Clinical trial NCT03566810
Conditions: Healthy
Keywords: Diabetes Mellitus Glucophage Extended Release (GXR) Bioequivalence Study
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2018-10-11; Completion date: 2018-11-28
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The study will assess the bioequivalence between single doses of GXR manufactured in Merck Nantong China (test drug) and GXR manufactured in Merck Darmstadt Germany (reference drug) under fed and fasted state in healthy participants.

Detailed description:

Arms: arm 1: Participants received a single oral dose of 500 milligrams (mg) of test GXR tablet (Merck Nantong/China) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GXR (Merck Darmstadt/Germany) on Day 8 in treatment period 2 under fasting conditions. 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 GXR tablet (Merck Darmstadt/Germany) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GXR (Merck Nantong/China) on Day 8 in treatment period 2 under fasting conditions. 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 GXR tablet (Merck Nantong/China) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GXR (Merck Darmstadt/Germany) on Day 8 in treatment period 2 under fed conditions. 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 GXR tablet (Merck Darmstadt/Germany) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GXR (Merck Nantong/China) on Day 8 in treatment period 2 under fed conditions. There was a wash-out period of 7 days between each treatment period.
Interventions: intervention 1: Test GXR intervention 2: Reference GXR
Intervention descriptions: intervention 1: Participants received a single oral dose of 500 mg of test GXR tablet (Merck Nantong/China) under fasting or fed conditions on either Day 1 (Treatment Period 1) or Day 8 (Treatment Period 2). intervention 2: Participants received a single oral dose of 500 mg of reference GXR tablet (Merck Darmstadt/France) under fasting or fed conditions on either Day 1 (Treatment Period 1) or Day 8 (Treatment Period 2).

Protocol documents:
Prot_000.pdf: 
GXR/China and GXR/Germany
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Clinical Study Protocol
Title Page
Clinical Study Protocol Title:
A Randomized, Open-label, 2-Way-Crossover 
Study Assessing the Bioequivalence between 
Single Doses of 500 mg Glucophage Extended 
Release
(GXR)
Tablets 
(Merck/China 
Nantong-Manufactured) and 500 mg GXR Tablets 
(Merck/Germany Darmstadt-Manufactured) under 
Fed and Fasted State in Two Groups of Healthy 
Volunteers 
Study Number:
MS200084_0013
Amendment Number
Not Applicable
Merck Compound Number:
200084
Short Title:
GXR 
China 
Bioequivalence
Study 
(Nantong - Darmstadt)
Principal Investigator:
Sponsor Name and Legal Registered 
Address:
Merck Pharmaceutical Manufacturing (Jiangsu) 
Co., Ltd.
No. 168 Hexing Road, NETDA, Nantong, Jiangsu, 
China 226010
Protocol Lead:
Merck Serono (Beijing) Pharmaceutical R&D Co., 
Ltd.
25F, NUO Center Office
No. 2A, Jiangtai Road, Chaoyang District
Beijing 100016
P. R. China
Regulatory Agency Registry:
Chinadrugtrials.org.cn
Protocol Version:
19 Apr 2018/Version 1.0
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Replaces Version:
Not Applicable
Approval Date:
TBD
Medical Monitor Name and Contact 
Information:
Merck Serono Co., Ltd.
25F, NUO Center Office
No. 2A, Jiangtai Road, Chaoyang District
Beijing 100016
P. R. China
Protocol History
Version Number
Type
Version Date
1.0
Original Protocol
19-Apr-2018
This document is the property of Merck KGaA, Darmstadt, Germany, 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 Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2018 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved.
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Table of Contents
Title Page
1
Protocol History
2
Table of Contents 3
1
Protocol Summary ................................................................................6
1.1
Synopsis................................................................................................6
1.2
Schema..................................................................................................8
1.3
Schedule of Activities...........................................................................9
1.4
Estimated Blood Sample Volumes per Participant.............................11
2
Introduction.........................................................................................12
2.1
Study Rationale...................................................................................12
2.2
Background.........................................................................................12
2.2.1
Diabetes Mellitus and Treatment........................................................12
2.2.2
Glucophage Extended Release ...........................................................13
2.3
Benefit/Risk Assessment ....................................................................14
3
Objectives and Endpoints ...................................................................14
4
Study Design.......................................................................................16
4.1
Overall Design....................................................................................16
4.2
Scientific Rationale for Study Design ................................................17
4.3
Justification for Dose..........................................................................17
4.4
End of Study Definition......................................................................17
5
Study Population.................................................................................17
5.1
Inclusion Criteria ................................................................................18
5.2
Exclusion Criteria...............................................................................19
5.3
Lifestyle Considerations .....................................................................20
5.4
Screen Failures....................................................................................20
6
Study Interventions.............................................................................20
6.1
Study Interventions Administration....................................................20
6.1.1
Description of the Study Interventions...............................................20
6.1.2
Dosage and Administration ................................................................21
6.2
Study Interventions Preparation, Handling, Storage, and 
Accountability.....................................................................................22
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6.3
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................24
6.3.1
Study Intervention Assignment ..........................................................24
6.3.2
Blinding ..............................................................................................25
6.4
Study Intervention Compliance..........................................................25
6.5
Concomitant Therapy .........................................................................25
6.5.1
Permitted Medications........................................................................25
6.5.2
Prohibited Medications.......................................................................26
6.6
Dose Selection and Modification........................................................26
6.7
Study Intervention After the End of the Study...................................26
6.8
Special Precautions.............................................................................26
6.8.1
Alcohol Prohibition ............................................................................26
6.8.2
Smoking Prohibition...........................................................................26
6.8.3
Food Restriction..................................................................................26
6.9
Management of Adverse Events of Interest........................................27
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal...............................................................27
7.1
Discontinuation of Study Intervention................................................27
7.2
Participant Discontinuation/Withdrawal From the Study...................27
7.3
Lost to Follow-up ...............................................................................28
7.4
Premature Termination of the Study...................................................28
8
Study Assessments and Procedures....................................................29
8.1
Efficacy Assessments and Procedures................................................29
8.2
Safety Assessments and Procedures ...................................................29
8.2.1
Physical Examinations........................................................................29
8.2.2
Vital Signs ..........................................................................................30
8.2.3
Electrocardiograms.............................................................................30
8.2.4
Clinical Safety Laboratory Assessments ............................................30
8.3
Adverse Events and Serious Adverse Events.....................................31
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information....................................................31
8.3.2
Method of Detecting Adverse Events and Serious Adverse Events...31
8.3.3
Follow-up of Adverse Events and Serious Adverse Events ...............32
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8.3.4
Regulatory Reporting Requirements for Serious Adverse Events .....32
8.3.5
Pregnancy ...........................................................................................33
8.4
Treatment of Overdose .......................................................................33
8.5
Pharmacokinetics................................................................................33
8.6
Pharmacodynamics.............................................................................35
8.7
Genetics ..............................................................................................35
8.8
Biomarkers..........................................................................................35
8.9
Medical Resource Utilization and Health Economics........................35
8.10
Immunogenicity Assessments ............................................................36
9
Statistical Considerations....................................................................36
9.1
Statistical Hypotheses.........................................................................36
9.2
Sample Size Determination ................................................................36
9.3
Populations for Analyses ....................................................................38
9.4
Statistical Analyses.............................................................................38
9.4.1
General Considerations.......................................................................38
9.4.2
Analysis of Primary Endpoints...........................................................38
9.4.3
Analysis of Secondary Endpoints.......................................................39
9.4.4
Analysis of Safety and Other Endpoints.............................................39
9.4.5
Sequence of Analyses.........................................................................41
10
References...........................................................................................42
11
Appendices .........................................................................................44
Appendix 1
Abbreviations......................................................................................45
Appendix 2
Study Governance...............................................................................47
Appendix 3
Contraception......................................................................................52
Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting................................................54
Appendix 5
Clinical Laboratory Tests ...................................................................57
Appendix 6
Sponsor Signature Page......................................................................60
Appendix 7
Principal Investigator Signature Page.................................................61
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1
Protocol Summary
1.1
Synopsis
Protocol Title: A Randomized, Open-label, 2-Way-Crossover Study Assessing the 
Bioequivalence between Single Doses of 500 mg Glucophage Extended Release (GXR) Tablets 
(Merck/China 
Nantong-Manufactured) 
and 
500 mg 
GXR 
Tablets 
(Merck/Germany 
Darmstadt-Manufactured) under Fed and Fasted State in Two Groups of Healthy Volunteers
Short Title: GXR China Bioequivalence Study (Nantong – Darmstadt)
Rationale: A bioequivalence (BE) study is proposed to investigate the GXR tablet manufactured 
by 2 different sites, Merck Darmstadt (Germany) and Merck Nantong (China). While the Merck 
Darmstadt-manufactured GXR tablet has been approved in multiple countries including China, 
Merck Nantong is a new manufacturing site with production of GXR expected to start in 2020.
The aim of this clinical BE study is to investigate the BE of GXR 500 mg tablets manufactured 
by Merck Nantong (test product) and GXR 500 mg tablets manufactured by Merck Darmstadt 
(as reference) as a key demonstration of quality of the test product being equal to the reference. 
The clinical BE result also serves 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.
Objectives and Endpoints:
Objectives
Endpoints (Outcome Measures)
Endpoints (Outcome 
Measures) 
Timeframe
Primary
To assess BE between the GXR 
manufactured in Merck Nantong China 
(test) and that manufactured in Merck 
Darmstadt Germany (reference product) 
following single oral dose administrations 
under fasting and fed conditions.
The following PK parameters calculated from 
metformin plasma concentrations: 
!
AUC0→t
!
Cmax.
Time from predose 
(Baseline) to 
48 hours after each 
dosing.
Secondary
1.
To compare additional PK parameters 
of GXR after single dose 
administrations of test and reference 
products.
2.
To examine the safety and tolerability 
of GXR after single dose 
administrations of test and reference 
products.
1.
Additional PK parameters: tmax, t1/2, 
AUC0→∞, AUC%extra, ∀z, CL/f, Vz/f.
2.
Safety assessments including:
!
Adverse events
!
Vital signs
!
Clinical laboratory tests 
(biochemistry, hematology, and 
urinalysis)
!
12-lead ECG
!
Physical examination
!
Concomitant medications
PK: Time from 
predose 
(Baseline) to 
48 hours after 
each dosing.
Safety: Time from 
informed consent 
to End-of-Study 
assessment at 
Day 10 (or the 
conditional 
follow-up visit at 
Day 15)
AUC0→∞= area under the plasma concentration-time curve from time zero to infinity; AUC0→t = 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 
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quantification; AUC%extra = extrapolated part of AUC0→∞calculated by Clast calc/λz, expressed in percent; BE = bioequivalence; 
CL/f = total body clearance of drug from plasma following extravascular administration; Cmax = the maximum plasma 
concentration observed; ECG = electrocardiogram; GXR = Glucophage Extended Release; ∀z = terminal elimination rate 
constant; PK = pharmacokinetics; t1/2 = apparent terminal half-life; tmax = time to reach the maximum plasma concentration; 
Vz/f = apparent volume of distribution during the terminal phase following extravascular administration.
Overall Design: This study is designed as a Phase I, open-label, randomized, 2-period, 
2-sequence, crossover study to assess BE between a single oral dose of GXR from 2 different 
manufacturing facilities, each given as a single dose in a fasting or fed state.
Number of Participants: A total of 54 healthy male and female Chinese participants will be 
enrolled in the study, with each gender representing no less than 1/4 of the total number and also 
adequately allocated to fasting vs. fed group (i.e., no less than 10 participants of each gender in 
the fasting group and no less than 4 participants of each gender in the fed group), and are 
statistically powered to provide adequate sample size for BE evaluation.
Study Intervention Groups and Duration: The planned study duration consists of initial 
screening assessments (within 14 days prior to the first GXR administration) followed by 
2 treatment periods (consisting of GXR administration followed by 2 days of blood sampling) in 
a crossover study design. Participants will be randomized to receive, in each period, either 1
tablet of 500 mg GXR (manufactured in Merck Nantong China), or 1 tablet of 500 mg GXR 
(manufactured in Merck Darmstadt Germany). The treatment periods are separated by a 7-day 
Washout period. Participants will be discharged at End-of-Study visit on Day 10. A conditional 
follow-up visit (Day 15) will be conducted 7 days after administration in Period 2 (only for 
participants who have any ongoing adverse events at the End-of-Study visit). The overall study
duration for each participant is approximately 4 weeks (or approximately 29 days) including the 
screening and conditional follow-up visit.
Involvement of Special Committee(s): Not applicable.
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1.2
Schema
Figure 1
Schematic Chart of Study Design
GXR = Glucophage Extended Release
Fasting (n= 38)
Test GXR (19)
Reference GXR (19)
Fasting (n= 38)
Test GXR (19)
Reference GXR (19)
Fed (n= 16)
Test GXR (8)
Reference GXR (8)
Fed (n= 16) 
Test GXR (8)
Reference GXR (8)
7-day Washout
Period 2 (Day 8)
Period 1 (Day 1)
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1.3
Schedule of Activities
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
Prior medicationsc
X
X
Laboratory tests (including 
blood and urine tests)
X
X
X
X
Pregnancy testd (women 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; IMP = investigational medicinal product; PK = pharmacokinetic; TP = Treponema pallidum.
a.
Participant will participate in the clinical study on an inpatient basis during Day -1 to Day 10.
b.
Demographic data include: date of birth, sex, race, height, and weight. The BMI (kg/m2) will be calculated automatically.
c.
Prior medications within 30 days before the date of first signature of informed consent will be collected at the screening visit. 
Medications administered before the first IMP dose 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.
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e.
See Table 6 for a detailed schedule of sampling during the inpatient at the research center. There will be an extra PK sampling 
for participants with premature withdrawal; for participants 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 
participant has rested comfortably for at least 5 minutes (The blood pressure normal range is considered ≥ 90 mmHg and 
≤139 mmHg for systolic blood pressure; ≥ 60 mmHg and ≤ 90 mmHg for diastolic blood pressure])). At Day 1 and Day 8, vital signs 
will be measured 1 hour (±30 minutes) prior to dosing and at 4 hours (±30 minutes) postdose. Vital signs will also be assessed at 
Day 10.
h.
Electrocardiogram (12-lead electrocardiogram, including QTc evaluation) will be performed 4 hours (±30 minutes) postdose at 
Day 1 and Day 8. Electrocardiogram will also be performed at Day 10 before discharge from the research unit.
i.
Adverse events will be collected starting from Day -1. At Day -1, the AEs since the date of signing of informed consent will be 
recorded; the subsequent visits will record any AEs since the last visit.
j.
Participants will be discharged on Day 10, after final sample collection and safety examinations are completed (final 
examination).
k.
If a participant has ongoing AE at End-of-Study discharge on Day 10, the participant must come back for the follow-up visit.
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1.4
Estimated Blood Sample Volumes per Participant
The blood sample volumes of each participant are estimated in Table 2.
Table 2
Estimated Blood Sample Volumes per Participant
Time Points
Evaluation Indexes
Total Blood Volume (mL)
Screening
(including Randomization)
Serum virology
4
Hematology
2*2
Biochemistry
4*2
Serum Pregnancy Test (if applicable)
4*2
Subtotal
24 (16 for male)
Period 1
Pharmacokinetics
3*17
Subtotal
51 
Period 2
Hematology
2
Biochemistry
4
Pharmacokinetics
3*17
Subtotal
57
Conditional follow-up
Or
Premature withdrawal
Hematology
2
Biochemistry
4
Subtotal
6
Pharmacokinetics
(only for premature 
withdrawal)
3
Approximate Total Amount of Blood for Each Participant
132 (124 for male)
With conditional follow-up:
138 (130 for male)
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2
Introduction
Glucophage® Extended Release (GXR) tablet contains metformin hydrochloride, an active 
pharmaceutical ingredient that belongs to the biguanide group antihyperglycemic drugs used in 
the management of type 2 diabetes mellitus (T2DM). Metformin has been used for clinical
management of diet-failed T2DM patients since 1959 and is presently authorized in 
140 countries and marketed in 127 of them. Complete information on the chemistry, 
pharmacology, efficacy, and safety of GXR tablet is in the Investigator’s Brochure (IB) [1].
2.1
Study Rationale
A bioequivalence (BE) study is proposed to investigate GXR tablet manufactured by 2 different 
sites, 
Merck 
Darmstadt 
(Germany) 
and 
Merck 
Nantong 
(China). 
While 
Merck 
Darmstadt-manufactured GXR tablet has been approved in multiple countries including China, 
Merck Nantong is a new manufacturing site with production of GXR expected to start in 2020.
The aim of this clinical BE study is to investigate the BE of GXR 500 mg tablets manufactured 
by Merck Nantong (test product) and GXR 500 mg tablets manufactured by Merck Darmstadt 
(as reference) as a key demonstration of quality of the test product being equal to the reference. 
The clinical BE result also serves 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.
2.2
Background
2.2.1
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 [2]. The 
disease has a long asymptomatic preclinical phase, but complications are usually present at the 
time of diagnosis [3].
Type 2 diabetes mellitus (T2DM) accounts for 90% to 95% of patients with diabetes [2]. It is 
usually acquired secondarily and during adulthood, with a tendency to earlier onset, especially in 
connection with obesity, even in adolescence and childhood [4]. The T2DM is a worldwide 
health concern, with the global prevalence estimated to be as high as 9% amongst adults aged 
18+ years [5]. According to World Health Organization, the diagnosis of T2DM is based on a 
glycosylated 
hemoglobin 
type A1C
(HbA1C) 
≥ 
6.5%; 
or 
fasting 
plasma 
glucose 
(FPG) ≥126 mg/dL (7.0 mmol/L); or 2-hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) in a 
75 g oral glucose tolerance testing; or a random plasma glucose ≥ 200 mg/dL (11.1 mmol/L) in a 
patient with classic symptoms of hyperglycemia or hyperglycemic crisis [2,3,5,6].
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A prospective study in T2DM patients revealed the lack 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 [7]. 
The primary effectiveness of T2DM treatment therapy in present time is determined by a 
surrogate outcome, i.e., change in HbA1C [8,9]. The IDF recommends a general HbA1C target of 
7% [3]. 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 [10], 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 [11].
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 [12]. Metformin was established as first-line oral antidiabetic therapy in patients with 
T2DM by findings of the United Kingdom Prospective Diabetes Study in 1998 and further 
confirmed in all internationally accepted guidelines [13,14] unless contraindicated or not 
tolerated.
2.2.2
Glucophage Extended 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 Extended Release 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 IB
[1] for further information about the nonclinical and clinical programs of GXR and guidance for 
the Investigator.
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2.3
Benefit/Risk Assessment
Metformin has been demonstrated by extensive clinical experience to be well tolerated in 
diabetic and prediabetic individuals with an acceptable safety profile. The most common 
side-effects observed in association with metformin are mild to moderate gastrointestinal events, 
which occur mainly during initiation of therapy and resolve spontaneously in most cases. Serious 
side-effects under treatment with metformin are very rare and generally limited to the condition 
of lactic acidosis, which is very rare and occurs primarily in patients with diabetes with acute 
deterioration of renal function or severe renal failure.
This BE study will only enroll healthy participants. Only a single dose of the investigational 
medicinal product (IMP) will be administered per period. Since metformin does not act by 
stimulating insulin secretion, single dose of metformin does not significantly influence the 
average fasting or 6-hour postprandial plasma insulin levels in either patients with T2DM or 
healthy subjects. During the study participants will be closely monitored by means of adverse 
events (AEs), vital signs, 12-lead electrocardiograms (ECGs), clinical safety laboratory 
assessments, and physical examinations.
More detailed information about the known and expected risks and reasonably expected AE of
the IMP may be found in Section 4.2 and the IB.
Based on the available nonclinical and clinical data to date, the conduct of the study, as specified 
in this protocol, is considered justifiable.
3
Objectives and Endpoints
Objectives
Endpoints (Outcome Measures)
Endpoints (Outcome 
Measures) 
Timeframe
Primary
To assess BE between the GXR 
manufactured in Merck Nantong China 
(test) and that manufactured in Merck 
Darmstadt Germany (reference product) 
following single oral dose administrations 
under fasting and fed conditions.
The following PK parameters calculated from 
metformin plasma concentrations: 
!
AUC0→t
!
Cmax.
Time from predose 
(Baseline) to 
48 hours after each 
dosing.
Secondary
1.
To compare additional PK parameters 
of GXR after single dose 
administrations of test and reference 
products.
2.
To examine the safety and tolerability 
of GXR after single dose 
administrations of test and reference 
products.
1.
Additional PK parameters: tmax, t1/2, 
AUC0→∞, AUC%extra, ∀z, CL/f, Vz/f.
2.
Safety assessments including:
!
Adverse events
!
Vital signs
!
Clinical laboratory tests 
(Biochemistry, hematology, and 
urinalysis)
!
12-lead ECG
!
Physical examination
!
Concomitant medications
PK: Time from 
predose 
(Baseline) to 
48 hours after 
each dosing.
Safety: Time from 
informed consent 
to End-of-Study
assessment at 
Day 10 (or the 
conditional 
follow-up visit at 
Day 15)
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AUC0→∞= area under the plasma concentration-time curve from time zero to infinity; AUC0→t = 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; AUC%extra = extrapolated part of AUC0→∞calculated by Clast calc/ λz, expressed in percent; BE = bioequivalence; 
CL/f = total body clearance of drug from plasma following extravascular administration; Cmax = the maximum plasma 
concentration observed; ECG = electrocardiogram; GXR = Glucophage Extended Release; ∀z = terminal elimination rate 
constant; PK = pharmacokinetics; t1/2 = apparent terminal half-life; tmax = time to reach the maximum plasma concentration; 
Vz/f = apparent volume of distribution during the terminal phase following extravascular administration.
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4
Study Design
4.1
Overall Design
This study is designed as a Phase I, open-label, randomized, 2-period, 2-sequence, crossover 
study to assess BE between a single oral dose of GXR from 2 different manufacturing facilities, 
each given as a single dose in fasting or fed state. Participants will be randomized within each 
food consumption group (fasting or fed) to receive, in each period, either:
!
1 tablet of 500 mg test GXR (manufactured in Merck Nantong China), or
!
1 tablet of 500 mg reference GXR (manufactured in Merck Darmstadt Germany).
!
Drug administration will be done with or without food depending on group allocation to 
either fed or fasted condition.
The study has a duration of approximately 4 weeks (or approximately 29 days, as shown in 
Table 3), including:
!
A screening period within 2 weeks before the first GXR administration
!
First dosing/sampling period up to 2 days (48 hours) after dosing
!
A Wash-out period of 7 days after the first GXR administration
!
Second dosing/sampling period up to 2 days (48 hours) after dosing
!
End-of-Study examinations and discharge on Day 10
!
A conditional follow-up examination period (only for participants with any ongoing AEs
at discharge) up to 7 days following the last drug administration.
Table 3
Instruction of Study Periods
Screening 
Period
Randomization
Treatment 
Period 1
Washout
Period
Treatment 
Period 2
End-of-
Study 
Discharge
Conditional 
Follow-up
Day -14 –
Day -1
Day -1
Day 1 – Day 3
Inpatient
7 days
Inpatient
Day 8 – Day 10
Inpatient
Day 10
Day 15
A total of 54 healthy male or female Chinese participants will be enrolled in the study.
Participants will be allocated to a fasting or fed group, i.e., 38 participants will be enrolled into 
the fasting group and 16 participants in the fed group, respectively (Figure 1). Based on local 
regulations and Investigator’s opinion, each gender should represent no less than 1/4 of the total 
number (i.e., no less than 10 participants of each gender in the fasting group and no less than 
4 participants of each gender in the fed group). Each participant will be administered both the 
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test and reference products in this 2 × 2 crossover BE study to minimize the effect of the 
individual difference and periodic difference of the testing results.
4.2
Scientific Rationale for Study Design
This is a single-center, open-label, 2-way crossover design. This study 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 study in a crossover design, allowing 
for each participant to serve as his/her own control. The study will be performed in an open-label 
manner, which will not influence the outcome as the primary objectives and endpoints are related 
to pharmacokinetic (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 38 participants in the fasting group and 16 participants 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). In a BE study conducted in 2014 in France 
(Study EMR200084-108) [16], it was shown that a 500 mg GXR tablet manufactured by Merck 
Darmstadt Germany met the BE criteria with the respective reference product of GXR 
manufactured in USA (Bristol-Myers Squibb, Mount Vernon).
4.3
Justification for Dose
The treatment schedule and dose of metformin has been chosen according to the standard 
treatment regimen applied for patients suffering from T2DM. The 500 mg dose of GXR is one of 
the intended clinical doses and one of the most commonly supplied tablet strengths of Merck 
Darmstadt and Merck Nantong sites.
4.4
End of Study Definition
A participant has completed the study if he/she has completed all study parts, including the 
End-of-Study visit (Day 10)/or the conditional follow-up visit (Day 15)/or any special day for 
premature withdrawal visit.
The end of the study is defined as the date of the last contact of the last participant (End-of-Study 
visit [Day 10]/or the conditional follow-up visit [Day 15]/or any special day for premature 
withdrawal visit).
5
Study Population
The criteria in Sections 5.1 (Inclusion Criteria) and 5.2 (Exclusion Criteria) are chosen to enroll 
only participants who are appropriate for the study; thereby, ensuring that the study objectives
are met. All relevant medical and nonmedical conditions are to be taken into consideration when 
deciding whether a potential participant is suitable for this study.
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Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted.
Before performing any study assessments that are not part of the participant’s routine medical 
care, the Investigator will confirm that the participant or the participant’s legal representative has 
provided written informed consent, as indicated in Appendix 2 (Study Governance).
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
1. Are 18 to 55 years of age inclusive, at the time of signing the informed consent.
2. Are overtly healthy as determined by medical evaluation, including medical history and a 
physical examination.
3. Have a body weight within 50 to 90 kg and BMI within the range 18 to 30 kg/m2 (inclusive).
4. Are Chinese male and female (at least 1/4 of each gender per study group)
! A male participant must agree to use and to have their female partners use a highly 
effective contraception (i.e., methods with a failure rate of less than 1 % per year) as 
detailed in Appendix 3 of this protocol for a period of at least 1 month before and after 
dosing.
! A female is eligible if she is not pregnant (i.e., after a confirmed menstrual period and a 
negative serum pregnancy test), not breastfeeding, and at least one of the following 
conditions applies:
a. Is not a woman of childbearing potential (WOCBP), as defined in Appendix 3.
OR
b. Is a WOCBP who agrees to use a highly effective contraceptive method (i.e., has a 
failure rate of less than 1 % per year), as listed in Appendix 3, for a period of at least 
1 month before and after dosing.
5. Can give signed informed consent, as indicated in Appendix 2 (Study Governance), which 
includes compliance with the requirements and restrictions listed in the informed consent 
form (ICF) and this protocol.
6. Non-smoker (0 cigarettes, pipes, cigars, or others) since at least 3 months.
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. Pulse, body temperature, and respiration in sitting position within the normal range or 
showing no clinically relevant deviation as judged by the Investigator. Blood pressure in 
sitting position within normal range: ≥ 90 mmHg and ≤ 139 mmHg for systolic blood 
pressure; ≥ 60 mmHg and ≤ 90 mmHg for diastolic blood pressure.
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10. Negative screen for alcohol and drugs of abuse (cannabis, benzodiazepines, barbiturates, 
opiates, cocaine, and methyl amphetamine) at screening and on admission.
11. 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.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
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 
pre-study 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 study or that 
could interfere with the study 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 study.
7. Receipt of any prescription or non-prescription medication within 2 weeks before the first 
IMP administration, including multivitamins and herbal products (e.g. St John’s Wort, or 
traditional Chinese medicines), except for the permitted medications defined in Section 6.5.1.
8. Renal failure or renal dysfunction (creatinine clearance [Ccr] <80 mL/min) as assessed by
using the estimated measure with the Cockcroft-Gault equation [17,18]. The equation for Ccr
calculation is as follows:
(	/) =
(140 −) × ℎ()
72 ×  !(/ 	) ("!)
(	/) =
(140 −) × ℎ()
85 ×  !(/ 	) (%!)
9. Known lack of subject compliance or inability to communicate or cooperate with the 
Investigator (e.g., language problem, poor mental status).
10. Non-acceptance of study high-fat breakfast (e.g., vegetarians, vegans and subjects who 
follow special diets).
11. Consumption of large quantities of methylxanthine-containing beverages (>5 cups of 
coffee/day or equivalent).
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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.
5.3
Lifestyle Considerations
During the hospitalized period, the physical activity of the subjects should be kept to a minimum 
and no stress-inducing activities will be allowed. Subjects will be requested to avoid strenuous 
exercises outside the clinical unit from 48 hours prior to the first IMP administration.
Participants of the fed group must eat the complete breakfast.
Restrictions on food and drinks are detailed in Section 6.8.
5.4
Screen Failures
Screen failures are defined as potential participants who consent to participate in the clinical 
study but are not eligible according to the inclusion and exclusion criteria. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure subjects to 
meet the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failures) may not 
be rescreened.
6
Study Interventions
6.1
Study Interventions Administration
6.1.1
Description of the Study Interventions
All IMPs will be sourced from respective manufacturer as listed below (Table 4). All IMPs will 
be packaged and labeled per all applicable regulatory requirements and Good Manufacturing 
Practice Guidelines.
Table 4
Information of Study Interventions
Drug Treatment
Test Product
Reference Product
Product Name:
GXR (Metformin HCL XR)
GXR 
(Metformin 
Hydrochloride 
Extended-release Tablets)
Formulation:
Tablet
Tablet
Strength:
0.5 g
0.5 g
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Manufacturer:
Merck 
Nantong, 
China
(Merck 
Pharmaceutical 
Manufacturing 
(Jiangsu) Co., Ltd.)
Merck Darmstadt, Germany
(Merck 
KGaA)
Expiry Date:
Refer to the label content
Refer to the label content
Storage Condition:
According to medication label 
According to medication label
GXR = Glucophage Extended Release.
6.1.2
Dosage and Administration
Potential study participants 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 IMP
administration (Day 1, Period 1).
On the evening before the dosing day in Period 1, participants will be admitted to the Clinical 
Research Unit (CRU) to fast prior to Day 1 dosing (administered the next morning). During the 
fast, participants 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.
!
The participants in the fasting group will have fasted for at least 10 hours by the time of 
predose blood sample collected after on Day 1.
!
For the fed group, participants will consume a standard breakfast within 30 minutes 
before dosing. The single dose of study drug administration will occur immediately after 
breakfast completion 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 [19].
Following the administration of the drug, hands and mouth will be checked in order to confirm 
the consumption of the medication. All participants will refrain from drinking water during the
first 2 hours after drug administration and to 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 in-house period for all participants. 
The participants should drink approximately 2 L of water during the first 24 hours after drug 
administration. The participants will have their meals at the research unit on Day 1. The fasting 
condition; time of breakfast uptake and corresponding time to IMP administration, and the 
scheduled time and exact time of lunch and dinner, will be recorded. Participants should also be 
restricted from consuming any grapefruit and/or grapefruit-containing beverages during the 
study.
Period 1
On Day 1 before IMP administration, vital signs will be assessed. If the subject does not meet all 
eligibility requirements, the subject cannot participate in the study and will be considered as a 
screen failure.
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Eligible participants will be randomly assigned to 1 of 2 sequences. Each participant will receive 
single dose GXR 500 mg (China manufactured) or a single dose of GXR 500 mg (Germany
manufactured) separated by a Washout period of 7 days.
Period 2
Participants 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.
Study eligibility assessments will include: physical examination and concomitant medications 
(Table 1). 
If the participant is determined to be ineligible for any of the above assessments, the participant
will be dismissed from the CRU and will not continue with the study.
Eligibility assessments (vital signs measurements) outlined on Day 1 will be repeated on Day 8. 
Drug administration and PK blood sampling outlined on Day 1 in Period 1 will be repeated on 
Day 8 for participants still eligible.
6.2
Study Interventions Preparation, Handling, Storage, and 
Accountability
All IMP boxes supplied to the study center must be stored carefully, safely, and separately from 
other drugs. The handling and storage of IMPs should follow the regulatory requirements from 
authorities. The Sponsor must provide the study center with enough drugs, including participant
treatment and, in addition, at least 5 times the full testing sample size for any requested testing 
for inspection in the future. In terms of the test product as well as the reference product, the 
supplies for clinical use and the extra 5 times of full testing samples must be from 1 identical 
batch and be labeled identically to fulfill the randomized IMPs / retention sample selection 
requirement at the study center. This requirement is appropriate for both test products and 
reference products.
The IMP must not be used for any purpose other than the study. The administration of the IMP to 
subjects who have not been enrolled into the study is not covered by the participant’s study
insurance.
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).
Upon receipt of the IMP, the Investigator or designee must confirm appropriate temperature 
conditions have been maintained during transit and any discrepancies are reported and resolved 
before use. Also, the responsible person will check for accurate delivery and acknowledge 
receipt by signing or initialing and dating the appropriate document and returning it to the 
location specified. A copy will be archived for the Investigator Site File.
Only participants enrolled in the study may receive the IMP and only authorized site staff may 
supply or administer it. All IMP(s) must be stored in a secure, environmentally-controlled, and 
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monitored (manual or automated) area, in accordance with the labeled storage conditions, and 
with access limited to the Investigator and authorized site staff.
Dispensing will be recorded on the appropriate accountability forms so that accurate records will 
be available for verification at each monitoring visit.
The IMP accountability records at the study site will include the following:
! Confirmation of receipt, in good condition and in the defined temperature range.
! The inventory provided for the clinical study and prepared at the site.
! The dose(s) each participant used during the study.
! The disposition (including return, if applicable) of any unused IMP(s).
! Dates, quantities, batch numbers, kit numbers, expiry dates, formulation (for IMPs 
prepared at the site), and the participant numbers.
The Investigator site will maintain records, which adequately documents that participants were 
provided the doses specified in this protocol, and all IMP(s) provided were fully reconciled.
Unused IMP must not be discarded or used for any purpose other than the present study. No IMP
that is dispensed to a participant may be redispensed to a different participant.
A Study Monitor will periodically collect the IMP(s) accountability forms.
Further guidance and information for the final disposition of unused IMP are provided in the
Operation Manual.
It must be ensured that the IMP is not used at the study center:
!
After the expiry date or
!
After the retest date unless the study product is reanalyzed and its release date extended.
!
Before to receive any written greenlight from Sponsor when temperature deviation 
occurred to study products during the study center storage
These procedures are to be closely monitored by the study monitor and study manager.
The drugs for the participants must be random drawing from all the study drugs and reference 
drugs provided by 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 deviation 
occurring during the study center storage should be reported to the responsible clinical research 
associate (CRA) immediately. The responsible CRA must report it to Merck immediately and
obtain a written decision from Merck with regard to whether to use or block the impacted IMPs.
The retention samples should be stored at study center or a third party under appropriate 
condition. It is the study center to decide the retention sample storage place and the retention 
samples will not be returned to Sponsor. The study center must collect the Sponsor’s written 
confirmation before to proceed any retention sample destruction activity.
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6.3
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding
6.3.1
Study Intervention Assignment
Each eligible participant will receive his allocated treatment according to a computer-generated 
randomization schedule. Participants will be identified only by their assigned participant number. 
The participants will receive consecutive participant numbers in the order of their enrollment 
into the study.
A total of 54 eligible healthy male and female Chinese participants (38 in fasting group and 16 in 
fed group) who meet the eligibility criteria will be randomized (with each gender representing no 
less than 1/4 of the total number within each group, i.e., no less than 10 participants of each 
gender in the fasting group and no less than 4 in the fed group) on Day -1, in a 1:1 ratio to 1 of 
2 treatment sequences: Sequence A-B or Sequence B-A as presented below (Table 5).
Sequence A to B:
!
Day 1 (Period 1), Treatment A: the administration of a single dose of test GXR
!
Day 8 (Period 2), Treatment B: the administration of a single dose reference GXR.
Sequence B to A:
!
Day 1 (Period 1), Treatment B: the administration of a single dose reference GXR
!
Day 8 (Period 2), Treatment A: the administration of a single dose of test GXR.
The 2 doses will be separated by a Washout period of approximately 7 days (Table 3).
Table 5
Assignment to Administration Sequences
Day 1 of Period 1
Day 1 of Period 2
Sequence A to B
GXR 500 mg (Merck Nantong
manufactured)
(Test Product)
GXR 500 mg (Merck Darmstadt
manufactured)
(Reference Product)
Sequence B to A
GXR 500 mg (Merck Darmstadt
manufactured)
(Reference Product)
GXR 500 mg (Merck Nantong
manufactured)
(Test Product)
GXR= Glucophage Extended Release.
This 2 × 2 crossover design for comparison of 2 treatments complies with the Chinese guideline 
for BE studies [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 
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.
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Participants will only be replaced if the number of participants within each group falls below 
28 (fasting) or 12 (fed). The participant who is replacing a discontinued participant will then be 
allocated to the treatment sequence of the participant who discontinued.
6.3.2
Blinding
Not applicable as this is an open label study.
6.4
Study Intervention Compliance
The study treatments will be administered either by the Investigator or under his or her direct 
supervision in a CRU.
Investigational medicinal product administration should be recorded in the electronic clinical 
report form (eCRF). Any reason for missed dose will trigger the subject’s discontinuation from 
the study. 
6.5
Concomitant Therapy
Concurrent administration of any medication including herbal medications and traditional 
Chinese medicines are prohibited during the study (except for the permitted medications defined 
in Section 6.5.1).
Medications administered between Screening (date of ICF signed) and first IMP dosing (Day 1) 
will be recognized as prior medication and used for eligibility check. After dosing, any 
medication will be recorded as concomitant medication. The medication (including prescription 
and over-the-counter medicines, vaccines, vitamins, and herbal supplements) taken after the 
signing of ICF, if any, shall be documented in the eCRF stating the international nonproprietary 
name and trade name of the medication, its dose, duration, unit, route of administration, date and 
time of all administrations and indication, including any changes. Upon use of any prohibited 
concomitant medication, the participant shall then discontinue his/her participation in the study
treatment and be withdrawn from the study as described in Section 7. The data recorded up to the 
time at which the participant in question was withdrawn shall be taken for the evaluation of the 
study treatment’s safety and tolerability.
The Medical Monitor should be contacted for any questions on concomitant or prior medication.
6.5.1
Permitted Medications
Only pain relief medication (paracetamol), and the hormone-based highly effective contraceptive 
methods listed in Appendix 3 are permitted medications. The administration of paracetamol 
should not exceed 1 g per day or exceed 3 consecutive days and should be documented in eCRF.
Any medicines that are considered necessary to protect the participant’s welfare in emergencies
may be given at the Investigator’s discretion, regardless if it results in a protocol deviation.
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6.5.2
Prohibited Medications
Concurrent administration of any medication except the permitted medications defined in 
Section 6.5.1 is prohibited during the study.
Participants enrolled in this study should be in good general health and therefore should not be 
taking any other medication.
Upon use of any prohibited concomitant medication the participant shall then discontinue his/her 
participation in the study treatment.
6.6
Dose Selection and Modification
Not applicable.
6.7
Study Intervention After the End of the Study
After a participant has completed the study or has withdrawn prematurely, an End-of-Study visit 
(Day 10, if participant completes the study) will be conducted and safety assessments will be 
performed. If a participant has any ongoing AE at the End-of-Study discharge visit on Day 10, 
the participant must attend the conditional follow-up visit on Day 15 for safety assessments.
Upon the careful screening for healthy participants such as detailed in the eligibility criteria for 
this study, no serious AEs related to study treatment are expected during this study. 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.
6.8
Special Precautions
6.8.1
Alcohol Prohibition
The participants must abstain from alcohol from 2.5 days (approximately 60 hours) prior to 
dosing and through the study period.
In case of any suspicion of alcohol consumption, a test for alcohol may be performed to confirm 
the Investigator's judgment.
6.8.2
Smoking Prohibition
Smoking is included as an exclusion criterion barring eligibility into the study (nonsmoker for at 
least 3 months before signing the ICF, Section 5.1) and smoking is also prohibited during the 
study.
6.8.3
Food Restriction
Fluids
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Participants 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. Participants 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
Participants included in the fed group must agree to consume the 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 study center. During the 
hospitalization periods, participants will receive breakfast, lunch, and dinner at regular times (as 
applicable).
Prior to each drug administration (i.e., Day 1 or Day 8), participants in both groups need to fast 
overnight for at least 10 hours.
All participants 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 participants. The participants should drink approximately 2 L of water 
during the first 24 hours after each drug administration.
6.9
Management of Adverse Events of Interest
Not applicable.
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention
Participants who withdraw from the study will also be withdrawn from the IMP. A participant
who drops out will not be replaced for this study as long as the minimum sample size of 
evaluable participants is met.
The Schedule of Assessments (SoA, Table 1) specifies the data to collect at IMP discontinuation 
and follow-up, and any additional evaluations that need to be completed.
7.2
Participant Discontinuation/Withdrawal From the Study
!
A participant may withdraw from the study at any time, at his/her own request (i.e., 
withdrawal of consent), and without giving a reason.
!
The participant may be withdrawn by the Investigator due to participation in another clinical 
study.
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!
The participant may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioral, compliance, or administrative reasons.
!
The SoA specifies the data to collect at study discontinuation and follow-up, and any 
additional evaluations that need to be completed.
!
Details of reasons for premature withdrawal of participants will be recorded and documented 
in the final report.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
! The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit 
schedule, and ascertain if the participant wants to or should continue in the study.
! Before a participant is deemed “lost to follow-up,” the Investigator or designee must make 
every effort to regain contact with the participant: 1) where possible, make 3 telephone 
calls; and 2) if necessary, send a certified letter (or an equivalent local method) to the 
participant’s last known mailing address. These contact attempts should be documented in 
the participant’s medical record.
! Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
7.4
Premature Termination of the Study
This study is to be conducted in healthy participants using products in which the safety profile is 
well known and also proven in the population with the target disease. The conduct of this study
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 6.7).
In addition, the clinical study 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 GXR. The Sponsor may discontinue the study if it becomes unjustifiable for 
medical or ethical reasons, for poor enrollment, or because of discontinuation of clinical 
development of GXR or withdrawal of GXR 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 study in accordance with applicable 
regulations.
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8
Study Assessments and Procedures
!
Study assessments and procedures and their timing are summarized in the SoA (Table 1).
!
No protocol waivers or exemptions are allowed.
!
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue the 
IMP.
!
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all potential participants screened, to confirm eligibility, and if applicable, 
record reasons for screening failure.
!
Prior to performing any study assessments that are not part of the participant’s routine 
medical care, the Investigator will obtain written informed consent as specified in 
Appendix 2 (Study Governance).
!
Procedures conducted as part of the participant’s routine medical care (e.g., blood count) and 
obtained before signing of the ICF may be used for screening or baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA.
8.1
Efficacy Assessments and Procedures
Not applicable.
8.2
Safety Assessments and Procedures
The safety profile of the IMP will be assessed through the recording, reporting and analysis of 
baseline medical conditions, AEs, physical examination findings, vital signs, ECG, and 
laboratory tests.
Comprehensive assessment of any potential toxicity experienced by each participant will be 
conducted starting when the participants give informed consent and throughout the study. The 
Investigator will report any AEs, whether observed by the Investigator or reported by the 
participant; the reporting period is specified in Section 8.3.1.
8.2.1
Physical Examinations
!
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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8.2.2
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 participant has rested comfortably for at 
least 5 minutes.
8.2.3
Electrocardiograms
Single 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.
After the participant 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 to V6 and all 12-leads recorded. At least 2 to 3 beats will be monitored at a speed of 
25 mm/s 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 (i.e., a medical physician). Results of the ECG recordings will be included in the 
participant's eCRF.
The following parameters will be assessed:
!
RR interval (ms)
!
PR interval (ms)
!
QRS duration (ms)
!
QT interval (ms)
!
QTcB (Bazett) (ms)
!
QTcF (Fridericia) (ms)
!
Heart rate (beats per minute)
!
Rhythm (sinusal - other).
QTc interval will be automatically computed using the Bazett correction formula (QTcB = QT / 
√RR) and the Fridericia correction formula (QTcF = QT / 3√RR) according to the recently 
approved International Council for Harmonisation (ICH) Guidance E1. 
8.2.4
Clinical Safety Laboratory Assessments
!
Safety and tolerability will be assessed by monitoring laboratory measurements. Please see
Appendix 5 for the scope of 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 study will additionally 
be forwarded to the Sponsor.
!
Additional tests may be performed at any time during the study, as determined necessary by 
the Investigator or required by local regulations.
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!
The Investigator must review each laboratory report, document their review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents.
8.3
Adverse Events and Serious Adverse Events
The definitions of an AE and a SAE are in Appendix 4.
8.3.1
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information
The AE reporting period for safety surveillance begins when the participant is included into the 
study (date of first signature of informed consent) and continues through the study’s post 
treatment period. The complete study 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 study 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 participant has 
ongoing AE at the End-of-Study visit on Day 10). In case of early termination, AEs until 
Premature Withdrawal visit will be collected.
Any SAE assessed as related to the IMP must be recorded and reported, as indicated in 
Appendix 4, whenever it occurs, irrespective of the time elapsed since the last administration of 
IMP.
The method of recording, evaluating, and assessing causality of AEs (including SAEs) and the 
procedures for completing and transmitting SAE reports are in Appendix 4.
8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events
At each study visit, the participant will be queried on changes in his/her condition. During the 
reporting period of the study any unfavorable changes in the participant’s condition will be 
recorded as AEs, whether reported by the participant 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 non-serious adverse 
drug reactions (ADRs) must be additionally documented and reported using an SAE Report 
Form as described in Appendix 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 participant
2.
Date/time of onset (only in relation to administration of IMP: before, during, or 
after)
3.
Severity Grade assessed by the Investigator according to the Qualitative Toxicity 
Scale
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4.
Causal relationship to the IMP applied per protocol, assessed by the Investigator
5.
Action taken with regard to study 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 study
treatment, 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.
8.3.3
Follow-up of Adverse Events and Serious Adverse Events
Any AE that occurs during the course of the clinical study and is considered to be related to the 
IMP must be monitored and followed up until the outcome is known, unless the participant 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.
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
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 participants 
to the IEC/IRB that approved the study.
The Sponsor will send appropriate safety notifications to regulatory authorities in accordance 
with applicable laws and regulations.
In accordance with ICH Good Clinical Practice (GCP), the Sponsor/designee will inform the 
Investigator of “findings that could adversely affect the safety of participants, impact the conduct 
of the study or alter the IEC’s/IRB’s approval/favorable opinion to continue the study.” 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 the safety reports in the Investigator Site File. National 
regulations with regard to safety report notifications to Investigators will be taken into account.
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When specifically required by regulations and guidelines, the Sponsor will provide appropriate 
safety reports directly to the concerned 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.
8.3.5
Pregnancy
Only pregnancies considered by the Investigator to be related to study treatment (e.g., 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 8.3.1 must be 
recorded by convention in the AE page/section of the eCRF. The same rule applies to 
pregnancies in female participants and to pregnancies in female partners of male participants. 
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 Appendix 4.
Investigators must actively follow-up, document and report on the outcome of all these 
pregnancies, even if the participants are withdrawn from the study.
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 participant
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 Appendix 4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a participant occurring during the course of the study, the 
participant must be discontinued from study medication immediately. The Sponsor/designee 
must be notified without delay and the participant must be followed as mentioned above.
8.4
Treatment of Overdose
This is a study where GXR (test or reference) will be administered once per period by the 
Investigator/Clinical Study Coordinator. Therefore, the risk of overdose is 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.
8.5
Pharmacokinetics
For metformin, 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. 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.
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For every participant, during each treatment period, a total of 17 samples, approximately 3 mL 
each whole blood, will be collected at the following times (Table 6):
!
at predose (Baseline) and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 30, 36, and 48 hours 
after dosing.
!
One sample will be collected at Premature Withdrawal if applicable.
Eligible participants will have their Baseline blood sample collected at approximately 10 minutes 
before GXR administration in Periods 1 and 2 for both the fasting and fed group participants.
The PK collection time is based on known single-dose PK profiles of the extended 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 -20°C or lower. 
Participants 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.
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 participant in the eCRF. 
The actual sampling times, if available, will always be used for calculation.
Pharmacokinetic parameters will be calculated by the PK/PD Data Processing Group of QPD, 
Merck, Darmstadt, Germany, or by a contract research organization selected by the Sponsor, 
using standard non-compartmental methods and the actual administered dose. Pharmacokinetic 
parameters will be calculated using the actual elapsed time since dosing, given with a precision 
of 14 significant digits or the SAS format Best12. The following PK parameters will be 
calculated from plasma concentrations of metformin by applying non-compartmental standard 
methods according respective Standard Operating Procedures.
Cmax
the maximum plasma concentration observed
tmax
time to reach the maximum plasma concentration
AUC0→t
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
AUC0→∞
area under the plasma concentration-time curve from time zero to infinity
AUC%extra
extrapolated part of AUC0→∞calculated by Clast calc/ λz, expressed in 
percent
λz
terminal elimination rate constant
t1/2 
apparent terminal half-life
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CL/f 
total body clearance of drug from plasma following extravascular 
administration
Vz/f 
apparent volume of distribution during the terminal phase following 
extravascular administration
The PK parameter evaluation will be performed using the validated PK software tool 
Phoenix/WinNonlin.
Table 6
Sampling Collection Schedule
Study 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 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14
±2
2
2 
24, 30, 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 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14
±2
9
2 
24, 30, 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 2000 g) or otherwise 
should be kept in an ice water bath pending processing. There will be an extra PK sampling for participants who have premature 
withdrawal. For participants having a conditional follow-up visit for safety, no PK sampling is required.
PK = pharmacokinetics.
8.6
Pharmacodynamics
Not applicable.
8.7
Genetics
Not applicable.
8.8
Biomarkers
Not applicable.
8.9
Medical Resource Utilization and Health Economics
Not applicable.
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8.10
Immunogenicity Assessments
Not applicable.
9
Statistical Considerations
9.1
Statistical Hypotheses
The null and alternative hypotheses for the analysis of primary endpoints are stated in 
Section 9.4.2.
9.2
Sample Size Determination
The BE is declared if all comparisons in primary hypotheses achieve the criteria – the 90% 
confidence intervals (CIs) for the ratios between test and reference of geometric means of both 
AUC0→t 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 study PK data (EMR200084-108 [16]), GXR
formulation showed intra-individual coefficient of variations (CVs) as below (Table 7 and 
Table 8).
Table 7
Results from EMR200084-108 Study Fed 
AUC0→t= 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; Cmax= the maximum plasma concentration observed; CV= Coefficient of Variation; 
LS= least squares
Table 8
Results from EMR200084-108 Study Fasting 
AUC0→t= 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; Cmax= the maximum plasma concentration observed; CV= Coefficient of Variation; 
LS= least squares
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9.3
Populations for Analyses
The analysis populations are specified below. The final decision to exclude participants from any 
analysis population will be made prior to database lock.
Analysis 
Population
Description
Screening Population
The Screening Population includes all subjects who have signed the main informed 
consent (i.e., screening failures plus subjects enrolled).
Safety Population
The Safety Population includes all participants who received at least 1 dose of IMP. 
In general, clinical data will be analyzed for the Safety Population.
Pharmacokinetic 
Population
The PK Population includes all participants who completed the study with adequate 
study medication compliance, without any relevant protocol violations or events 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. 
If participants receive concomitant medication that potentially affects PK for the 
treatment of an AE, their inclusion in the PK Population will be decided on a 
case-by-case basis. Emesis occurring within 2 times of the median tmax for a given 
treatment will be considered a relevant event likely to affect the comparability of PK 
results. Similarly, a predose concentration for a given treatment period that exceeds 
5% of Cmax will be considered a relevant event affecting PK results. All PK analyses 
will be based on the PK Population. Data for subjects excluded from the PK 
Population will be included in listings.
PK = pharmacokinetic.
9.4
Statistical Analyses
9.4.1
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 study will be presented in individual data listings performed on the 
Screening or Safety Population. All data will be evaluated as observed values; no imputation 
method for missing values will be used, unless otherwise stated. Methods for concentration data 
below the lower limit of quantification will be described in the statistical analysis plan. 
9.4.2
Analysis of Primary Endpoints
The primary endpoints are the following PK parameters calculated from metformin plasma 
concentrations:
!
AUC0→t of metformin 
!
Cmax of metformin 
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The null and alternative hypotheses for establishing BE within each group, fasted and fed, 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
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 the PK Population.
The primary variable, Cmax and AUC0→t in the 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. Participants nested within sequence will be included as random effect. Bioequivalence 
will be assessed separately, in the fed and in the fasted group, and the study 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%.
9.4.3
Analysis of Secondary Endpoints
The secondary PK endpoints are the following parameters in plasma for metformin: 
!
tmax, t1/2, ∀Z, AUC0→∞, AUC%extra, CL/f, Vz/f.
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 AUC0→∞. A 90% CI will be 
calculated for the ratios of geometric means of the test IMP and reference IMP.
All secondary endpoints will be summarized descriptively by group and treatment in the PK 
Population.
9.4.4
Analysis of Safety and Other Endpoints
All data recorded during the study will be presented in individual data listings performed on the 
Safety Population.
All safety variables will be analyzed using descriptive statistics.
T
&
C
&
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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.
Vital sign measurements and ECG recordings will be individually listed by treatment, participant
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 sequence on observed values. Urinalysis will be 
summarized in frequency tables.
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 study will be listed by treatment and participant number.
The AE listings will include the following items:
!
System organ class
!
Preferred term
!
Investigator’s description
!
Whether the event is treatment-emergent
!
Study 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.
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Incidence of treatment-emergent adverse events (TEAEs) will be summarized using frequency of 
events and number of participants 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, participant, period, time point, 
and body system.
Other Endpoints
Analyses described in this subsection will be performed in general for the PK population.
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 participants not in the PK population will be annotated and listed together with the 
data of the other participants, 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 participants simultaneously) and by participant (showing all treatments 
simultaneously).
Handling of Discontinued Participants and Missing Data
Participants will only be replaced if the number of participants within the 2 groups falls below 28
(fasting) or 12 (fed). The participant who is replacing a discontinued participant will then be 
allocated to the treatment sequence of the participant who discontinued.
9.4.5
Sequence of Analyses
No formal interim analyses are planned.
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10
References 
1. Investigator Brochure of Glucophage Extended Release (GXR). Version 2017.
2. American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes Care. 
2014;37 Suppl 1:S81-90.
3. International 
Diabetes 
Federation 
(IDF). 
E-Atlas 
of 
diabetes 
seventh 
edition. 
http://www.idf.org/diabetesatlas 
4. 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.
5. World Health Organization (WHO). Definition and diagnosis of diabetes mellitus and 
intermediate hyperglycemia. Report of a WHO/IDF Consultation. 2006
6. Colagiuri S. Epidemiology of prediabetes. Med Clin North Am. 2011;95(2):299-307, vii.
7. 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.
8. 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.
9. Singh S. Type 2 diabetes pharmacoepidemiology update 2014: safety versus efficacy. Curr 
Diab Rep. 2014;14(12):563.
10. 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.
11. 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.
12. Tran L, Zielinski A, Roach AH, et al. Pharmacologic treatment of type 2 diabetes: oral 
medications. Ann Pharmacother. 2015;49(5):540-56.
13. 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.
14. 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.
15. Chinese Food and Drug Administration Guideline: “Technical Guidelines for Human 
Bioequivalence Studies with Pharmacokinetic Endpoints for Chemical Generic Drugs” 
Released March 2016.
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16. Merck Clinical Study Report (EMR200084-108) "A randomized, open-label trial assessing 
the bioequivalence between single doses of 500 mg Glucophage XR Tablets (Merck/ 
Darmstadt) and 500 mg Glucophage XR Tablets (BMS/ Mt. Vernon) under fed and fasted 
state in two 2-way-crossover groups in healthy volunteers".
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. Wan X, Lu X. (2013). Diagnostics. 8th Edition. Beijing: People’s Medical Publishing 
House.
19. USA Food and Drug Administration Guidance “Food-Effect Bioavailability and Fed 
Bioequivalence Studies”. 2002.
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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11
Appendices
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Appendix 1
Abbreviations
ADR
Adverse Drug Reaction
AE
Adverse Event
AUC0→∞
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity
AUC0→t
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 t
AUC%extra
Extrapolated Part of AUC0→∞Calculated by Clast calc/ λz, Expressed in Percent
BE
Bioequivalence
BMI
Body Mass Index
Ccr
Creatinine Clearance
CI
Confidence Interval
CL/f
Total Clearance of Drug From Plasma Following Extravascular Administration
Cmax
The Maximum Plasma Concentration Observed
CRA
Clinical Research Associate 
CRU
Clinical Research Unit
CV
Coefficient of Variation
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
GCP
Good Clinical Practice
GXR
Glucophage Extended Release
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
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IMP
Investigational Medicinal Product
IRB
Institutional Review Board
PK
Pharmacokinetic(s)
SAE
Serious Adverse Event
SD
Standard Deviation
SEM
Standard Error of the Mean
t1/2
Apparent Terminal Half-Life
T2DM
Type 2 Diabetes Mellitus
TEAE
Treatment-emergent Adverse Event
tmax
Time of Maximum Plasma Concentration Observed
TP
Treponema Pallidum
Vz/f
Apparent Volume of Distribution During the Terminal Phase Following 
Extravascular Administration 
WOCBP
Woman of Childbearing Potential
λz
Terminal Elimination Rate Constant
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Appendix 2
Study Governance
Informed Consent Process
! The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions on the 
study.
! Participants must be informed that their participation is voluntary.
! The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.
! If the ICF is updated during their participation in the study, participants must be 
re-consented to the most current, approved version.
! A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
! The original signed and dated consent will remain at the Investigator’s site and must be 
safely archived so that it can be retrieved at any time for monitoring, auditing and 
inspection purposes.
Data Protection
! The Sponsor will assign a unique identifier to participants after obtaining their informed 
consent. All participant records or datasets transferred to the Sponsor will contain the 
identifier only; participant names or any identifiable information will not be transferred.
! The Sponsor must inform participants that their personal study-related data will be used 
per local data protection and privacy laws. The level of disclosure must also be explained 
to the participant.
! The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other Sponsor-appointed, authorized personnel, by 
appropriate IRB/IEC members, and by regulatory authority inspectors.  All such persons 
will strictly maintain participants’ confidentiality.
Study Administrative
! This study is sponsored by Merck Pharmaceutical Manufacturing (Jiangsu) Co., Ltd. The 
study will be conducted by a contract research organization.
! The study will be conducted in single center in China.
! The Principal Investigator listed on the title page represents all Investigators for decisions 
and discussions on this study, per ICH GCP. The Principal Investigator will provide expert 
medical input and advice on the study design and execution and is responsible for the 
review and signoff of the clinical study report.
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Regulatory and Ethical Considerations
! This study will be conducted in accordance with the protocol and the following:
! Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
! Applicable ICH GCP Guidelines
! Applicable laws and regulations
! The Investigator must submit the protocol, protocol amendments (if applicable), ICF, 
Investigator Brochure, and other relevant documents (e.g., advertisements) to an IRB/IEC 
and the IRB/IEC must review and approve them before the study is initiated.
! Any protocol amendments (i.e., changes to the protocol) will be documented in writing and 
require IRB/IEC approval before implementation of changes, except for changes necessary 
to eliminate an immediate hazard to study participants. When applicable, amendments will 
be submitted to the appropriate Health Authorities.
! The Investigator will be responsible for the following:
! Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently per the IRB’s/IEC’s requirements, policies, and procedures.
! Notifying the IRB/IEC of SAEs or other significant safety findings, as required by 
IRB/IEC procedures
! Providing oversight of the study conduct at the site and adherence to requirements of 
ICH guidelines and the IRB/IEC for clinical studies (if applicable), and all other 
applicable local regulations
! The protocol and any applicable documentation will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site.
Emergency Medical Support
! The Sponsor or designee will provide Emergency Medical Support cards to participants for 
use during the study. These provide the means for participants to identify themselves as 
participating in a clinical study. Also, these give health care providers access to any 
information about this participation that may be needed to determine the course of medical 
treatment for the participant. 
! The first point of contact for all emergencies will be the clinical study Investigator caring 
for the participant. Consequently, the Investigator agrees to provide his or her emergency 
contact information on the card. If the Investigator is available when an event occurs, they 
will answer any questions. Any subsequent action will follow the standard process 
established for Investigators.
! When the Investigator is not available, the Sponsor provides the appropriate means to 
contact a Sponsor physician. This includes provision of a 24-hour contact number at a call 
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center, whereby the health care providers will be given access to the appropriate Sponsor 
physician to assist with the medical emergency.
Clinical Study Insurance and Compensation to Participants
! Insurance coverage will be provided for each country participating in the study. Insurance 
conditions shall meet good local standards, as applicable.
Clinical Study Report
! After completion of the study, a clinical study 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.
Publication
! The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows Merck to protect proprietary information and to provide 
comments. 
! The Sponsor will comply with the requirements for publication of study results.
! Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.
Data Quality Assurance
! All participant study data will be recorded on electronic CRFs or transmitted to the 
Sponsor or designee electronically. The Investigator is responsible for verifying that data 
entries are complete, accurate, legible, and timely by physically or electronically signing 
the eCRF. 
! The Investigator must maintain accurate documentation (source data) that supports the 
information in the eCRF.
! The Investigator must permit study-related monitoring, quality assurance audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to the study file and 
source data.
! The Sponsor or designee is responsible for data management of this study, including 
quality checking of the data and maintaining a validated database. Database lock will occur 
once quality control and quality assurance procedures have been completed. Portable 
document format files of the eCRFs will be provided to the Investigators at study 
completion.
! Study monitors will perform ongoing source data verification to confirm that data in the 
eCRF are accurate, complete, and verifiable; that the safety and rights of participants are 
being protected; and that the study is being conducted per the currently approved protocol 
and any other study agreements, ICH GCP and all applicable regulatory requirements.
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! After study completion, records and documents, including signed ICFs, pertaining to the 
conduct of this study must be retained by the Investigator for a time length that is in 
compliance with ICH GCP and local regulatory requirements. No records may be 
destroyed during the retention period without the Sponsor’s written approval. No records 
may be transferred to another location or party without the Sponsor’s written notification.
! Monitoring will be carried out as determined by the risk assessment process conducted on 
the study.
Source Documents
! Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.
! The Investigator must keep a paper or electronic file (medical file and original medical 
records) at the site for each study participant. The file must identify each participant, 
contain the following demographic and medical information for the participant, and should 
be as complete as possible:
! Participant’s full name, date of birth, sex, height, and weight
! Medical history and concomitant diseases
! Prior and concomitant therapies (including changes during the study)
! Study identifier (i.e. the Sponsor’s study number) and participant’s study number.
! Dates of entry into the study (i.e., signature date on the informed consent) and each visit 
to the site
! Any medical examinations and clinical findings predefined in the protocol
! All AEs
! Date that the participant left the study, including any reason for early withdrawal from 
the study or the IMP, if applicable.
! All source data must be filed (e.g., CT or MRI scan images, ECG recordings, and 
laboratory results). Each document must have the participant number and the procedure 
date; ideally, printed by the instrument used for the procedure. As necessary, medical 
evaluation of these records should be performed, documented, signed and dated by the 
Investigator. 
! Data recorded on eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available.
! The study monitors will use printouts of electronic files for source data verification. These 
printouts must be signed and dated by the Investigator, countersigned by the Monitor and 
kept in the study file.
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! Source documents are stored at the site for the longest possible time permitted by the 
applicable regulations, and/or as per ICH GCP guidelines, whichever is longer. The 
Investigator ensures that no destruction of medical records is performed without the 
Sponsor’s written approval.
Study and Site Closure
! The Sponsor reserves the right to close the study site or terminate the study at any time and 
for any reason. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a site 
closure visit has been completed.
! The Investigator may initiate site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
! Reasons for the early closure of a study site by the Sponsor or Investigator may include:
! Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines
! Inadequate recruitment of participants by the Investigator
! Discontinuation of further development of the Sponsor’s compound
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Appendix 3
Contraception
Woman of Childbearing Potential (WOCBP)
A woman is of childbearing potential (i.e., fertile), following menarche and until either:
1)
Becoming postmenopausal; or,
2)
is permanently sterile by means of a hysterectomy, bilateral salpingectomy or bilateral 
oophorectomy.
Postmenopausal is defined as no menses for 12 months without an alternative medical cause. 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.
Highly Effective Contraceptive Methods
Highly effective methods are those with a failure rate of less than 1% per year when used 
consistently and correctly.
These methods are further classified into user-independent and user-dependent methods.
Because user-independent methods do not depend on the participant’s ability to use them 
consistently and correctly, they are preferred when contraception is introduced as a condition 
for study participation.
Caution should be taken for hormonal contraception, as it may be susceptible to interaction 
with the IMP(s), which may reduce the efficacy of the contraception method. In this case, a 
second highly effective method of contraception should be used during the treatment period 
and for at least 14 days after the last dose of study treatment.
User Dependent
! Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation
! Oral
! Intravaginal
! Transdermal
! Progestogen-only hormonal contraception associated with inhibition of ovulation
! Oral
! Injectable
User Independent
! Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation
! Intrauterine device (IUD)
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! Intrauterine hormone-releasing system (IUS)
! Bilateral tubal occlusion
! Vasectomized partner: This is a highly effective contraception method only if the partner is 
the sole sexual partner of the WOCBP and he has received medical assessment of the 
surgical success.
! Sexual abstinence: This is a highly effective method only if the WOCBP refrains from 
heterosexual intercourse during the entire period of risk associated with the IMP. 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.
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Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions
Adverse Event
An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product, regardless of causal relationship with this treatment. Therefore, an AE can be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, regardless if it is 
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 per the Qualitative Toxicity Scale, as follows:
Mild:
The participant is aware of the event or symptom, but the event or symptom is 
easily tolerated.
Moderate:
The participant experiences sufficient discomfort to interfere with or reduce his 
or her usual level of activity.
Severe:
Significant impairment of functioning: the participant is unable to carry out his 
or her usual activities.
Investigators must also systematically assess the causal relationship of AEs to the 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, and study procedures.
Unrelated:
Not 
reasonably 
related 
to 
the 
IMP. 
AE 
could 
not 
medically 
(pharmacologically/clinically) be attributed to the IMP under study in this 
clinical study 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 study protocol. 
Adverse Drug Reaction
In accordance with GCP, 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 (e.g., on an ECG 
trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to IMP discontinuation or are considered otherwise medically important by 
the Investigator. If a laboratory abnormality fulfills these criteria, the identified medical 
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condition (e.g., anemia or 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. Life-threatening refers to an event in which the participant 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
! Is a congenital anomaly or birth defect
! Is otherwise considered to be medically important. 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 participant 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.
For the purposes of reporting, any suspected transmission of an infectious agent via the IMP
is also considered an SAE.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify IMP administration or procedures (e.g., 
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 (i.e., undesirable effects of any administered 
treatment) must be documented and reported as SAEs.
Recording and Follow-up of AE and/or SAE
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and also onset and resolution times, when it is important to assess the time of 
AE onset relative to the recorded IMP administration time), its severity, its causal relationship 
with the IMP, any other potential causal factors, any treatment given or other action taken, 
including dose modification or discontinuation of the IMP, and its outcome. In addition, 
serious cases should be identified and the appropriate seriousness criteria documented.
Reporting Serious Adverse Events and Nonserious Adverse Drug Reactions
In the event of any SAE and non-serious ADRs 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.
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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:
ICSR_GDS@merckgroup.com
Fax: +49 6151 72 6914 (Germany)
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 participant 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 (e.g.,
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.
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.
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Appendix 5
Clinical Laboratory Tests
Laboratory tests include blood tests and urinalysis. Parameters of hematology assessments are 
tabulated in Table 11 and Table 12, biochemistry assessment parameters are tabulated in 
Table 13. 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 11
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 12
Hematology Assessments for Differential White Blood Cell Counts
Parameter
Dimension/Unit
Neutrophils
109/L and %
Monocytes
109/L and %
Lymphocytes
109/L and %
Table 13
Biochemistry Assessments
Parameter
Dimension/Unit
Alanine aminotransferase
IU/L
Aspartate aminotransferase
IU/L
Total bilirubin
μmol/L
Direct bilirubin
μmol/L
Indirect bilirubin
μmol/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
μmol/L
Cholesterol
mmol/L
Triglycerides
mmol/L
Glucose
mmol/L
Creatine kinasea
IU/L
Lactate dehydrogenase
IU/L
Calcium
mmol/L
Phosphorus
mmol/L
α-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 
(e.g., cannabis, benzodiazepines, barbiturates, opiates, cocaine, and methyl amphetamine).
Breath test of alcohol
Concentration of alcohol in breath will be tested.
Urine nicotine
The presence of nicotine in urine will be tested.
Document No. 
Object No. 
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Appendix 6
Sponsor Signature Page
Study Title:
A Randomized, Open-label, 2-Way-Crossover Study 
Assessing the Bioequivalence between Single Doses of 
500 mg Glucophage Extended Release (GXR) Tablets 
(Merck/China Nantong-Manufactured) and 500 mg GXR 
Tablets 
(Merck/Germany 
Darmstadt-Manufactured) 
under Fed and Fasted State in Two Groups of Healthy 
Volunteers 
Clinical Study Protocol Version:
Version 1.0, 19 APR 2018
Protocol Lead:
I approve the design of the clinical study:
____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Institution:
Merck Serono (Beijing) Pharmaceutical R&D 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:
Document No. 
Object No. 
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Appendix 7
Principal Investigator Signature Page
Study Title:
A Randomized, Open-label, 2-Way-Crossover Study 
Assessing the Bioequivalence between Single Doses of 
500 mg Glucophage Extended Release (GXR) Tablets 
(Merck/China Nantong-Manufactured) and 500 mg GXR 
Tablets 
(Merck/Germany 
Darmstadt-Manufactured) 
under Fed and Fasted State in Two Groups of Healthy 
Volunteers 
Clinical Study Protocol Version:
Version 1.0, 19 APR 2018
I approve the design of the clinical study, am responsible for the conduct of the study at this site, 
and understand and will conduct it per the clinical study 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:
Principal Investigator
Institution:
Address:
 
Telephone number:
Fax number:
E-mail address:
Document No. 
Object No. 
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SAP_001.pdf: 
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Statistical Analysis Plan
Clinical Trial Protocol 
Identification No.
MS200084_0013
Title:
A Randomized, Open-label, 2-way-crossover Study Assessing 
the Bioequivalence between Single Doses of 500 mg 
Glucophage Extended Release (GXR) Tablets (Merck/China 
Nantong-Manufactured) 
and 
500 mg 
GXR 
Tablets 
(Merck/Germany Darmstadt-Manufactured) under Fed and 
Fasted State in Two Groups of Healthy Volunteers
Trial Phase
I
Investigational Medicinal 
Product(s)
Glucophage Extended Release (GXR)
Clinical Trial Protocol 
Version
19 Apr 2018 /Version1.0
Statistical Analysis Plan 
Author
Biostatistician
Biostatistician
Pharmacokineticist
Statistical Analysis Plan
Date and Version
20 December 2018/Version 2.0
Statistical Analysis Plan 
Reviewers
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its affiliated companies.
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 Merck KGaA, Darmstadt, Germany or its affiliate. 
Copyright © 2017 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights reserved.
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1
Signature Page
Statistical Analysis Plan: MS200084_0013
A Randomized, Open-label, 2-way-crossover Study Assessing the Bioequivalence between 
Single Doses of 500 mg Glucophage Extended Release (GXR) Tablets (Merck/China Nantong-
Manufactured) and 500 mg GXR Tablets (Merck/Germany Darmstadt-Manufactured) under Fed
and Fasted State in Two Groups of Healthy Volunteers
Trial Biostatistician
Merck-Serono (Beijing) Pharmaceutical R&D Co., Ltd.
Date: ..............................
Signature: ..............................
Trial Biostatistician
Date: ..............................
Signature: ..............................
Date: ..............................
Signature: ..............................
 Pharmacokineticist
Date: ..............................
Signature: ..............................
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 Biostatistician
Date: ..............................
Signature: ..............................
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Statistical Analysis Plan - V2.0 Signature - 20-Dec-2018
Electronic Signature Manifestation
This page is a manifestation of the electronic signature(s) used in compliance with the organization's
electronic signature policies and procedures.
Page 2 - Object 
Signer Full Name
Meaning of Signature
Date and Time
Document Approval
20 Dec 2018 16:31:46 UTC
Document Approval
20 Dec 2018 17:08:13 UTC
Document Approval
20 Dec 2018 17:22:16 UTC
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2
Table of Contents
1 
Signature Page ......................................................................................2 
2 
Table of Contents..................................................................................4 
3
List of Abbreviations and Definition of Terms.....................................6 
4 
Modification History ............................................................................9 
5 
Purpose of the Statistical Analysis Plan ...............................................9 
6 
Summary of Clinical Trial Features .....................................................9 
7 
Sample Size/Randomization...............................................................12 
7.1 
Sample Size ........................................................................................12 
7.2 
Randomization....................................................................................13 
8 
Overview of Planned Analyses...........................................................15 
9 
Changes to the Planned Analyses in the Clinical Trial Protocol........15 
10 
Protocol Deviations and Analysis Sets...............................................15 
10.1 
Definition of Protocol Deviations.......................................................15 
10.2 
Definition of Analysis Sets and Subgroups........................................16 
11 
General Specifications for Statistical Analyses..................................17 
11.1 
Output Presentations...........................................................................17 
11.2 
Listings ...............................................................................................17 
11.3 
Tables and Descriptive Statistics........................................................18 
11.4 
Presentation of PK Concentration Data..............................................18 
11.5 
Presentation of PK Parameter Data ....................................................18 
11.6 
Presentation of continuous and qualitative variables..........................19 
11.7 
Software..............................................................................................19 
11.8 
Definition of baseline .........................................................................19 
11.9 
Definition of End of Study .................................................................20 
11.10 
Unscheduled visits..............................................................................20 
11.11 
Conversion factors..............................................................................20 
11.12 
Common calculations .........................................................................20 
11.13 
Handling of discontinued subjects......................................................20 
11.14 
Handling of missing data....................................................................20 
11.15 
Trial day..............................................................................................21 
12 
Trial Subjects......................................................................................22 


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12.1 
Disposition of Subjects and Discontinuations....................................22 
12.2 
Protocol Deviations ............................................................................23 
12.2.1 
Important Protocol Deviations............................................................23 
13 
Demographics and Other Baseline Characteristics.............................23 
13.1 
Demographics.....................................................................................23 
13.2 
Medical History ..................................................................................24 
13.3 
Other Baseline Characteristics............................................................24 
13.4 
Urine drug abuse test and breath test of alcohol.................................24 
14 
Previous or Concomitant Medications/Procedures.............................24 
15 
Treatment Compliance and Exposure.................................................25 
16 
Endpoint Evaluation ...........................................................................25 
16.1 
Primary Endpoint Analyses ................................................................25 
16.2 
Secondary Endpoint Analyses ............................................................26 
16.3 
Other Endpoint Analyses....................................................................27 
16.3.1 
Analysis of PK Endpoints...................................................................27 
16.3.2 
Estimation of Individual Pharmacokinetic Parameters by 
Noncompartmental Analysis ..............................................................28 
17 
Safety Evaluation................................................................................30 
17.1 
Adverse Events ...................................................................................31 
17.1.1 
All Adverse Events.............................................................................32 
17.1.2 
Adverse Events Leading to Treatment Discontinuation.....................32 
17.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................32 
17.2.1 
Deaths .................................................................................................33 
17.2.2 
Serious Adverse Events ......................................................................33 
17.3 
Clinical Laboratory Evaluation...........................................................33 
17.4 
Vital Signs ..........................................................................................34 
17.5 
Other Safety or Tolerability Evaluations............................................35 
17.5.1 
ECG Evaluation..................................................................................35 
17.5.2 
Physical Examinations, and Chest X-ray............................................35 
18 
References...........................................................................................36 


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3                             List of Abbreviations and Definition of Terms
Abbreviation
Definition
ADaM
Analysis Data Model
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under the Plasma Concentration-Time Curve
AUC0→∞
The AUC from time zero (= dosing time) extrapolated to infinity
AUC0→t
The AUC from time zero (= dosing time) to the last sampling 
time (tlast) at which the concentration is at or above the lower 
limit of quantification
AUCextra%
The AUC from time tlast extrapolated to infinity given as 
percentage of AUC0→f
BE
Bioequivalence
BMI
Body Mass Index
CI
Confidence Interval
CL/f
The apparent total body clearance of drug following 
extravascular administration.
Cmax
The Maximum Plasma Concentration Observed
CRO
Contract Research Organization
CSR
Clinical Study Report
CTMS
Clinical Trial Management System
CTP
Clinical Trial Protocol
CV
Coefficient of Variation (%)
DBP
Diastolic Blood Pressure
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
GCP
Good Clinical Practice
GeoCV%
Geometric Coefficient of Variation
GeoMean
Geometric Mean
GXR
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HAV
Hepatitis A Virus
HbA1C
Glycosylated Hemoglobin Type A1C
HBsAg
Hepatitis B Surface Antigen
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
ICF
Informed Consent Form
ICH
International Conference on Harmonization
LCI
Lower Confidence Interval
IMP
Investigational Medicinal Product
LC/MS/MS
Liquid Chromatography-tandem Mass Spectrometry
LC/MS
Liquid Chromatography-Mass Spectrometry
LLOQ
Lower Level of Quantification
Max
Maximum
Mean
Arithmetic Mean
Min
Minimum
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
MSS
Merck Santé s.a.s. in Semoy
N
Number of non-missing observations
N.R.
No result or result not valid
PK
Pharmacokinetic(s)
PR
Partial Response
PT
Preferred team
Q1
The First Quartile
Q3
The Third Quartile
Rsq
Goodness-of-fit statistic
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
Standard Deviation
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SDTM
Study Data Tabulation Model
SEM
Standard Error of the Mean
SOC
System Organ Class
t1/2
Apparent terminal half-life
T2DM
Type 2 Diabetes Mellitus
TEAE
Treatment-Emergent Adverse Event
tlast
The last sampling time at which the concentration is at or above 
the lower limit of quantification
tmax
Time of Maximum Plasma Concentration Observed
TP
Treponema Pallidum
UCI
Upper Confidence Interval
Vz/f
Apparent volume of distribution during the terminal phase 
following extravascular administration
λz
Terminal Elimination Rate Constant
WHO DDE
World Health Organization Drug Dictionary Enhanced


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4
Modification History
Unique
Identifier for
SAP Version
Date of
SAP Version
Author
Changes from the Previous Version
Draft V0.1
26 June 2018
Not Applicable –First Version 
Draft V0.2
02 July 2018
Updated based on Sponsor comments
Draft V0.3
10 July 2018
Updated based on Sponsor comments through email
Draft V0.4
21 August 2018
Updated based on Sponsor comments
Final V1.0
07 September 2018
Updated based on Sponsor comments
Final V2.0
20 December 2018
Updated based on Medical Writer’s comments according 
to CFDA BE CSR template
5
Purpose of the Statistical Analysis Plan
The purpose of this Statistical Analysis Plan (SAP) is to document technical and detailed 
specifications for the final analysis of data collected for protocol MS200084_0013, Version 1.0.
Results of the analyses described in this SAP will be included in the Clinical Study Report (CSR). 
Additionally, the planned analyses identified in this SAP will be included in regulatory 
submissions or future manuscripts. Any post-hoc, or unplanned analyses performed to provide 
results for inclusion in the CSR but not identified in this prospective SAP will be clearly identified 
in the CSR. 
The SAP is based upon Section 8 (Statistics) of the trial protocol and protocol amendments and is 
prepared in compliance with ICH E9. 
6
Summary of Clinical Trial Features
Trial Objectives
Primary Objective:
To assess bioequivalence (BE) between the GXR tablet manufactured in 
Merck Nantong China (test) and that manufactured in Merck Darmstadt
Germany (reference product) following single oral dose administrations 
under fasting and fed conditions. 
Secondary Objectives:
x
To compare additional pharmacokinetic (PK) parameters of GXR
after single dose administrations of test and reference products.
x
To examine the safety and tolerability of GXR after single dose 
administrations of test and reference products.
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Trial Endpoints
Primary Endpoints:
x
The following PK parameters calculated from metformin plasma 
concentrations:
x
Cmax: maximum plasma concentration observed of
metformin
x
AUC0→t: area under the (plasma) concentration-time 
curve from time 0 (dosing time) to the last sampling time 
(tlast) at which the concentration is at or above the lower 
limit of quantification (LLOQ)
Secondary Endpoints:
x
Pharmacokinetic endpoints: additional PK parameters: AUC0→∞,
AUCextra%, λz, tmax, t1/2, CL/f, Vz/f.
x
Safety Endpoints: Safety assessments including:
x
Adverse events
x
Vital signs 
x
Clinical laboratory tests (Biochemistry, hematology, and 
urinalysis)
x
12-lead ECG
x
Physical examination
x
Concomitant medications.
Trial Design 
This study is designed as a Phase I, open-label, randomized, 2-period, 
2-sequence, crossover study to assess BE between a single oral dose of 
GXR from 2 different manufacturing facilities, each given as a single 
dose in fasting or fed state. Participants will be randomized within each 
food consumption group (fasting or fed) to receive, in each period, 
either: 
x
1 tablet of 500 mg test GXR (manufactured in Merck Nantong 
China), or
x
1 tablet of 500 mg reference GXR (manufactured in Merck 
Darmstadt Germany).
x
Drug administration will be done with or without food depending 
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Planned number 
of subjects
A total of 54 healthy male and female Chinese participants (28 evaluable 
participants in the fasted group and 12 evaluable participants in the fed 
group) will be enrolled in the study, with each gender representing no less 
than 1/4 of the total number and also adequately allocated to fasting 
versus. fed group (i.e., no less than 10 participants of each gender in the 
fasting group and no less than 4 participants of each gender in the fed 
group), and are statistically powered to provide adequate sample size for 
BE testing.
Treatment and 
Trial Duration
The trial has a duration for each subject of approximately 4 weeks (or 
approximately 29 days), including:
x
A screening period within 2 weeks before the first GXR 
administration
x
First dosing/sampling period up to 2 days (48 hours) after dosing
x
A washout period of at least 7 days after the first GXR
administration
x
Second dosing/sampling period up to 2 days (48 hours) after 
dosing 
x
End-of-Study examinations and discharge on Day 10
x
A conditional follow-up examination period (only for participants 
with any ongoing AEs at discharge) up to 7 days following the 
last drug administration.
Pharmacokinetics
The plasma concentrations of metformin will be determined by a 
validated liquid chromatography-mass spectrometry (LC/MS) analytical 
method. 
Pharmacokinetic 
parameters 
(Primary 
and 
Secondary 
Endpoints) will be calculated according to noncompartmental analysis 
methods. The mixed log linear trapezoidal rule will be used to calculate 
the AUC.
Randomization 
and Blinding
A total of 54 eligible healthy male and female Chinese subjects (38 in 
fasting state and 16 in fed state) who meet the eligibility criteria will be 
randomized (with each gender representing no less than 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 this is an open-label trial, no method of blinding was used.


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7
Sample Size/Randomization
7.1
Sample Size 
The BE is declared if all comparisons in primary hypothesis achieve the criteria - the 90% 
confidence intervals (CI) for the ratios between test and reference of geometric means of both 
AUC0→t 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, (EMR200084-108 [1]), GXR 
formulation showed intra-individual coefficient of variations (CVs) as below(Table 1 and Table 
2).
x
Test: Single dose (Day 1) of GXR 500 mg tablets of manufactured at Merck Darmstadt 
(Germany) under fed/fast condition
x
Reference: Single dose (Day 1) of GXR 500 mg tablets of manufactured at Bristol-Myers 
Squibb (USA) under fed/fast condition 
Table 1
Results from EMR200084-108 Fed 
AUC0→t = 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; Cmax= the maximum plasma concentration observed; 
CV= Coefficient of Variation; LS=least squares
Table 2
Results from EMR200084-108 Fasting 
AUC0→t = 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; Cmax= the maximum plasma concentration observed; 
CV= Coefficient of Variation; LS=least squares
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7.2
Randomization
Each eligible participant
will be allocated to a treatment sequence according to a 
computer-generated randomization schedule. Subjects will be identified only by their assigned 
participant number. The participants will receive consecutive participant numbers in the order of 
their enrollment into the study.
A total of 54 eligible healthy male and female Chinese participants (38 in fasting group and 16 in 
fed group, Table ) who meet the eligibility criteria will be randomized (with each gender 
representing no less than 1/4 of the total number within each group, i.e., no less than 10 participants 
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of each gender in the fasting group and no less than 4 in the fed 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 .
Sequence A to B:
x
Day 1 (Period 1), Treatment A: the administration of a single dose of test GXR
x
Day 8 (Period 2), Treatment B: the administration of a single dose of reference GXR
Sequence B to A:
x
Day 1 (Period 1), Treatment B: the administration of a single dose of reference GXR
x
Day 8 (Period 2), Treatment A: the administration of a single dose of test GXR
The 2 doses will be separated by a Washout period of approximately 7 days (Table 7).
Table 5
Randomization Allocation
Day 1
Day 8
Fasting group (n= 38)
Treatment A (n= 19)
Treatment B (n= 19)
Treatment B (n= 19)
Treatment A (n= 19)
Fed group (n= 16)
Treatment A (n= 8)
Treatment B (n= 8)
Treatment B (n= 8)
Treatment A (n= 8)
Table 6
Assignment to Administration Sequences
Day 1
Day 8
Sequence A to B
GXR 500 mg (Merck Nantong 
manufactured)
(Test Product)
GXR 500 mg (Merck Darmstadt 
manufactured)
(Reference Product)
Sequence B to A
GXR 500 mg (Merck Darmstadt 
manufactured)
(Reference Product)
GXR 500 mg (Merck Nantong 
manufactured)
(Test Product)
GXR=Glucophage® Extended Release.
Table 7
Instruction of Study Periods
Screening 
Period
Randomization
Treatment 
Period 1
Washout 
Period
Treatment 
Period 2
End-of-
Study 
Discharge
Conditional 
Follow-up


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Day -14 to
Day -1
Day -1
Day 1 to Day
3 Inpatient
7 days 
Inpatient
Day 8 to Day
10 Inpatient
Day 10
Day 15
This 2 x 2 crossover design for comparison of 2 treatments complies with the Chinese guideline 
for BE studies [2].The guideline recommends 2 sequences in order to minimize the effect of
individual and periodic differences. The guideline suggests that the duration of a Washout Period
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.
Participants will only be replaced if the number of participants within each group falls below 
28 (fasting) or 12 (fed). The participant who is replacing a discontinued participant will then be 
allocated to the treatment sequence of the participant who discontinued.
8
Overview of Planned Analyses
The methods described in this document will be applied to the preparation of tables, figures and 
listings (TLFs). Statistical analyses will be performed using cleaned electronic case report form 
(eCRF) data collected. 
This SAP will cover the final analysis only. The final analysis will be performed only after the last 
subject has completed the study with all study data in-house and all data queries resolved. The 
SAP will be finalized prior to database lock.
9
Changes to the Planned Analyses in the Clinical Trial 
Protocol
There are no changes to the planned analyses.
10
Protocol Deviations and Analysis Sets
10.1
Definition of Protocol Deviations 
Protocol deviations describe how close the study has been conducted according to the protocol as 
expected per GCP. Some of these deviations may be significant contributors to analysis bias. 
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
subject's rights, safety, or well-being. 
Examples of clinically important protocol deviations or important events for PK include, but may 
not be limited to, the following:
x Subjects that are dosed on the study despite not satisfying the inclusion criteria
x Subjects that develop withdrawal criteria whilst on the study but are not withdrawn
x Subjects that receive the wrong treatment or an incorrect dose


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x Subjects that receive an excluded concomitant medication
x Vomiting following oral dosing (each instance will be discussed in the CSR)
x Deviation from GCP
x Sample processing errors that may lead to inaccurate bioanalytical results
x Failure to fast (in fasted arm) or incomplete meal consumption (in fed arm) prior to dosing
The following deviations will be identified and confirmed prior to or at the Data Review Meeting 
at the latest. Important protocol deviations include:
x Deviations from the inclusion and exclusion criteria
x Deviations post inclusion
A data review meeting will be held to discuss and update the definition of important protocol 
deviations so as to determine the evaluability of the subjects prior to database lock.
All important protocol deviations should be documented in CDISC datasets whether identified 
through sites monitoring or medical review. Please refer to Protocol Deviation Guide for more 
details.
10.2
Definition of Analysis Sets and Subgroups
Screening Population
The Screening population includes all subjects who have signed the main informed consent (i.e., 
screening failures plus subjects enrolled).
Randomized Population
The Randomized population includes all randomized subjects.
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 Population includes all participants who completed the study with adequate study
medication compliance (Section 15), without any relevant protocol violations or events 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. If participants receive 
concomitant medication that potentially affects PK for the treatment of an AE, their inclusion in 
the PK Population will be decided on a case-by-case basis. Emesis occurring within 2 times of the 
median tmax for a given treatment will be considered a relevant event likely to affect the
comparability of PK results. Similarly, a predose concentration for a given treatment period which 


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exceeds 5% of Cmax will be considered a relevant event affecting PK results. All PK analyses will 
be based on the PK Population. Data for subjects excluded from the PK Population will be included 
in listings.
11
General Specifications for Statistical Analyses
11.1
Output Presentations
The shells provided with this SAP describe presentations for this study and therefore the format
and content of the summary tables, listings and figures to be provided by 
.
Unless otherwise indicated all analyses will be presented separately for the two treatments
(Treatment A and Treatment B) and/ or for two treatment sequences (Sequence A-B and 
Sequence B-A) under different food consumption condition (fed and fasted). 
11.2
Listings
All listings will be reported separately by food consumption condition and sorted by treatment or 
treatment sequence (A-B or B-A), and/or scheduled time point, as appropriate. Data which are 
only collected before administration of study drug will be sorted by subject, food consumption 
condition and treatment sequence. Data which are only collected end of study (Day 10) will be 
sorted by subject and post-baseline timepoints are sorted under the treatment most recently 
received.
All PK concentrations will be reported and analyzed with the same precision as the source data 
provided by the bioanalytical laboratory or clinical laboratory regardless of how many significant 
figures or decimal places the data carry. In export datasets, as well as in the Study Data Tabulation 
Model (SDTM) PP/XD domain, PK parameters will be provided with full precision, and will not 
be rounded. 
Pharmacokinetic parameters and actual elapsed sample collection times will be rounded for 
reporting purposes in by-subject listings. Actual elapsed sample collection times will be rounded 
to two decimal places with units of hours. For PK parameters, the standard rounding procedure 
will be as follows:
x Parameters directly derived from source data (e.g., Cmax) will be reported and analyzed with
the same precision as the source data.
x Parameters derived from actual elapsed sample collection times (e.g., tmax) will be reported 
to two decimal places with units of hours.
x Values of AUC will be rounded to 3 significant figures.
x Percentages not derived directly from source data (e.g., AUCextra%) will be reported to 
3 significant figures.
x Other parameters (e.g., t1/2, λZ, CL/f, Vz/f) will be reported with 3 significant figures.
PPD


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11.3
Tables and Descriptive Statistics 
All data will be summarized by food consumption condition, treatment or treatment sequence, 
and/or scheduled time point, as appropriate. Repeated and unscheduled measurements included in 
the listings will not be used for statistical analyses or summaries, unless the repeated measurement 
was performed due to unreliable values/technical reasons, e.g., clotted samples. 
Metformin concentration in plasma and its PK parameters will be presented in tables and 
descriptively summarized by food consumption condition, treatment, and/or nominal time point, 
as appropriate. 
11.4
Presentation of PK Concentration Data
Pharmacokinetic concentration data will be descriptively summarized using: number of 
non-missing observations (N), arithmetic mean (Mean), standard deviation (SD), standard error of 
the mean (SEM), CV%, minimum (Min), median (Median), and maximum (Max). 
Descriptive statistics of PK concentration data will be calculated using values with the same 
precision as the source data, and rounded for reporting purposes only. The following conventions 
will be applied when reporting descriptive statistics of PK concentration data:
Mean, Min, Median, Max: 
3 significant digits
SD:
4 significant digits
CV%:
1 decimal place
Descriptive statistics of plasma concentrations below the LLOQ will be taken as zero.
11.5
Presentation of PK Parameter Data
Pharmacokinetic parameter data will be descriptively summarized using: N, Mean, SD, CV%, 
Min, Median, Max, geometric mean (GeoMean), the geometric CV% (GeoCV%), and the 95% CI 
for the GeoMean (LCI 95% GM, UCI 95% GM). 
Descriptive statistics of PK parameter data will be calculated using full precision values, and 
rounded for reporting purposes only.
The following conventions will be applied when reporting descriptive statistics of PK parameter 
data:
Mean, Min, Median, Max, GeoMean, 95% CI: 
3 significant digits
GeoMean ratio: 
2 decimal places 
SD:
4 significant digits
CV%, GeoCV%:
1 decimal place 


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11.6
Presentation of continuous and qualitative variables
Continuous variables will be summarized using the following descriptive statistics unless 
otherwise specified, i.e.
x
Number of subjects with non-missing values (n)
x
Mean
x
SD
x
Median
x
Minimum and maximum
Qualitative variables will be summarized by counts and percentages. 
Unless otherwise stated, the calculation of proportions will be based on the number of subjects of 
the analysis set of interest. Therefore, counts of missing observations will be included in the 
denominator and presented as a separate category.
In case the analysis refers only to certain visits, percentages will be based on the number of subjects 
still present in the trial at that visit, unless otherwise specified.
11.7
Software
Pharmacokinetic parameters will be derived using noncompartmental methods with the validated 
computer program Phoenix® WinNonlin® 6.4 or higher (
). Pharmacokinetic figures will be developed by Phoenix® WinNonlin® 6.4 or higher, or SAS®
Windows Version 9.4 or higher (
).
All other statistical analyses will be conducted using SAS® Version 9.4 or higher.
11.8
Definition of baseline
Unless otherwise specified, baseline for end of study is defined as the last non-missing 
measurement taken prior to or on the day of the first IMP administration (including unscheduled 
assessments as applicable). However, if time is missing, an unscheduled assessment on study day 
1 will be considered to have been obtained after study treatment administration.
For vital signs, the assessment performed within 1 hour (±30 minutes) prior to IMP administration 
in each treatment period will be considered as baseline for the treatment period. If there is no time 
point, the last non-missing assessment prior to dosing in each period will be taken as baseline.
In the case where the last non-missing measurement and the dosing date/time coincide, that 
measurement will be considered baseline, but medications commencing on the first IMP
administration date will be considered post-baseline.
PPD
PPD


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11.9
Definition of End of Study
Unless otherwise specified, end of study is defined as the last measurement taken prior to or on 
the day of discharge (Day10 or any special day for Premature Withdrawal Visit).
11.10
Unscheduled visits           
Unscheduled measurements will not be included in by-visit table summaries, but will contribute 
to the baseline value and best/ worst case value where required.
Descriptive statistics (mean, SD, median, minimum, maximum) by normal visit or time point for 
safety endpoints such as laboratory measurements, ECGs and vital signs will include only data 
from scheduled visits.
11.11
Conversion factors
The following conversion factors will be used to convert days into months or years: 
1 month = 30.4375 days
1 year = 365.25 days.
11.12
Common calculations
For quantitative measurements, change from baseline will be calculated as:
Test Value at Visit X – Baseline Value
11.13
Handling of discontinued subjects.
Unless otherwise specified, data from discontinued subjects will not be replaced.
11.14
Handling of missing data
Handling of missing data for PK parameter calculations are discussed under Section 16.3.2.
In all subject data listings, imputed values will be presented. In all listings imputed information 
will be flagged. 
Missing statistics, e.g., when they cannot be calculated, should be presented as “nd”. For example, 
if n=1, the measure of variability (SD) cannot be computed and should be presented as “nd”.
For the derivation of new date variable, the following rules will apply:
Partial birth dates will be handled this way: day will be imputed as 15 if it is missing, and month 
imputed as June if missing. If both of day and month are missing, they will be imputed as July 1st. 
If year is missing then the date will not be imputed.


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In case the last administration date is incomplete the date of last administration will be taken from 
the Treatment Termination eCRF page.
Any adverse event (AE) with incomplete start/time and or end date will be handled as described 
below for the classification as treatment-emergent, assignment to treatment periods, and 
calculation of duration.
x
AE with unknown start time but known start date, will be imputed with a time of 
00:00 hours, unless the start date corresponds to any given dosing date, in which case time 
of dosing will be used instead. However, if this results in a start time after end time of the 
AE, then the start time will be imputed to 00:00 hours instead.
x
Any AE with completely unknown start date will be imputed with date and time of the first
IMP administration, unless the end date (imputed if needed) is known and prior to first 
IMP administration. In the latter case, the start date will be missing.
x
AE with partially missing start date but in the same year (when day and month are missing) 
or in the same month and year (if the day is missing) as first IMP administration then the 
start date will be replaced by the minimum between first IMP administration and AE 
resolution date. In all other cases the missing onset day or onset month will be replaced by 
01.
x
Adverse event with completely unknown end date will be imputed with the date of study 
completion (or in case of withdrawal, date of discontinuation).
Partially known end dates will be treated as follows:
x
If only the day is missing, the last day of the month will be imputed or the date of study 
completion/discontinuation if earlier.
x
If day and month are both missing, then the end date of 31 December will be imputed or 
the date of study completion/discontinuation if earlier.
Assignment to the different treatment periods will be performed after the imputations have been 
performed. An AE will be assigned to a specific treatment period if it occurs on or after the IMP 
administration scheduled for that period and before the IMP administration in the next period (or 
study completion for the last period).
11.15
Trial day
Trial day will be calculated from the reference start date, and will be used to show start/end day of 
assessments and events. Reference start date is defined as the day of the first IMP administration
in period 1. Trial Day 1 is the day of first IMP administration in period 1. The day before is defined 
as Trial Day -1 (no Trial Day 0 is defined). Trial day will be calculated accordingly:
x
If the date of the event is on or after the reference start date then:
Trial day = (date of event – reference start date) + 1.


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x
If the date of the event is prior to the reference start date then: 
Trial day = (date of event – reference start date).
12
Trial Subjects
This section includes specifications for reporting subject disposition and treatment/trial 
discontinuations. Additionally, procedures for reporting protocol deviations are provided.
12.1
Disposition of Subjects and Discontinuations
All subjects who provide informed consent will be accounted into this study. Subject disposition 
and withdrawals will be presented for the Screening Population.
The following summaries will be produced by treatment sequence and overall for each food 
consumption condition group:
x
Total number of subjects screened (i.e. subjects who gave informed consent)
x
Number of subjects screening failures, grouped by the primary reason for study exclusion
x
Numbers of randomized subjects
x
Number of subjects treated in each period
x
Number of subjects who complete the trial
x
Number of subjects who discontinued the study treatment after administration, grouped by 
the main reason
x
Number of subjects who terminated the study prematurely, grouped by the main reason
x
Number of subjects included in Safety Population
x
Number of subjects included in PK Population
Corresponding individual listings will be prepared (sorted by group, treatment sequence and 
subject). 
Additionally, a listing of the screening failures will be produced with the reason of non-inclusion 
in the treatment phase. 
Listings with visit dates will also be carried out by group, treatment sequence and subject.


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12.2
Protocol Deviations
12.2.1
Important Protocol Deviations
Important protocol deviations will be based on the Clinical Trial Management System (CTMS)
data and determined by medical review process. All important protocol deviations will be included 
in SDTM datasets, if identified through medical review. The Analysis Data Model (ADaM) 
datasets will be derived from SDTM and include all important protocol deviations.
A data review meeting will be held to discuss and update the definition of important protocol 
deviations, so as to determine the evaluability of the subjects prior to database lock.
The following outputs will be provided by treatment sequence and overall, for each food 
consumption condition group:
x
Summary of important protocol deviations relating to inclusion/exclusion criteria
x
Summary of other important protocol deviations post inclusion criteria
All important protocol deviations will be listed. A listing presenting protocol deviations relating 
to inclusion/exclusion criteria and a listing presenting other deviations will be produced.
13
Demographics and Other Baseline Characteristics
Unless otherwise specified, demographic data and other baseline characteristics will be presented 
for the Safety Population.
Summaries of the key demographics overall and by treatment sequence for each group are to be 
provided. Continuous variables will be summarized using the descriptive statistics. Quantitative 
variables will be summarized by counts and percentages. No statistical testing will be carried out 
for demographic or other baseline characteristics.
13.1
Demographics
Demographic characteristics will be summarized using the following information from the 
Screening/Baseline Visit eCRF pages. 
Demographic characteristics 
x Age (years): summary statistics 
Age (years) = (date of informed consent - date of birth + 1) / 365.25
x Sex: Male, Female 
x Race: Asian
x Weight (kg): summary statistics
x Height (cm): summary statistics


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x BMI (kg/m2): summary statistics
13.2
Medical History
The medical history will be summarized from the “Medical History” eCRF page, using MedDRA,
Version 21.0 or higher version, preferred term (PT) as event category and MedDRA system organ 
class (SOC) body term as Body System category.
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and PT 
in alphabetical order.
13.3
Other Baseline Characteristics
The following baseline characteristics will be reported overall and by treatment sequence for each 
food consumption group: 
x
Nicotine and Alcohol Consumption
x
Serology: HAV antibody, HBsAg, HCV antibody, HIV antibody, TP antibody
Baseline characteristics with respect to vital signs, ECG recordings and laboratory tests will be 
part of Section 17 (Safety Evaluation).
Results of chest x-ray and serum pregnancy test (for women of childbearing potential) will be 
presented only in the listings.
13.4
Urine drug abuse test and breath test of alcohol
Urine screening of drug and breath test of alcohol will be overall and by treatment sequence and 
visit for each food consumption group.
14
Previous or Concomitant Medications/Procedures
Previous and concomitant medication/ procedure will be tabulated for Safety Population. All 
medications and procedures will be presented in the listings. 
Medications will be coded using World Health Organization Drug Dictionary Enhanced (WHO-
DDE) Version March 1, 2018 or higher version. Procedures will be coded using MedDRA Version 
21.0or higher version.
Previous medications are medications started and ended before first IMP administration.
Concomitant medications/ procedures are medications/ procedures, other than trial medications/
procedures, which are taken by subjects any time on-trial (include medications/ procedures which 
started before the first IMP administration and were ongoing after first IMP administration, or 
started on or after the first IMP administration day).
Previous and concomitant medications will be summarized overall for both food consumption 
groups as well as overall and by treatment sequence for each food consumption group, and by PT


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and ATC 2nd level, respectively. The listing of previous and concomitant medications/procedures 
will be generated.
The listing of previous and concomitant procedures will be generated.
Missing or partial dates for medication/ procedure will not be imputed. In the case where it is not 
possible to define a medication/ procedure as previous or concomitant, the medication/ procedure
will be classified by the worst case; i.e. considered as both previous and concomitant.
15
Treatment Compliance and Exposure
Population: Safety Population
Safety Population will be used to list the IMP administration. IMP administration will be listed by 
group, treatment sequence and subject with treatment, date and time of administration.
Missing or partial dates or time for IMP administration will not be imputed.
The food intake information will be listed by subject, treatment sequence for each group at Day 1 
and Day 8.
16
Endpoint Evaluation
16.1
Primary Endpoint Analyses
The primary endpoints are the following PK parameters calculated from metformin plasma 
concentrations under fasting or fed condition:
Cmax of metformin 
AUC0→t of metformin 
The null and alternative hypotheses are the following:
25
.1
/
8.0
/
25
.1
/
8.0
/
:
max
0
0
t
d
t
d

C
T
C
T
C
T
C
T
t
or
C
for
or
AUC
for
H
P
P
P
P
P
P
P
P
, for at least 1 primary endpoint
25
.1
/
8.0
25
.1
/
8.0
:
max
0
1





C
T
C
T
t
C
for
AUC
for
H
P
P
P
P
, for both primary endpoints and for both fasting and 
fed groups 
where 
and 
are the means of primary endpoints following test IMP and reference IMP 
(Treatment A and Treatment B), respectively.
T
P
C
P


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The analysis of primary endpoints will be based on PK Population.
The primary endpoints, Cmax and AUC0→t in fasting and fed group, will be log-transformed and a
mixed-effects model will be applied. The model will include fixed effects for sequence, treatment,
and period and a random effect of subject nested within sequence. Treatment differences on the 
log scale will be estimated for the parameters together with their 90% CIs. The least squares mean
together with their 95% CIs by treatment will also be estimated. Point estimates and CIs will be 
back-transformed to the original scale for presentation, i.e., ratios of geometric means and 
corresponding 90% CIs for Treatment A/Treatment B, and geometric means and corresponding 
95% CIs by treatment, respectively. Intra-subject CV estimated from the model will also be 
presented. Bioequivalence will be assessed separately in the fed and in the fasted group, and the
trial will be considered successful only if BE is established for both primary parameters in both 
groups. The BE will be considered established if the 90% CIs for the ratios of geometric means 
between the investigational product and the comparator fall within 80.00% to 125.00% for all these 
comparisons.
The following example code could be used:
proc mixed data=pkparam; 
 by foodconsumption param; 
 class sequence period trt subjid; 
 model lnest = sequence period trt /ddfm=kr; 
 random subjid(sequence); 
 estimate 'A vs B' trt 1 -1 /alpha=0.1 cl; 
 lsmeans trt /alpha=0.05 cl; 
run; 
All primary PK endpoints will be descriptively summarized as described in Section 16.3.2. Graphs 
of individual values and geometric mean will be presented for primary PK parameters versus 
treatment and food consumption condition. Boxplots will also be created for primary PK 
parameters versus treatment for the fed and the fasted conditions.
16.2
Secondary Endpoint Analyses
All secondary PK endpoints will be descriptively summarized as described in Section 11. The 
secondary PK endpoints are the following parameters in plasma for metformin:
tmax, t1/2, λZ, AUC0→∞, AUCextra%, CL/f, Vz/f.
For tmax, the Hodges-Lehmann estimates for the treatment differences and corresponding 90% CIs 
according to the Tukey method will be calculated.
The mixed-effects model for treatment comparison as described for the primary endpoints will 
also be applied to AUC0→∞. The ratios of geometric means and corresponding 90% CIs for 
Treatment A/Treatment B will be estimated separately for fed and fasted treatments. Graphs of 
individual AUC0→∞values and geometric mean will be presented by treatment and food 
consumption condition.


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16.3
Other Endpoint Analyses
16.3.1
Analysis of PK Endpoints 
Predose samples that occur before the first drug administration will be assigned a time of 0 hours, 
as if the sample had been taken simultaneously with the study drug administration.
Pharmacokinetic concentrations which are erroneous due to a protocol deviation (as defined in the 
protocol), documented handling error or analytical error (as documented in the bioanalytical 
report) may be excluded from the PK analysis if agreed upon prior to performing a statistical 
analysis. In this case, the rationale for exclusion must be provided in the Clinical Study Report 
(CSR). Any other PK concentrations that appear implausible to the Pharmacokineticist must not 
be excluded from the analysis. Any implausible data will be documented in the CSR.
All statistical analyses and descriptive summaries of PK data will be performed on the PK 
Population. Pharmacokinetic concentrations will be listed for all subjects by treatment and 
fed/fasted group; concentrations excluded from the PK analysis will be flagged within the listing.
A listing of PK blood sample collection times by individual, as well as derived actual sampling 
time and time deviations, will be provided.
Plasma concentration data will be summarized descriptively for metformin as described in
Section 10. Values below the LLOQ will be taken as zero for descriptive statistics of PK 
concentrations. Missing concentrations (e.g., no sample, insufficient sample volume for analysis, 
no result, or result not valid) will be reported and displayed generally as “N.R.”. 
Samples that are collected outside the specified time windows will be included in the PK analysis 
but excluded from the concentration summary. The PK sampling collection schedule is presented 
in Table 8 below.


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Table 8
Pharmacokinetic Sample 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 
0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14
±2
2
2
24, 30, 36
±5
3
3
48
±5
4 – 7 (wash-out)
NA
NA
NA
8
1-Predose in Period 2
Baseline blood draw (10 minutes 
prior to drug administration)
±2
8
1 – Single dose 
administration 
0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14
±2
9
2
24, 30, 36
±5
10
3
48
±5
End of Trial (Day 15)/
Premature Withdrawal
1-sample 
±30
Individual concentration-time profiles showing all subjects by treatment and fed/fasted group (i.e., 
individual subject overlay plots), and/or showing all treatment groups by subject (i.e., by-subject 
plots) will be created using the actual time points and the numeric concentration data. Arithmetic 
mean concentration-time profiles by treatment and fed/fasted group will be provided using 
scheduled (nominal) time points and the numeric concentration data. All concentration-time plots 
for PK data will be presented both on a linear and on a semi-logarithmic scale. Mean plots will 
include SD error bars when plotted on a linear scale. 
16.3.2
Estimation of Individual Pharmacokinetic Parameters by 
Noncompartmental Analysis 
For the PK analysis, predose sample concentrations that are below the LLOQ or that are missing 
will be assigned a numerical value of zero for the calculation of AUC. Any anomalous 
concentration values observed at predose will be identified in the CSR, and if the anomalous 
predose concentration value is greater than 5.00% of the Cmax in the profile, the profile will be 
included in the PK analysis, but the concentration data and the corresponding derived PK 
parameters will be excluded from summaries and inferential statistics as appropriate; handling of 
the data will be documented in the CSR.
Pharmacokinetic parameters will be calculated using standard noncompartmental methods
(calculation method: linear up log down) and the actual administered dose. Pharmacokinetic 
parameters
will be calculated and listed for all volunteers who provide sufficient 
concentration-time data. At least 3 valid, postdose concentration points will be required in the PK 
profile to obtain any PK parameter estimate.


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Pharmacokinetic parameters will be calculated using the actual elapsed time since dosing, given 
with a precision of 14 significant digits or the SAS format Best12. In cases where the actual 
sampling time is missing, calculations will be performed using the scheduled time. Otherwise, 
there will be no further imputation of missing data other than for a missing predose concentration 
as stated above.
For each subject in the PK Population the following PK parameters will be calculated for 
metformin, where appropriate:
Symbol
Definition
AUC0→t
The AUC from time zero (= dosing time) to the time  the last concentration is at 
or above the LLOQ ( tlast). Calculated using the mixed log linear trapezoidal rule 
(linear up, log down). Units: ng*h/mL.
AUC0→f
The AUC from time zero (= dosing time) extrapolated to infinity, based on the 
predicted value for the concentration at tlast, as estimated using the linear 
regression from λz determination. AUC0→∞= AUC0→t + Clast pred / λz.
Units: ng*h/mL. The predicted AUC0→∞ will be reported.
AUCextra%
The AUC from time tlast extrapolated to infinity given as percentage of AUC0→f.
AUCextra% = (extrapolated area/AUC0→∞) *100. The predicted AUC0→∞ will be 
used. Units: %.
CL/f
The apparent total body clearance of drug following extravascular 
administration, taking into account the fraction of dose absorbed.
CL/f = Dosep.o./AUC0→∞. The predicted AUC0→∞ will be used. The dose amount 
to be used for this calculation is 500 mg. Units: L/h.
Cmax
Maximum observed concentration,
taken directly from the observed 
concentration-time profile. Units: ng/mL.
tmax
The time to reach the maximum observed concentration (unless otherwise 
defined, take the first occurrence in case of multiple/identical Cmax values).
Units: h.
t1/2
Apparent terminal half-life. t1/2 = ln (2)/λz. Units: h.
Vz/f
The apparent volume of distribution during the terminal phase following
extravascular administration, based on the fraction of dose absorbed.
Vz/f = Dose/*AUC0→∞*Oz) following single dose. The predicted AUC0→∞ will 
be used. Units: L.


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The predicted AUC0→∞ will be reported and used in the determination of other parameter estimates, 
i.e., AUCextra%, CL/f, and Vz/f. The following PK parameters will be calculated for diagnostic 
purposes and listed, but will not be summarized:
x
The time interval (h) of the log-linear regression (λz lower, λz upper) to determine λz.
x
Number of data points (Nλ) included in the log-linear regression analysis to determine λz.
x
Goodness-of-fit statistic (Rsq) for calculation of λz.
The regression analysis should contain data from at least 3 different time points in the terminal 
phase consistent with the assessment of a straight line on the log-transformed scale. Phoenix 
WinNonlin best fit methodology will be used as standard. The last quantifiable concentration 
should always be included in the regression analysis, while the concentration at tmax and any 
concentrations below the LLOQ which occur after the last quantifiable data point should not be 
used. 
The Rsq should be ≥0.800 and the observation period over which the regression line is estimated 
should be at least two-fold the resulting t1/2 itself. If these criteria are not met, then the rate 
constants and all derived parameters (e.g., AUC0→∞, AUCextra%, CL/f, t1/2, and Vz/f.) will be included 
in the parameter outputs and descriptive statistics but will be flagged and discussed appropriately.
Any flags should be included in the study specific SDTM. 
To ensure a reliable estimate of the extent of exposure in pivotal trials (e.g., BE), AUCextra% should 
be less than or equal to 20.0%. If AUCextra% is greater than 20.0%, all parameters derived using λz
(i.e., AUC0→f, AUCextra%, λz, t1/2, Vz/f, and CL/f) will not be included in the calculation of 
descriptive statistics or statistical analyses.
The dose amount for IMP administered is that of the active, free drug substance only, and is 
synonymous with the measured analyte. No adjustment for the dose amount value of IMP will be 
applied when ‘dose’ is used in calculating PK parameters with formulas needing a dose value.
The Phoenix WinNonlin NCA Core Output will be provided in a separate listing.
17
Safety Evaluation
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical trials such as adverse events, laboratory tests, ECG recordings and vital 
signs. Safety analyses will be done on the Safety Population. All safety data will be listed in 
individual subject listings by group, treatment sequence and subject. 
Oz
Terminal elimination rate constant. Determined from the terminal slope of the 
log-transformed concentration curve using linear regression on terminal data 
points of the curve. Units: h-1.


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All safety variables will be analyzed using descriptive statistics. For the evaluation of safety 
parameters, the continuous variables will be summarized descriptively by N, mean, median, SD, 
Q1-Q3, and minimum and maximum values. 
17.1
Adverse Events
AEs will be coded using the MedDRA Version 21.0or higher.
An AE will be considered as 'treatment emergent' if it occurred after the first IMP administration 
of each period or if it was present prior to first IMP administration but exacerbated after the first 
IMP administration of each period. All other adverse events will be considered ‘pre-treatment’.
In the case where it is not possible to define an AE as TEAE or not, the AE will be classified as 
TEAE as the most conservative approach.
The AE listings will include the following items:
x
System organ class
x
Preferred term
x
Investigator’s description
x
Whether the event is treatment-emergent
x
Trial treatment at onset of event
x
Date and time of onset and resolution
x
Duration of the event
x
Date and time of last administration before AE
x
Study Day
x
Severity
x
Causality relationship to investigational product
x
Outcome
x
Action taken to investigational product
x
Other action


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x
Seriousness
17.1.1
All Adverse Events
A summary table describing all the TEAEs occurring during the trial will be produced overall and 
by group as well as by treatment for each group using frequency of events and number and 
percentage of subjects experiencing these events overall and by SOC and PT.
Group/SOC terms will be sorted by decreasing total frequency. Preferred terms (PT) within each
group/SOC term will likewise be sorted by decreasing total frequency.
In addition, all TEAEs will be tabulated by severity and relationship to IMP in the same manner.
The relationship to the trial treatment, as indicated by the investigator, is classified as ‘unrelated’ 
or ‘related’. TEAE with a related or missing relationship to the trial treatment will be regarded as 
‘related’.
Multiple occurrences of the same TEAE in one subject during the same treatment in the trial will 
be counted as multiple events in the frequency counts for adverse events. If a subject experiences 
more than one occurrence of the same AE during the same treatment in the trial, the subject will 
only be counted once for that treatment using the worst severity and the strongest relationship. The 
AE will be categorized as ‘unrelated’ only when all relationship records are ‘unrelated’, otherwise 
it will be classed as ‘related’ in the corresponding relationship summaries.
In case a subject had events with missing and non-missing severities, the maximum of the non-
missing severities will be displayed. In case all the TEAEs of a subject are all with missing 
severities then Moderate will be used unless there is any evidence that it should be Severe.
17.1.2
Adverse Events Leading to Treatment Discontinuation
AEs leading to permanent discontinuation of IMP will be identified as those records with a 
response of “Drug Withdrawn” to the item “Action taken with study drug” on the “Adverse Events
Details” page of the eCRF.
For AEs leading to discontinuation of IMP, summaries of incidence rates (frequencies and 
percentages) by SOC and PT will be prepared.
All adverse events leading to trial or treatment discontinuation will be listed by group, treatment 
sequence and subject including SOC, PT and investigators’ verbatim. 
17.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events


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17.2.1
Deaths
AEs leading to Death are those events which are recorded as “Fatal” to the item “Change in 
severity and outcome” on the “Adverse Events Details” page of the eCRF. AEs leading to deaths 
will be listed by group, treatment sequence and subject including SOC, PT and investigators’ 
verbatim, if applicable.
17.2.2
Serious Adverse Events
Serious adverse events (SAEs) are those events recorded as “Yes” to the item “Serious adverse 
event” on the “Adverse Events Details” page of the eCRF. All SAEs will be listed by group, 
treatment sequence and subject including SOC, PT and investigators’ verbatim.
17.3
Clinical Laboratory Evaluation
Results from the central laboratory will be included in the reporting of this study for hematology, 
biochemistry, and urinalysis. Laboratory evaluations to be included in the outputs are as below:
Hematology:
Erythrocytes,
Hemoglobin,
Hematocrit, Mean corpuscular volume, Mean 
corpuscular hemoglobin, Mean corpuscular hemoglobin concentration, Red blood cell distribution 
width, Platelets, Mean platelet volume, Thrombocytocrit, Platelet distribution width, White blood 
cells, Neutrophils (both percentage and absolute counts), Monocytes (both percentage and absolute 
counts), Lymphocytes (both percentage and absolute counts).
Biochemistry: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Total 
Bilirubin, Total Bilirubin, Direct Bilirubin, Indirect Bilirubin, Protein total, Albumin, Globulin, 
Albumin/globulin ratio, Alkaline Phosphatase, Glutamyl Transpeptidase, Urea Nitrogen, 
Creatinine, Cholesterol, Triglycerides, Glucose, Creatine Kinase, Creatine Phosphokinase MB 
Isoenzyme, Lactate Dehydrogenase, Calcium, Phosphorus, ¢-Amylase, Sodium, Potassium, 
Chloride.
Urinalysis: Appearance, Blood, Nitrite, Ketone, Protein, Glucose, Leukocytes, pH, Microscopic 
examination (Microscopic examination will be performed if dipstick test is positive for leukocytes, 
blood, nitrites, or proteins).
All hematology, biochemistry and urinalysis quantitative parameters will be summarized using 
descriptive statistics overall and by treatment sequence for each group at baseline and at end of 
study visit with raw data and change from baseline. 
For all hematology and biochemistry parameters, frequency tables based on the classification of 
values as Low, Normal, High and Missing with respect to the reference ranges will be summarized
by treatment sequence at baseline and end of study for each group. Frequency tables of urinalysis
will be summarized by treatment sequence at baseline and end of study for each group, based on
different types of classification rules. For urinalysis parameter, pH, the classification of values as 
Low, Normal, High and Missing will be applied. For urinalysis parameters, Blood, Nitrite, Ketone, 
Protein and Glucose, the classification of values as Normal/-, +-, +, ++, +++, ++++ will be applied. 
For urinalysis parameters, Appearance and Microscopic Examination, the classification of values 


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as Normal, Abnormal, Missing, or Total will be applied. For urinalysis parameters, Leukocytes,
the classification of values as Not Negative, Negative, Missing and Total will be applied.
In addition, shift tables from baseline to end of study for all hematology, biochemistry and 
urinalysis will be summarized and presented by treatment sequence for each group at End of Study.
All marked abnormal laboratory values will be listed by subject, treatment sequence and group. 
All data will be listed by group, treatment sequence, subject, treatment, visit, and time point.
17.4
Vital Signs
The following Vital Signs measurements will be reported for this study: 
x
Systolic Blood Pressure (mmHg)
x
Diastolic Blood Pressure (mmHg)
x
Pulse Rate (bpm)
x
Temperature (ͼC)
x
Respiratory Rate (breaths/min)
Systolic and diastolic blood pressures (mmHg) and pulse rate (beats/min) measurements as well 
as body temperature (°C) and respiration (breaths/min) will be presented by descriptive statistics
overall and by treatment sequence for each group at baseline and end of study visit, and by group, 
treatment and time point for the values obtained during the treatment periods as raw data and 
change from baseline in the corresponding treatment period.
Frequency tables based on the classification of values as Low, Normal, High and Missing with 
respect to the reference ranges will be summarized by treatment sequence at end of study for each 
group, and by group, treatment and time point for the values obtained during the treatment period.
All marked abnormal for vital signs values will be listed. 
All data will be listed by group, treatment sequence, subject, treatment, visit, and time point.
Markedly abnormal quantitative Vital Sign measurements will be identified in accordance with 
the following predefined markedly abnormal criteria:
Variable
Unit
Low
High
SBP
mmHg
< 85 mmHg
> 139 mmHg
DBP
mmHg
< 50 mmHg
> 90 mmHg


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Variable
Unit
Low
High
Pulse rate
bpm
< 50 Beats/min
> 100 Beats/min
Body temperature ˚C
< 36 ͼC
> 37.3 ͼC
17.5
Other Safety or Tolerability Evaluations
17.5.1
ECG Evaluation
Results from the 12-Led Electrocardiogram (ECG) be presented by descriptive statistics overall 
and by treatment sequence for each group at baseline and end of study visit.
The following ECG parameters will be reported for this study:
x
RR Interval (ms)
x
PR Interval (ms)
x
QRS Duration (ms)
x
QT Interval (ms)
x
QTcB (Bazett) (ms)
x
QTcF (Fridericia) (ms)
x
Heart Rate (beats/min)
x
Rhythm (sinusal – other).
Frequency tables for overall evaluation of ECG based on the classification of values as Normal, 
ANCS (Abnormal, Not Clinically Significant), ACS (Abnormal, Clinically Significant) and 
Missing will be presented by treatment sequence and overall for each group at the end of study
visit.
12-lead ECG parameters and result of ECG will be listed in individual subject listing by group, 
treatment sequence, subject, visit, treatment and time point. All marked abnormal values of ECG 
evaluation will be listed by subject, treatment sequence and group. 
17.5.2
Physical Examinations, and Chest X-ray
Full physical examination and chest X-ray examination will be performed, abnormal values will 
be marked in listing.


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18
References

1. Merck Clinical Study Report (EMR200084-108) "A randomized, open-label trial 
assessing the bioequivalence between single doses of 500 mg Glucophage XR Tablets 
(Merck/ Darmstadt) and 500 mg Glucophage XR Tablets (BMS/ Mt. Vernon) under fed 
and fasted state in two 2-way-crossover groups in healthy volunteers".
2. Chinese Food and Drug Administration Guideline: “Technical Guidelines for Human 
Bioequivalence Studies with Pharmacokinetic Endpoints for Chemical Generic Drugs”
Released March 2016.