum pregnancy test 
will be performed for females of childbearing potential only.
If AEs or pathological findings, ie, clinically relevant deviations 
from Baseline findings are obtained during the final examination, 
these findings must be monitored until they have either returned to 
normal or are no longer considered as clinically relevant or can be 
explained. If necessary, other medical disciplines should be 
consulted.
Pharmacokinetic Blood Sampling
Blood samples for the determination of GIR will be taken once 
(Table 8).
Premature Withdrawal
The assessments at Premature Withdrawal visit include: physical 
examination, vital signs, ECG, laboratory tests (hematology, 
biochemistry, and urinalysis), AEs, and concomitant treatments 
(Table 1). The case conclusion has to be filled in for every 
subject who has received at least one dose of the IMPs. Serum 
pregnancy test will be performed for females of childbearing 
potential only.
Updated AE 
reporting 
period
Section 
7.4.1.3
43-44
The AE reporting period for safety surveillance begins when the 
subject is included into the trial (date of first signature of informed 
consent) and continues through the trial’s post treatment period. 
The complete trial duration for collecting AEs is defined as 
beginning with the date of the signing of the consent form (up to 
14 days before Day 1 of trial Period 1), continuing during the IMP 
administration, and collection continued until 7 days after the day 
of the last IMP administration (ie, End-of-Trial visit, Day 15). In 
case of early termination, AEs until Premature Withdrawal visit 
will be collected.
The AE reporting period for safety surveillance begins when the 
subject is included into the trial (date of first signature of informed 
consent) and continues through the trial’s post treatment period. 
The complete trial duration for collecting AEs is defined as 
beginning with the date of the signing of the consent form (up to 
14 days before Day 1 of trial Period 1), continuing during the IMP 
administration, and collection continued until Day 10 or 7 days 
after the day of the last IMP administration (ie, End-of-Trial
conditional follow-up visit, Day 15, if subject has AE during 
the trial and ongoing at discharge). In case of early termination, 
AEs until Premature Withdrawal visit will be collected.
Updated 
Safety report 
e-mail
Section 
7.4.1.4
44
E-mail:
E-mail:
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GIR China Bioequivalence Study
MS200084_0009
87/92
Change
Section
Page
Previous Wording
New Wording
Updated 
description 
on ECG 
assessment
Section 7.4.4
47
QT/QTc interval will be automatically computed using the Bazett 
correction formula (QTcB = QT/gRR) and the Fridericia 
correction formula (QTcF = QT/3gRR) by the ECG device 
according to the recently approved ICH guidance E1. In case of 
QTc values outside of the normal range, ECGs will be manually 
re-evaluated by a physician.
QT/QTc interval will be automatically computed using the Bazett 
correction formula (QTcB = QT/gRR) and the Fridericia 
correction formula (QTcF = QT/3WRRQTcF = QT/3gRR) by the 
ECG device according to the recently approved ICH guidance E1. 
In case of QTc values outside of the normal range, ECGs will be 
manually re-evaluated by a physician.
Updated the 
sample 
collection 
time of PK 
Section 7.5
47
One sample will be collected at End-of-Trial visit (Day 15 or 
Premature Withdrawal)
One sample will be collected at End-of-Trial visit (Day 15 or
Premature Withdrawal) if applicable.
Updated the 
total sample 
number for 
PK sample 
collection 
Section 7.5
47
Subjects who complete both treatment periods plus an End-of-
Trial PK sample will have a total of 35 samples (approximately 3 
mL whole blood each sample) collected. Total PK blood volume 
collection is approximately 105 mL over 2 weeks.
Subjects who complete both treatment periods plus an End-of-
Trial PK sample will have a total of 3534 samples (approximately 
3 mL whole blood each sample) collected. Total PK blood volume 
collection is approximately 105102 mL over 2 weeks.
Updated the 
wording for 
subject 
replacement
Section 8.2
51
The first 6 (fasting) or 4 (fed) discontinued subjects of each group 
will not be replaced. Subjects will only be replaced if the number 
of subjects within each group falls below 20 (fasting) or 12 (fed). 
The subject who is replacing a discontinued subject will then be 
allocated to the treatment sequence of the subject who 
discontinued.
The first 6 (fasting) or 4 (fed) discontinued subjects of each group 
will not be replaced. Subjects will only be replaced if the number 
of subjects within each group falls below 20 (fasting) or 12 (fed). 
The subject who is replacing a discontinued subject will then be 
allocated to the treatment sequence of the subject who 
discontinued.
Updated 
recording 
information 
of subject 
files
Section 10.2
58
!
Date of subject’s End-of-Trial visit, or
!
Date of subject’s End-of-Trial last visit, or
Updated 
Investigator 
Site File and 
Archiving
Section 10.3
59
The file must be available for review by the Monitor, during 
Sponsor audits and for inspection by Health Authorities during and 
after the trial, and must be safely archived for at least 15 years (or 
longer, per local requirements or as otherwise notified by the 
Sponsor) after the end of the trial.
The file must be available for review by the Monitor, during 
Sponsor audits and for inspection by Health Authorities during and 
after the trial, and must be safely archived for at least 15 5 years 
(or longer, per local requirements or as otherwise notified by the 
Sponsor) after the end of the trial.
Updated PI 
affiliation
Signature 
page-
Principal 
Investigator
68
Name, academic degree:
 
Function/Title:
Chief pharmacist 
Institution:
 
Address:
 
Telephone number:
Name, academic degree:
Chen Yu Lan 
Function/Title:
Chief pharmacist Principle Investigator
Institution:
 
 
Address:
 
 
 
 
 
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GIR China Bioequivalence Study
MS200084_0009
88/92
Change
Section
Page
Previous Wording
New Wording
Fax number:
E-mail address:
Telephone number:
Fax number:
E-mail address:
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GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
89/92
Changes on Schedule of Assessment Table 1
Assessments 
Screening 
(Baseline)
Period 1
Period 2
End-of-Trial
Conditional follow-
up visit or
Premature 
Withdrawaljk
Daya
-14 to -2
-1
1
2
3
7
8
9
10j
15 (or specific day)
Informed consent form signed
X
Inclusion/ exclusion criteria
X
X
Demographic informationb
X
History of alcohol and nicotine 
consumption
X
Medical history
X
X
Priorc medications
X
X
Laboratory tests including 
blood test and urinalysis
X
X
X
X
X
X
Pregnancy testd (females of 
childbearing potential)
X
X
X
X
HAV antibody, HBsAg, HCV 
antibody, HIV antibody and TP 
antibody tests
X
Urine drug abuse test and 
breath test of alcohol
X
X
X
Urine nicotine
X
Randomization
X
X
Drug administration
X
X
Meal Recording
X
X
Blood sampling for 
Pharmacokineticse
X
X
X
X
X
X
Xe
Physical examinationf
X
X
X
X
X
X
Vital signsg
X
X
Xgh
Xi
Xi
X
Xgh
Xi
Xi
X
Electrocardiogram
X
X
Xjh
Xk
X
Xjh
Xkh
X
Chest X-ray
X
AE recordingli
X
X
X
X
X
X
X
X
X
Concomitant therapy recording
X
X
X
X
X
X
X
X
AE= adverse event; BMI= body mass index; HAV= hepatitis A virus; HBsAg= hepatitis B surface antigen; HCV= hepatitis C virus; HIV= human 
immunodeficiency virus; TP = Treponema pallidum 
a.
Subject will participate in the clinical trial on an inpatient basis during Day -1 to Day 3 and also during Days 7 to 10.
b.
Demographic data includes: date of birth, sex, race, and height and weight. The BMI (kg/m2) will be calculated.
c.
Prior medications within 30 days before the date of first signature of informed consent will be collected at screening visit. Medications 
administered before first IMP dosing will also be recognized as prior medication and used for eligibility check.
d.
Urine Serum pregnancy test will be done at screening, serum pregnancy test will be done and at Day -1, 7, and End-of-Treatment.
e.
Refer to Table 8Table 8 for detail schedule of sampling during inpatient at research center. There will be an extra PK sampling for 
subjects with premature withdrawal, for subjects having conditional follow-up visit for safety, no PK sampling is required.
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GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
90/92
f.
Physical examination includes assessments of the general appearance, skin and mucosa, superficial lymph nodes, head and neck, chest, 
abdomen, musculoskeletal, and neurological systems.
g.
Vital signs including blood pressure (systolic and diastolic pressures), pulse rate, body temperature, and respiration (frequency per minute) 
will be measured and recorded. Blood pressure and pulse rate will be recorded in a sitting position after the subject has rested comfortably for 
at least 5 minutes. (The blood pressure normal range is considered O 90 mmHg and P 139 mmHg for SBP; O 60 mmHg and P 90 mmHg 
for DBP)
Day 1and Day 8: Vital signs will be repeated prior to dosing and at 4 and 8 hours postdose.
Vital signs will be assessed before blood sampling from Day 2 to Day 3 and Day 9 toat Day 10.
h.
Electrocardiogram (12-lead ECG, including QTc evaluation) will be performed 4 hours postdose at Day 1 and Day 8. Electrocardiogram (12-
lead ECG, including QTc evaluation) will also be performed at48 hours postdose at Day 3 and Day 10 before discharge from research unit.
i.
Adverse events will be collected starting from Day -1, the AEs since the date of first signature of informed consent will be recorded. The 
following visits will record any AEs since the last visit.
j.
Subjects will be discharged on Day 10, after final sample collection and safety examinations are completed (final examination).
k.
If subject has AE during trial and ongoing at discharge, the subject has to come back for the conditional follow-up visit.
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GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
91/92
Changes on Table 9: Estimated Blood Sample Volumes per Subject
Original Table
Time Points
Evaluation Indexes
Total Blood Volume (mL)
Screening
Serum virology
4
Hematology
2
Biochemistry
4
Approximate Total
10
Period 1
Hematology
2*2
Biochemistry
4*2
Serum Pregnancy Test (if applicable)
4
Pharmacokinetics
3*17
Approximate Total
67
Period 2
Hematology
2*2
Biochemistry
4*2
Serum Pregnancy Test (if applicable)
4
Pharmacokinetics
3*17
Approximate Total
67
End-of-Trial 
Or
Premature Withdrawal
Hematology
2
Biochemistry
4
Serum Pregnancy Test (if applicable)
4
Pharmacokinetics
3
Approximate Total
13
Approximate Total of Each Subject
157 (145 for male)
New Table
Time Points
Evaluation Indexes
Total Blood Volume (mL)
Screening
Serum virology
4
Hematology
2
Biochemistry
4
Serum Pregnancy Test (if applicable)
4
Approximate Total
10 14 (10 for male)
Period 1
Hematology
2*2
Biochemistry
4*2
Serum Pregnancy Test (if applicable)
4
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GIR/China & GIR/France
GIR China Bioequivalence Study
MS200084_0009
92/92
Pharmacokinetics
3*17
Approximate Total
67 61 (57 for male)
Period 2
Hematology
2*2
Biochemistry
4*2
Serum Pregnancy Test (if applicable)
4
Pharmacokinetics
3*17
Approximate Total
67 57
Conditional follow-up
Or
Premature Withdrawal
Hematology
2
Biochemistry
4
Serum Pregnancy Test (if applicable)
4
'Approximate Total
'136
(Pharmacokinetics (only for premature 
withdrawal)
(3
Approximate Total of Each Subject
157 (145 for male)
132(124 for male)
With conditional follow-up:
138 (130 for male)
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