A Randomized Phase I, Open-Label, Active-Controlled Study Assessing The BE Between Single Doses of 500 mg GXR RM Tablets and 500 mg GXR Tablets Under Fasted and Fed State in Two 2-Way Crossover Groups of Healthy Participants
Phase: PHASE1
Conditions: Healthy
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

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Clinical Study Protocol 
Title Page 
Clinical Study Protocol Title: 
A randomized Phase I, open-label, active-controlled study 
assessing the bioequivalence between single doses of 500 
mg Glucophage® XR Reduced Mass tablets and 500 mg 
Glucophage® XR tablets under fasted and fed state in two 
2-way crossover groups of healthy participants 
Study Number: 
MS200084_0028 
Amendment Number 
Amendment 6 
Merck Compound Number: 
200084 
Short Title: 
GXR RM 500 mg Korea BE study 
Principal Investigator: 
 
 
 
Sponsor 
Name 
and 
Legal 
Registered Address: 
Merck Ltd. Korea 
508 Teheran-ro, Gangnam-gu, Seoul, Korea 
  
 
 
  
 
 
Regulatory Agency Identifying 
Numbers: 
Not Applicable 
Protocol Version 
15 September 2021 / Version 6.1  
Replaces Version: 
08 July 2021 / Version 6.0 
Approval Date: 
15 September 2021 
Medical Monitor Name and 
Contact Information: 
Medical Responsible: 
 
 
  
 
 
 
 
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Protocol Amendment Summary of Changes 
Protocol History 
Version Number 
Type 
Version Date 
1.0 
Original Protocol 
02-May-2020 
2.0 
Revised Protocol 
05-October-2020 
3.0 
Revised Protocol 
01-December-2020 
4.0 
Revised Protocol 
08-December-2020 
5.0 
Revised Protocol 
04-January-2021 
6.0 
Revised Protocol 
08-July-2021 
6.1 
Revised Protocol 
15-September-2021 
Protocol Version 6.1 (XX-September-2021) 
This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union because it neither significantly 
impacts the safety or physical/mental integrity of participants nor the scientific value of the study. 
Overall Rationale for the Amendment 
Rationale Statement 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities 
Addition of “Physical Examination” 
on Day 2  
To clarify the activity to be implemented on 
Day 2, and to correct discrepancy in 
description of Day 2 activity(i.e., Interview 
and Physical Examination). 
 
8.2.2 Physical Examinations 
Addition of “Physical Examination” 
on Day 2 
8.10.4 Clinic Day 2 (Period 1 
and Period 2) 
“Interview” was changed to “Physical 
Examination”. 
6.3.1 
Study 
Intervention 
Assignment 
Change in Screening Number 
To differentiate subjects to be screened from 
the screened subjects in 2020 & beginning 
of 2021. 
 
 
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- Confidential – 
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 © 2021 by Merck KGaA, Darmstadt, Germany, or its subsidiary. 
All rights reserved. 
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Table of Contents 
Title Page 
 ..............................................................................................................1 
Table of Contents  ..............................................................................................................4 
1 
Protocol Summary ................................................................................8 
1.1. 
Synopsis ................................................................................................8 
1.2 
Schema ................................................................................................10 
1.3 
Schedule of Activities .........................................................................10 
2 
Introduction .........................................................................................12 
2.1 
Study Rationale ...................................................................................12 
2.2 
Background .........................................................................................12 
2.3 
Benefit/Risk Assessment ....................................................................12 
3 
Objectives and Endpoints ...................................................................14 
4 
Study Design .......................................................................................15 
4.1 
Overall Design ....................................................................................15 
4.1.1 
Treatment Method per Period .............................................................15 
4.1.2 
Rationale for determination of Pharmacokinetics Time Points ..........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 .................................................................................18 
5.1 
Inclusion Criteria ................................................................................18 
5.2 
Exclusion Criteria ...............................................................................20 
5.3 
Lifestyle Considerations .....................................................................22 
5.3.1 
Meals and Dietary Restrictions ...........................................................22 
5.3.2 
Caffeine, Alcohol, and Tobacco .........................................................23 
5.3.3 
Activity ...............................................................................................23 
5.4 
Screen Failures ....................................................................................23 
6 
Study Intervention(s) ..........................................................................24 
6.1 
Study Intervention(s) Administration .................................................24 
6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability .....................................................................................25 
6.3 
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................26 
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6.3.1 
Study Intervention Assignment ..........................................................26 
6.3.2 
Blinding ..............................................................................................27 
6.3.3 
Emergency Unblinding .......................................................................28 
6.4 
Study Intervention Compliance ..........................................................28 
6.5 
Concomitant Therapy .........................................................................29 
6.5.1 
Rescue Medicine .................................................................................30 
6.5.2 
Permitted Medicines ...........................................................................30 
6.5.3 
Prohibited Medicines ..........................................................................30 
6.5.4 
Other Interventions .............................................................................30 
6.6 
Dose Selection and Modification ........................................................30 
6.7 
Study Intervention after the End of the Study ....................................30 
6.8 
Special Precautions .............................................................................31 
6.9 
Management of Adverse Events of Interest ........................................31 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ...............................................................31 
7.1 
Discontinuation of Study Intervention................................................31 
7.1.1 
Temporary Discontinuation ................................................................32 
7.1.2 
Rechallenge .........................................................................................32 
7.2 
Participant Discontinuation/Withdrawal from the Study ...................32 
7.3 
Lost to Follow-Up...............................................................................33 
8 
Study Assessments and Procedures ....................................................33 
8.1 
Efficacy Assessments and Procedures ................................................34 
8.2 
Safety Assessments and Procedures ...................................................34 
8.2.1 
Adverse Events ...................................................................................34 
8.2.2 
Physical Examinations ........................................................................35 
8.2.3 
Vital Signs ..........................................................................................35 
8.2.4 
Electrocardiograms .............................................................................35 
8.2.5 
Clinical Safety Laboratory Assessments ............................................35 
8.2.6 
Suicidal Risk Monitoring ....................................................................36 
8.3 
Adverse Events and Serious Adverse Events .....................................36 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information ....................................................36 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ...37 
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8.3.3 
Follow-up of Adverse Events and Serious Adverse Events ...............37 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events .....38 
8.3.5 
Pregnancy ...........................................................................................38 
8.4 
Treatment of Overdose .......................................................................39 
8.5 
Pharmacokinetics ................................................................................39 
8.6 
Pharmacodynamics .............................................................................44 
8.10 
Study Schedule ...................................................................................44 
8.10.1 
Screening ............................................................................................44 
8.10.2 
Clinic Day -1 (Period 1 and Period 2) ................................................45 
8.10.3 
Clinic Day 1 (Period 1 and Period 2) ..................................................46 
8.10.4 
Clinic Day 2 (Period 1 and Period 2) ..................................................47 
8.10.5 
End of Study Visit ..............................................................................48 
9.2.3 
Replacement of Participant .................................................................50 
9.3 
Populations for Analyses ....................................................................50 
9.4 
Statistical Analyses .............................................................................51 
9.4.1 
Efficacy Analyses ...............................................................................51 
9.4.2 
Safety Analyses ..................................................................................51 
9.4.3 
Other Analyses ....................................................................................51 
9.4.3.1 
Analysis of Primary Endpoints ...........................................................51 
9.4.3.2 
Analysis of Secondary Endpoints .......................................................52 
9.4.3.3 
Analysis of Demographic Information ...............................................52 
9.4.3.4 
Sequence of Analyses .........................................................................52 
10 
Comparative Dissolution Test Method ...............................................52 
11 
References ...........................................................................................52 
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12 
Appendices .........................................................................................53 
Appendix 1 
Abbreviations ......................................................................................54 
Appendix 2 
Study Governance ...............................................................................56 
Appendix 3 
Data Management ...............................................................................64 
Appendix 4 
Contraception ......................................................................................66 
Appendix 5 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ................................................68 
Appendix 6 
Clinical Laboratory Tests ...................................................................73 
Appendix 7 
Pharmacokinetic Parameters ...............................................................75 
Appendix 8 
Protocol Amendment History .............................................................76 
Appendix 9 
Sponsor Signature Page ......................................................................80 
Appendix 10 
Principal Investigator Signature Page .................................................81 
Appendix 11 
Analytical Project Manager Signature Page .......................................82 
 
 
 
 
 
 
 
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1 
Protocol Summary 
1.1  
Synopsis 
Protocol Title: A randomized Phase I, open-label, active-controlled study assessing the 
bioequivalence between single doses of 500 mg Glucophage® XR Reduced Mass tablets and 500 mg 
Glucophage® XR tablets in fasted and fed state in two 2-way crossover groups of healthy participants 
Short Title: GXR RM 500 mg Korea BE study 
 
Rationale: The aim of this clinical study is to investigate the bioequivalence of a new Glucophage® 
XR formulation, i.e., Glucophage® XR Reduced Mass (RM) tablet (= test drug), which contains less 
excipients, is easier to swallow and might therefore improve patient compliance and efficacy of the 
product compared to the current marketed formulation (Glucophage® XR tablet = reference drug). 
For this purpose, and according to the “Regulation on Standard for Drug Equivalence Test” from the 
Ministry of Food and Drug Safety (MFDS), a 2-way crossover bioequivalence study under fasted and 
fed condition will be conducted. 
Objectives and Endpoints:  
Objectives 
Endpoints (Outcome Measures) 
Primary 
To demonstrate the bioequivalence of the 
newly developed “Glucophage® XR 
Reduced Mass tablet” (containing 
metformin hydrochloride 500 mg) and the 
current marketed “Glucophage® XR 
tablet” (containing metformin 
hydrochloride 500 mg) after single oral 
administration under fasted and fed 
conditions. 
Pharmacokinetic (PK) profile of metformin in 
terms of AUClast (area under the plasma 
concentration-time curve from time zero to time of 
last measurable concentration) and Cmax (Maximum 
observed concentration) 
Secondary 
To evaluate the safety and tolerability of 
the metformin formulations after single 
dose treatment under fasted and fed 
conditions. 
 Treatment-emergent adverse events (TEAEs) 
 Concomitant Medication 
 Laboratory safety tests, including blood 
glucose safety determination 
 Cardiac safety monitoring by 12-lead ECGs 
(Vent. rate, PR interval, QRS duration, QT 
and QTc) 
 Vital signs (body temperature [tympanic], 
Blood Pressure and pulse rate)  
 Physical examination 
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Objectives 
Endpoints (Outcome Measures) 
To characterize other PK parameters of the 
metformin formulations under fasted and 
fed conditions. 
AUCinf (if data allows to calculate), AUClast/AUCinf (if 
data allows to calculate), t1/2 (if data allows to calculate) 
and Tmax of metformin 
Overall Design: This bioequivalence study is divided into two parts according to the method of 
administration of the study interventions: Part 1 (Fasted state) and Part 2 (Fed state).  
Each part of the study is performed as an open-label, randomized, 2-period, 2-sequence, single oral 
dose and crossover design. 
Number of Participants: Eighty-two (82) healthy adult participants will be included in the study: 
48 in the fasted group (Part 1) and 34 in the fed group (Part 2). 
In the case of fasted group (Part 1), the sample size is 19 participants per sequence and in total, 38 
participants thus meeting the 2-period 2-sequence crossover study design that has a significance level 
of 0.05 and a power of 90%. Considering the drop-out rate of about 20% during the study, 24 
participants per sequence, hence 48 participants in total will be recruited. 
In the case of fed group (Part 2), the sample size is 11 participants per sequence and in total, 22 
participants thus meeting the 2-period 2-sequence crossover study design that has a significance level 
of 0.05 and a power of 90%. Considering the drop-out rate of about 35% during the study, 17 
participants per sequence, hence 34 participants in total will be recruited. 
When BE study was performed in Korea, it was found the drop-out rate of fed study was higher than 
that of fasted study. Therefore, a higher drop-out rate for the fed study is considered.  
Please see Section 9.2.2 (Sample Size Justification), also. 
Study Intervention Groups and Duration: A single oral dose of Test Drug, “Glucophage® XR 
Reduced Mass tablet” (containing metformin hydrochloride 500 mg) of Merck Ltd. Korea, and 
Reference Drug, “Glucophage® XR tablet” (containing metformin hydrochloride 500 mg) of Merck 
Ltd. Korea, will be administered under fasted and fed condition on Day 1 of Periods 1 and 2, in a 
crossover design. 
Involvement of Special Committee(s): No. 
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1.2 
Schema 
 
Screening 
Day-28 to Day-2 
Period 1 / Day 1 
Study Day 1 
Wash-out 
Study Day 2 to Day 7 
Period 2 / Day 1 
Study Day 8 
Study Cohorts and Periods 
 
 
 
 
82 
Participants 
 
 
Part 1 
(n = 48) 
 
GXR (fasted; n = 24) 
GXR RM (fasted; n = 24) 
 
GXR (fasted; n = 24) 
GXR RM (fasted; n = 24) 
 
 
 
 
 
 
Part 2 
(n = 34) 
 
GXR (fed; n = 17) 
GXR RM (fed; n = 17) 
 
GXR (fed; n = 17) 
GXR RM (fed; n = 17) 
     GXR = Glucophage® XR tablet (Reference Drug) 
GXR RM = Glucophage® XR Reduced Mass tablet (Test Drug) 
n= Number of Participants 
1.3 
Schedule of Activities 
 
Assessment 
Screening 
Day-28 to 
Day-2 
Period 1 and Period 2 
End of  
Study 
Visit 
Note 
Day  
-1 
Day 
1 
Day 
2 
End of study visit is conducted 10±3 days after 
Day 1 of Period 2. (In the case of participant 
discontinuation, End of study visit is conducted 
10±3 days after the last administration.) 
Informed Consent 
X 
 
 
 
 
 
Check of 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
Interview 
X 
 
 
 
 
 
Physical Examination 
X 
X 
 
X 
X 
A brief physical examination will be 
done on day -1, Day 2. See Section 
8.2.2. 
Medical History 
X 
 
 
 
 
 
Clinical Laboratory Tests 
X 
X 
 
 
X 
In the case of Day-1,  AST (GOT), ALT (GPT), 
γ-GT, UN, Cr, eGFR with MDRD, Lactic acid 
and pregnancy test (Serum-HCG) for female 
participants, only.  
Drug screening 
X 
X 
 
 
 
Urine sample 
Alcohol breath test 
X 
X 
 
 
 
 
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Vital Signs 
X 
 
X 
X 
X 
Screening and end of study visit: Body 
temperature (tympanic), blood pressure and pulse 
rate. 
Prior to administration of each Period and before 
blood collection at 24 and 32 hours after 
administration of each Period: Blood pressure and 
pulse rate. 
12-lead ECG 
X 
 
 
 
X 
 
Blood Sugar Test (BST) 
 
 
X 
 
 
Blood Sugar Test is performed before blood 
collection at 3 and 4 hours after study 
intervention administration of each Period. 
Admission 
 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
Performed in Period 1 only. 
Study Intervention 
Administration 
 
 
X 
 
 
Part 1 (Fasted state): On Day 1, after an overnight 
fast of at least 10 hours, participants will receive 
1 tablet of either the Reference or the Test drug 
orally, starting with the first participant at around 
08:00 am. 
Part 2 (Fed state): On Day 1, participants shall 
take a high-fat breakfast (over 900kcal, over 35% 
fat) from around 07:30 am within 20 minutes and 
30 minutes after the start of the meal (around 
08:00 am), participants will receive 1 tablet of 
either the Reference or the Test drug orally. 
Pharmacokinetic Profile 
 
 
X 
X 
 
Blood sample collection 
Part 1 (Fasted state): Before administration (just 
prior to administration) of  study intervention  and 
0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24 and 
32 hours thereafter (totally 16 times). 
Part 2 (Fed state): Before administration (just 
prior to administration) of  study intervention  and 
1, 2, 3, 4, 5, 5.5, 6, 6.5, 7, 8, 9, 10, 12, 24 and 32 
hours thereafter (totally 16 times). 
Adverse Events 
Monitoring 
X 
X 
X 
X 
X 
Signs and symptoms that occurred from the 
signing of informed consent to the end of the 
study are documented (please refer to Appendix 
5). 
Prior/Concomitant 
Medication 
X 
X 
X 
X 
X 
For prior medication, the medications 
administered from 30 days prior to screening up 
to the administration of study intervention of 
Period 1 are documented. For concomitant drug, 
the medications administered from Period 1 to the 
end of the observation are documented. 
Discharge 
 
 
 
X 
 
Participants can stay at the Study Center at the 
discretion of the Principal Investigator (or 
delegated investigator). 
Outpatient Visit 
 
 
 
 
X 
 
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2 
Introduction 
Glucophage Extended Release (GXR) tablet contains metformin hydrochloride (metformin 
HCl), 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 marketed in several forms and strengths in more than 130 countries. 
Metformin is an antihyperglycemic agent, which improves glucose tolerance in patients with 
T2DM, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms 
of action are different from other classes of oral antihyperglycemic agents. Metformin 
decreases hepatic glucose production, delays intestinal absorption of glucose, and improves 
insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike 
sulfonylureas, metformin, when used alone, does not cause hyperinsulinemia. With 
metformin therapy, insulin secretion remains unchanged while fasting insulin levels and 
daylong plasma insulin response may decrease. 
Complete information on the chemistry, pharmacology, efficacy and safety of metformin is 
in the Investigator’s Brochure. 
2.1 
Study Rationale 
The aim of this clinical study is to investigate the bioequivalence of a new Glucophage XR 
formulation, i.e., Glucophage XR Reduced Mass (RM), which contains less excipients, is 
smaller and thus easier to swallow and might therefore improve patient compliance and 
efficacy of the product. For this purpose, and according to the “Regulation on Standard for 
Drug Equivalence Test” from the Ministry of Food and Drug Safety, a 2-way crossover 
bioequivalence study under fasted and fed condition will be conducted.  
2.2 
Background 
Glucophage and Glucophage XR (metformin HCl Extended Release tablets) are 
antihyperglycemic drugs used in the management of T2DM. Metformin HCl (N,N-
dimethylimidodicarbonimidic diamide hydrochloride; 1,1-dimethylbiguanide hydrochloride; 
N,N-dimethyldiguanide hydrochloride; N’-dimethylguanylguanidine hydrochloride) is not 
chemically or pharmacologically related to any other class of oral antihyperglycemic agents. 
 
Glucophage XR consists of a dual hydrophilic polymer matrix system. Metformin is released 
slowly from the extended release (XR) dosage form via diffusion through the gel matrix that 
is essentially independent of pH.     
2.3 
Benefit/Risk Assessment 
Healthy participants participating in this bioequivalence study will not gain direct clinical 
benefit from their participation in the study. However, this study will help to evaluate the 
bioequivalence of the new Glucophage XR formulation. 
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Metformin is used for clinical management of diet-failed T2DM patients since 1959 and 
marketed in more than 100 countries. Based on clinical experience, Glucophage® XR is well 
tolerated and the most frequently reported adverse events (AEs) are nausea, vomiting, diarrhea, 
abdominal pain, and loss of appetite (reported in >1/10 patient receiving metformin). These 
symptoms are almost always transient, occur early during therapy initiation, and 
spontaneously resolve in most cases. Even more, this study will investigate single doses so 
that the likelihood of AEs is further reduced compared to chronic use in clinical practice.  
Based on the favorable safety profile of metformin, the risks in participating in this single 
dose study are considered low. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of metformin may be found in Section 4.2 (Scientific Rationale for 
Study Design) and the Investigator’s Brochure. 
Based on the available clinical data to date, the conduct of the study, as specified in this 
protocol, is considered justifiable. 
 
 
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3 
Objectives and Endpoints 
 
Objectives 
Endpoints (Outcome Measures) 
Primary 
To demonstrate the bioequivalence of 
the newly developed “Glucophage® 
XR Reduced Mass tablet” (containing 
metformin hydrochloride 500 mg) and 
the current marketed “Glucophage® 
XR tablet” (containing metformin 
hydrochloride 500 mg) after single oral 
administration under fasted and fed 
conditions. 
AUClast and Cmax for metformin in plasma. 
Secondary 
To evaluate the safety and tolerability 
of the metformin formulations after 
single dose treatment under fasted and 
fed conditions. 
 Treatment-emergent adverse events 
(TEAEs) 
 Concomitant Medication 
 Laboratory safety tests, including blood 
glucose safety determination 
 Cardiac safety monitoring by 12-lead 
ECGs (Vent. Rate, PR interval, QRS 
duration, QT and QTc)  
 Vital signs (body temperature [tympanic], 
Blood Pressure and pulse rate) 
 Physical examination 
To characterize other pharmacokinetic 
(PK) parameters of the metformin 
formulations under fasted and fed 
conditions. 
AUCinf (if data allows to calculate), 
AUClast/AUCinf (if data allows to calculate), t1/2 
(if data allows to calculate) and Tmax of 
metformin 
 
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4 
Study Design 
4.1 
Overall Design 
This bioequivalence study is divided into two parts according to the method of administration 
of the study interventions: Part 1 (Fasted state) and Part 2 (Fed state). More detailed 
information about overall design can be found in Sections 1.2 (Schema), 1.3 (Schedule of 
Activities) and 6.7 (Study Intervention after the End of the Study). 
Each part of the study is performed by an open-label, randomized, 2-period, 2-sequence, 
single oral dose and crossover design in a single-center. 
Metformin will be administered as a single dose of 500 mg either as a Glucophage XR RM 
tablet (Test drug) or Glucophage XR tablet (marketed formulation = Reference drug) under 
fasted or fed condition in a crossover design. 
The study duration for the individual participant will be approximately 7 weeks, including a 
screening period of maximum 27 days before Day 1 of Period 1, two 1-day hospitalization 
periods separated by a wash-out period of at least 7 days between Day 1 of each period, and 
an End of Study Visit at 10 days ± 3 days after the last drug administration. Part 1 and Part 2 
of the study will have a staggered start, therefore the total study duration (from the First 
Participant Screened to the Last Participant Last Visit) is approximately 3 months. 
The metformin single oral administration will be performed on Day 1 of each period either as 
Glucophage XR or Glucophage XR RM formulation. For logistical reasons, in the case of 
failure of enrollment of targeted number of participants per each part (Fasted/ Fed) as 
specified in the protocol, enrollment may be staggered within each study part. In this case, 
participants will be included in the relevant study part in two or more groups. All conditions 
will be identical for the groups. 
4.1.1 
Treatment Method per Period 
Total number of participants: 82 (Part 1: 48 participants, Part 2: 34 participants) 
 
1) Part 1: Fasted state (N=48) 
Sequence 
Period 
1 
Wash-out period 
2 
1(n=24): RT 
R 
At least7 days 
T 
2(n=24): TR 
T 
R 
R (Reference Drug): Glucophage® XR tablet  
T (Test Drug): Glucophage® XR Reduced Mass tablet  
 
2) Part 2: Fed state (N=34) 
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Sequence 
Period 
1 
Wash-out period 
2 
1(n=17): RT 
R 
At least 7 days 
T 
2(n=17): TR 
T 
R 
R (Reference Drug): Glucophage® XR tablet  
T (Test Drug): Glucophage® XR Reduced Mass tablet  
 
The wash-out period is set to be at least 7 days, which is considerably more than 5 times  the 
half-life of metformin (about 3.27 hours) (referred from the Article 15 (2) of the “Standard on 
Pharmaceutical Equivalence Study”), so that the administered study interventions can be 
completely excreted from body. 
4.1.2 
Rationale for determination of Pharmacokinetics Time Points 
Idkaidek et al (1) provided the following pharmacokinetic parameters of oral metformin 750 
mg XR in healthy adults: 
 
Formulation / Pharmacokinetic 
parameter 
XR-Fasted 
XR-Fed 
Cmax (ng/mL) 
832 (300) 
794 (143) 
Tmax (h) 
4.3 (1.0) 
6.35 (1.1) 
t1/2 (h) 
3.8 (1.2) 
3.66 (0.8) 
Metformin mean (SD) plasma pharmacokinetic parameters after 750 mg XR (Extended Release) oral doses to 
healthy volunteers 
 
In the Article 15 (2) of the Korean guideline "Standard on Pharmaceutical Equivalence 
Study"2, it is mentioned that “Blood collection shall be conducted with sufficient time period 
of more than 3 times the elimination half-life or AUC0-t to reach at least 80% of AUC∞.”. It is 
recommended that blood sampling needs more than 12 times and more than twice blood 
collection before reaching to the highest blood concentration (Cmax).”  
To reflect this requirements, the blood collection time period shall be 32 hours which is more 
than 3 times the elimination half-life, and totally 16 blood samples will be collected as in 
below. 
1) Part 1 (Fasted state) 
• 
Number of samples: 16 times (once just before administration of study 
intervention, 15 times thereafter) 
• 
Sampling time: Before administration (just prior to administration) of study 
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intervention and 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24 and 32 hours thereafter 
2) Part 2 (Fed state) 
• 
Number of samples: 16 times (once just before administration of study 
intervention, 15 times thereafter)  
• 
Sampling time: Before administration (just prior to administration) of study 
intervention and 1, 2, 3, 4, 5, 5.5, 6, 6.5, 7, 8, 9, 10, 12, 24 and 32 hours thereafter 
4.2 
Scientific Rationale for Study Design 
This is a single-center, open-label, two-way crossover design. This clinical study will be 
conducted in compliance with the “Regulation on Pharmaceuticals Approval, Notification and 
Review” (MFDS Notification No. 2020-36, 04 May 2020), Annex 4 Good Clinical Practice 
“Regulation on Safety of Medicinal Products, etc.” (Ordinance of the Prime Minister No. 
1650, 14 October 2020) and “Standard on Pharmaceutical Equivalence Study” (MFDS 
Notification No. 2020-91, 22 September 2020). According to these, it is justified to conduct 
the study in a crossover design allowing that each participant serves as its own control. The 
study will be performed in an open-label manner, which will not have influence on the 
outcome as the primary objectives and endpoints are related to PK parameters, which will be 
evaluated with validated methods. Bioanalytical assessments will also be done with validated 
methods not influenced by the respective treatment.   
Based on previous PK experience and the regulations, the sample size of 48 participants in 
fasted group (Part 1) and 34 participants in fed group (Part 2) will provide sufficient PK 
information as well as safety and tolerability data without exposing too many participants. 
Both sexes will be included in each group. Details on sample size justification can be found 
in Section 9.2.2 (Sample Size Justification). 
4.3 
Justification for Dose 
The usual starting dose of Glucophage XR to treat T2DM patients is 500 mg once daily with 
the evening meal and the maximum recommended daily dose is 2,000 mg. 
In this study, the starting dose of 500 mg will be used. Multiple dosing is not required as no 
accumulation is observed after repeated administration of metformin XR tablets in healthy 
volunteers. 
Metformin will be administered as a single dose of 500 mg either as a Glucophage XR 
Reduced Mass tablet (Test drug) or Glucophage XR tablet (marketed formulation = Reference 
drug) separated by an at least 7-days wash-out period. 
4.4 
End of Study Definition 
The end of the study is defined as the date of the last contact with the last participant who 
participated in the study (last participant last observation). 
A participant has completed the study if he/she has completed all study parts, including all 
study visits, including admission/discharge and outpatient visit. However, in the event blood 
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collection for PK is completed but safety confirmation test is not performed, the completion 
of the study by a particular participant will be determined at the discretion of the Principal 
Investigator.   
 
5 
Study Population 
For this bioequivalence study, healthy adult volunteers aged over 19 and below 55 years shall 
be recruited through announcement of applicants for bioequivalence study for each of fasted 
and fed state part of the study. Only volunteer recruitment announcements for bioequivalence 
study approved by the Institutional Review Board (IRB) will be used. Volunteers are also 
recruited through the website of the Clinical Trials Center of Chungnam National University 
Hospital & web site of an external recruiting company. Participants enrolled in the Clinical 
Trials Center can obtain detailed information regarding the bioequivalence study by telephone 
or visit prior to participating in the study.  
The criteria in Sections 5.1 (Inclusion Criteria) and 5.2 (Exclusion Criteria) are designed to 
enroll only participants who are appropriate for the study; thereby, ensuring the study fulfills 
its objectives. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a participant is suitable for this study. 
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: 
Age 
1.  Are between 19 and 55 years of age at the time of signing the informed consent.  
Type of Participant and Disease Characteristics 
2. All values for hematology and biochemistry tests of blood and urinalysis (especially 
eGFR > 80 mL/min/1.73m2 and normal Creatinine) within the normal range or 
showing no clinically relevant deviation as judged by the Investigator.  
3. Are not having congenital or chronic diseases, nor pathological symptoms based on 
the screening. 
4. Have no history of gastrointestinal resection that may affect drug absorption. 
5. Have no history of psychiatric disorder within 5 years prior to screening. 
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6. Vital signs (body temperature [tympanic], blood pressure [BP], and pulse rate in 
sitting position) within the normal range or showing no clinically relevant deviation 
as judged by the Investigator.  
7. Electrocardiogram recording (12-lead) without signs of clinically relevant pathology 
in particular QTc (Bazett) ≤ 450 ms.  
8. Non-smoker (i.e. zero cigarettes, pipes, cigars or others) at least three months before 
study entry. 
9. Negative screen for HBsAg, anti-HBc, HCV Ab, anti-HIV1&2 and RPR Ab. 
Weight 
10. Have a body weight within the range 55~95 kg and a Body Mass Index (BMI) within 
the range 18.5~29.9kg/m2 (inclusive). 
Sex 
11. Are female or male. 
Contraceptive use by males or females will be consistent with local regulations on 
contraception methods for those participating in clinical studies. 
a Female Participants 
 Are not pregnant or breastfeeding, and at least one of the following conditions 
applies: 
 
Not a WOCBP 
OR 
 
If a WOCBP, use a highly effective contraceptive method (i.e., with a failure 
rate of < 1% per year), preferably with low user dependency, as described in 
Appendix 4 for the following time periods: 
 Before the first dose of the study intervention(s), if using hormonal 
contraception: 
 
Has completed at least one 4-week cycle of an oral contraception pill 
and either has begun or finished her menses 
OR 
 
Has used a depot contraceptive or extended-cycle oral contraceptive 
for least 28 days and has a documented negative pregnancy test using 
a serum pregnancy test. 
 
During the intervention period 
 
After the study intervention period (i.e., after the last dose of study 
intervention is administered) for at least 7 days plus 30 days (a menstrual 
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cycle) after the last dose of study intervention and agree not to donate eggs 
(ova, oocytes) for reproduction during this period. 
 
Have a negative serum pregnancy test, as required by local regulations within 
7 days before the first dose of study intervention. The participant must be 
excluded from participation if the serum pregnancy result is positive. 
 
Additional requirements for pregnancy testing during and after study intervention 
are in Section 8.2.5 (Clinical Safety Laboratory Assessment) and Section 8.10 
(Study Schedule). 
 The Investigator reviews the medical history, menstrual history, and recent sexual 
activity to decrease the risk for inclusion of a female with an early undetected 
pregnancy. 
 
b Male Participants  
 
When having sexual intercourse with a WOCBP, who is not currently pregnant, 
and advise her to use a highly effective contraceptive method with a failure rate 
of < 1% per year, as described in Appendix 4 (Contraception) since a condom 
may break or leak. 
Informed Consent 
12. 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. 
5.2 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Participants determined ineligible to participate in this study at the discretion of the 
Principal Investigator (or delegated investigators). 
2. Hypersensitivity to venous puncture 
3. Known hypersensitivity to ingredients of study interventions or Biguanides, or having 
other clinically relevant hypersensitivities  
4. Type I diabetes mellitus, lactic acidosis, acute or chronic metabolic acidosis including 
diabetic ketoacidosis, with or without coma; diabetic pre-coma, pre-diabetes 
5. Patients with renal impairment (eGFR with MDRD < 80 mL/min/1.73m2 – calculations 
according to Modification of Diet in Renal Disease (MDRD) formula). Patient 
presenting with acute conditions with the potential to alter renal function such as 
dehydration, severe infection, cardiovascular collapse (shock), acute myocardial 
infarction, and septicemia 
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6. Participants with acute and unstable heart failure 
7. Participants with severe infection or severe traumatic general disorder 
8. Participants who are scheduled to undergo surgical procedures 
9. Participants with malnutrition, inanition, pituitary dysfunction or adrenal function 
failure 
10. Participants with hepatic dysfunction, acute or chronic disease which may cause tissue 
hypoxia such as respiratory failure, acute myocardial infarction, shock and GI disorder 
such as excessive alcohol intake, hydration, diarrhea, vomiting etc. 
11. Participants undergoing intravascular administration of iodinated contrast materials in 
radio diagnostic examinations (for example, intravenous urogram, intravenous 
cholangiography, angiography, and computed tomography (CT) scans with 
intravascular contrast materials etc.) 
Prior/Concomitant Therapy 
12. Participants who took drugs that significantly induce (e.g., barbiturate) or inhibit drug 
metabolism enzymes, and those drugs that may alter metformin pK, most importantly 
OCT1/2 inhibitors and inducers, within 30 days prior to screening. 
13. Use of a concomitant drug. However, any medications that are considered necessary 
for participant’s welfare and will not interfere with the trial medication may be given 
at the discretion of the Investigator. For the detail of prohibited medicines, see Section 
6.5.3 (Prohibited Medicines).  
14. Use of any medication that may affect the outcome of the study within 10 days prior to 
screening and during study conduct 
Prior/Concurrent Clinical Study Experience 
15. Participation in another bioequivalence or other clinical studies where the last 
administration of previous study medication was within 6 months, before the first drug 
administration in this study 
Other Exclusions 
16. Donation of whole blood or loss (≥ 400 mL) within 2 months, plasma donation or 
apheresis within 2 weeks prior to first drug administration 
17. History of regular alcohol drinking within 6 months prior to screening as shown below 
 
For females, > 14 cups/week 
 
For males, > 21 cups/week 
(1 cup: Soju 50 mL, Liquor 30 mL, Beer 250 mL) 
 
18. Excessive consumption of xanthine-containing food or beverages (>5 cups of coffee a 
day or equivalent) or inability to stop consuming caffeine, from 48 hours prior to drug 
administration until collection of last PK sample in each period (hour 32 [H32]). 
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19. Intake of grapefruit, orange, cranberry or juices of these three fruits, from 48 hours 
prior to drug administration until collection of last PK sample in each period (hour 32 
[H32]).  
20. Inability to communicate or cooperate with the Investigator (e.g., language problem, 
illiterates, poor mental status) or to comply with the requirement of the entire trial, 
including dietary restrictions.  
21. Non-acceptance of study high-fat breakfast for participant included in the fed group 
(e.g., vegetarians, vegans and participants who follow special diets).  
22. Legal incapacity or limited legal capacity.  
23. Participants kept in detention.  
 
5.3 
Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
(1) Part 1: Fasted state (both periods) 
 Refrain from all food and beverages (except water) for at least 4 hours prior to clinical 
laboratory tests (except for tests on Day-1). 
 Refrain from all food and beverages (except water) for at least 10 hours before and 4 
hours after dosing. 
 Refrain from water for 1 hour before and after dosing except 150 mL water for 
administration. 
 Lunch is served after blood collection at 4 hours after dosing. 
 Dinner is served around 06:00 pm on Day -1 after blood collection, and at 10 hours after 
dosing. 
(2) Part 2: Fed state (both periods) 
 Refrain from all food and beverages (except water) for at least 4 hours prior to clinical 
laboratory tests (except for tests on Day-1). 
 Refrain from all food and beverages (except water and milk or juice in the course of 
high-fat meal ) for at least 10 hours before high-fat meal intake and 4 hours after dosing. 
 Refrain from water for 1 hour before and after dosing. 
 From around 7:30 am on the day of the study, take all of breakfast (more than 900 Kcal, 
more than 35% fat) without leaving any food at 1-minute interval in the order of random 
assignment number, and the meal time should be completed within 20 minutes. 
 Lunch is served after blood collection at 4 hours after dosing. 
 Dinner is served around 06:00 pm on Day -1 after blood collection, and at 10 hours after 
dosing. 
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5.3.2 
Caffeine, Alcohol, and Tobacco 
 During each dosing session, participants will abstain from ingesting xanthine-
containing beverages (e.g., coffee, tea, cola drinks, and chocolate) from 48 hours before 
the start of dosing until after collection of the final pharmacokinetic (PK) and/or 
pharmacodynamic sample. 
 During each dosing session, participants will abstain from alcohol for 24 hours before 
the start of dosing until after collection of the final PK and/or pharmacodynamic sample. 
 Use of tobacco products will not be allowed from at least three months before study 
entry until after the final follow-up visit. 
 
 
5.3.3 
Activity 
 Participants will abstain from strenuous exercise for 48 hours before admission to the 
Clinical Facility for each Period. Participants may participate in light recreational 
activities (e.g., watching television or reading). 
 Participants should not lie down for at least 2 hours post administration of study 
interventions in a sitting position and should maintain similar posture and behavior to 
minimize the effect on blood flow velocity and motility of gastro intestines. 
 Because metformin may cause very rarely severe lactic acidosis, participants have to 
stay at clinical site for 32h after each administration though it is for pharmacokinetic 
samplings. Additionally, if any of the following symptoms or signs comes out, it should 
be notified to the investigators immediately, and the investigators should check for the 
abnormalities through careful monitoring. Hypoglycemia has not been seen with 
metformin doses of up to 85 g, although lactic acidosis has occurred in such 
circumstances. High overdose or concomitant risks of metformin may lead to lactic 
acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The 
most effective method to remove lactate and metformin is hemodialysis. 
- Lactic acidosis: Unexplained hyperventilation, myalgia, malaise, unusual somnolence, or 
other nonspecific symptoms 
 
5.4 
Screen Failures 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened for Clinical laboratory test, 12-lead ECG, etc.. If clinical laboratory test results 
are out of reference range, additional visits may be requested to conduct a re-test or further 
examination at the discretion of the Principal Investigator (or the delegated investigators). If 
the test result is judged to be a transient change due to lifestyle (specific diet, drinking, 
exercise, night shift, etc.), it is possible to re-test participants once after correction of lifestyle 
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at the discretion of the Principal Investigator (or delegated investigators). If re-test is 
performed, the inclusion criteria are confirmed based on the last result value. Re-screened 
participants will retain their initially assigned screening numbers.   
 
6 
Study Intervention(s) 
Study intervention is any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant per the study protocol. 
 
6.1 
Study Intervention(s) Administration 
 
 
Study Interventions 
 
Test Drug 
Reference Drug 
Study Intervention Name: 
500 mg Glucophage® XR 
Reduced Mass tablet  
500 mg Glucophage® XR 
tablet  
Dose Formulation: 
Tablet 
Tablet 
Unit Dose 
Strength(s)/Dosage Level(s): 
Metformin hydrochloride 
500 mg 
Metformin hydrochloride 
500 mg 
Physical Description 
White to off-white, round, 
biconvex tablet debossed 
with “500” on one side 
White 
to 
off-white, 
capsule-shaped, biconvex 
tablet engraved “500” on 
one side and “XR” on the 
other 
Route of Administration: 
p.o. 
p.o. 
Dosing Instructions: 
Metformin tablets will be administered as a single dose of 
500 mg either as a Glucophage XR Reduced Mass tablet 
(Test drug) or Glucophage XR tablet (Reference drug) in 
fasted or fed condition as described in Section 5.3.1 
(Meals and Dietary Restrictions). 
Supplier/Manufacturer: 
Manufacturer of (commercial) drug product: Merck Sante 
s.a.s 
– 
Semoy 
(France) 
Manufacturer of Study Intervention: Merck Healthcare 
KGaA, Darmstadt (Germany) 
Both the finished product of Test drug and Reference drug 
are manufactured at the same manufacturing site (Merck 
Sante s.a.s – Semoy (France)) 
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Storage Condition: 
In airtight container not above 30℃ 
Packaging and Labeling 
 
The study interventions shall be manufactured by the 
Sponsor in accordance with all applicable regulatory 
requirements 
and 
Good 
Manufacturing 
Practice 
Guidelines and will be supplied to Clinical Facility as QP 
(Qualified 
Person) 
released 
and 
labeled 
study 
intervention (unblinded labeled blister containing 15 
tablets each). Labeling will be done on the blister in 
accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines.  
 
GCP Dispensing 
Upon study intervention delivery, the PI delegated 
Clinical Trial Pharmacist for study intervention 
(hereinafter referred to as “the Clinical Trial Pharmacist”) 
checks the information (quantity and storage condition of 
study interventions) provided in the receipt form and 
enclosed documents. He/she then records the information 
in the study intervention logbook. The unopened carton is 
kept in the storage room as indicated. The Clinical Trial 
Pharmacist 
will 
generate 
the 
study 
intervention 
prescription codes so that the Investigator can prescribe 
the study intervention via the Electronic Medical Record 
(EMR). Detailed GCP Dispensing follows SOP of the 
Clinical Facility. 
6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). For this study, the PI will delegate these 
responsibilities to the Clinical Trial Pharmacist for study intervention (hereinafter referred to 
as “the Clinical Trial Pharmacist”). 
 Upon receipt of the study intervention(s), the Investigator or designee (i.e., Clinical 
Trial Pharmacist) 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 study intervention(s) and only 
authorized site staff may dispense it. All study intervention(s) must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area, in accordance 
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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. 
 Study intervention(s) 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 study intervention(s). 
 Dates, quantities, batch numbers, container numbers, expiry dates 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 study 
intervention(s) provided were fully reconciled. 
 Unused study intervention(s) must not be discarded or used for any purpose other than 
the present study. No study intervention that is dispensed to a participant may be re-
dispensed to a different participant. 
 A Study Monitor will periodically collect the study intervention(s) accountability forms. 
 Further guidance and information for the final disposition of unused study 
intervention(s) are provided in the SOP of Clinical Facility. 
 
6.3 
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding 
6.3.1 
Study Intervention Assignment 
 
Block Randomization 
Method at the Clinical 
Facility 
The Principal Investigator (or delegated investigators) uses a 
block randomization method in accordance with the Clinical 
Facility SOP to determine which product, Test Drug or 
Reference Drug, would be administered in Part 1 and Part 2 
respectively, and based on this, prescribes the study 
interventions for bioequivalence study. According to the 
prescription, the Clinical Trial Pharmacist prepares the study 
interventions for Part 1 and Part 2 in accordance with the 
Clinical Facility SOP. The Principal Investigator (or delegated 
investigators) keeps records of the prescription. 
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Participant identifier & 
Assignment to 
treatment sequence 
For Part 1 (Fasted state) and Part 2 (Fed state), screening 
number in the form of SXXX (e.g. ‘S301, S302, S303 …’ if 
it is for Part 1 and ‘S401, S402, S403 …’ if it is for Part 2) is 
given to the applicants who visited the Clinical Facility and 
agreed the informed consent in writing. The screening 
number will be used to identify the participants for the whole 
duration of the bioequivalence study. 
One day (Day -1) prior to administration of study intervention 
of Period 1, each participant is given a participant number 
according to the order of obtainment of the Informed Consent 
and the Sequence is randomly assigned to each of Part 1 
(Fasted state) and Part 2 (Fed state). Randomization is done 
using Excel or SAS programs, and a total of 82 participants 
(Part 1: 48 participants, Part 2: 34 participants) are randomly 
assigned to 2 Sequences (1 or 2) with 24 participants per 
Sequence in Part 1 and 2 Sequences (1 or 2) with 17 
participants per Sequence in Part 2 in a 1:1 ratio. 
Randomization number is given to the 48 participants if it is 
Part 1 (Fasted state) and to the 34 participants if it is Part 2, 
excluding the stand-by participants (waiting list), who 
satisfied the screening, inclusion/exclusion criteria and 
clinical laboratory tests. The randomization number is the 
number of the administration order of participants and its 
form is R1YY (e.g., R101, R102, R103, ..., R148) if it is Part 
1 (Fasted state) and R2YY (e.g., R201, R202, R203, ..., R234) 
if it is Part 2 (Fed state). Participants who have been assigned 
a randomization number but dropped out before the first 
administration of Period 1 can be replaced with stand-by 
participants. When the participant is replaced, the stand-by 
participant will be assigned the drop-out's randomization 
number. However, participants will not be replaced after the 
first administration of Period 1. 
6.3.2 
Blinding 
Blinding Method 
Not applicable, this is an open-label study. 
 
Assignment Method Retention 
Not applicable, this is an open-label study. 
 
Unblinding Clinical Studies for Sample Analysis of Special Data 
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This is an open-label study. However, the Analytical Facility will initially be blinded to 
prevent biases that might affect the result of sample analysis. The randomized sample code 
will be unblinded to the Analytical Facility only following the completion of sample analysis. 
Analytical Facility initiates statistical analysis after receiving the unblinded sample code from 
the Clinical Facility. 
The samples from Part 1 (Fasted state) and Part 2 (Fed state) that are delivered to the 
Analytical Facility are blinded so that Information on administration of study intervention 
(Test or Reference, blood collection time, Period) are not known. Samples are randomized 
according to the SOP of Clinical Facility to assign sample codes to the samples. 
 
The blinded sample code should be indicated only on the sample or source data 
(Eppendorf tube, Box, Sample transfer related documents, etc.). Example of 
Eppendorf tube label is as follows. 
 
Protocol No. 
 Part 1 or 
 
Sampling time point, period and Participant number / 
 
For Analysis or Back-up / AN or BU 
 
Information on blinded sample is not disclosed to the Analytical Facility until the 
concentration measurement is completed. Once the concentration analysis at the Analytical 
Facility is completed, the concentration of each sample from Part 1 (Fasted state) and Part 2 
(Fed state) is informed to the Clinical Facility. After the Principal Investigator of Clinical 
Facility receives the concentration of each sample from Part 1 (Fasted state) and Part 2 (Fed 
state) from the Analytical Facility, he/she provides the blinded information on the sampling 
time and period to the Analytical Facility. After the Analytical Facility confirms the blinded 
information on the sampling time and period, the Analytical Facility performs Incurred 
Sample Reanalysis (ISR). After the Principal Investigator of Clinical Facility receives the ISR 
result from the Analytical Facility, he/she provides the blinded information on the sample 
code. After the Analytical Facility confirms the blinded information on the sample code, the 
sample code is unblinded. 
6.3.3 
Emergency Unblinding 
Not applicable, this is an open-label study. 
 
6.4 
Study Intervention Compliance 
 A mouth check will be performed by Principal Investigator (or delegated investigators) or 
Clinical Trial Pharmacist to ensure that the participants have swallowed the study 
interventions. 
 This study shall be processed as two parts: Part 1 (Fasted state) and Part 2 (Fed state).  
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 In the event of failure of enrollment of targeted number of participants as stated in the 
protocol, for each study of Part 1 (Fasted state) and Part 2 (Fed state), a separate 
hospitalization, that is, a separate administration to 2 groups can be arranged for the quality 
assurance and performance convenience of this study. The clinical trials of the divided 
participants will follow the same performance methods and procedures described in this 
protocol. The separate hospitalizations should be made in two groups. If from the first dose 
of the first hospitalization group to the first dose of the second hospitalization group is 
completed within 6 weeks, the effect of separate hospitalization would not considered and 
for the situation where it exceeds 6 weeks, interaction due to separate hospitalization must 
be checked. 
1) Part 1: Fasted state  
After an overnight fast of at least 10 hours, participants will receive 1 tablet (metformin 
hydrochloride 500 mg) of either the Reference or the Test drug orally with 150 mL of room-
temperature water, starting with the first participant at around 08:00 am. Participants should 
swallow the entire study intervention with water, without chewing or crushing. 
The difference of administration time between participants has to be about 1-minute interval 
considering the blood sampling time. 
2) Part 2: Fed state 
After an overnight fast of at least 10 hours, participants shall take a high-fat breakfast (over 
900 kcal, over 35% fat) from around 07:30 am within 20 minutes according to the 
randomized number sequence on the day of the study. The difference of taking breakfast 
time between participants has to be about 1-minute interval considering the administration 
time. 30 minutes after the start of the meal (around 08:00 am), participants will receive 1 
tablet (metformin hydrochloride 500 mg) of either the Reference or the Test drug orally with 
150 mL of room-temperature water. Participants should swallow the entire study 
intervention with water, without chewing or crushing. 
6.5 
Concomitant Therapy 
Record in the CRF all concomitant therapies (e.g., medicines or nondrug interventions) used 
from the time the participant signs the informed consent until completion of the study 
including any changes. For prescription and over-the-counter medicines, vaccines, vitamins, 
and herbal supplements, record the name (preferably INN name), reason for use, dates 
administered, and dosing information. 
Contact the Medical Monitor for any questions on concomitant or prior therapy. 
Participants are prohibited from taking any of concomitant medications during the entire 
period of the bioequivalence study. If taking of a concomitant medication is confirmed, the 
participant will be dropped out. Participants who have been dropped out by taking 
concomitant medication for the treatment of adverse events shall be subject to appropriate 
medical treatment in accordance with 'Measures to Protect Safety of Participants' in Appendix 
2 (Study Governance). 
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Medications administered from 30 days before screening to prior to administration of study 
interventions on Day 1 of Period 1 shall be recorded as prior medications. Medications 
administered from the 1st administration of study interventions to the end of observation shall 
be recorded as concomitant medications. For prior medications/ concomitant medication, 
name of the medications, the dosage per administration, the frequency of administration, the 
route of administration, the purpose of administration, the beginning/ ending date of 
administration, and whether the administration was continued or not shall be recorded. 
6.5.1 
Rescue Medicine 
Not applicable. 
6.5.2 
Permitted Medicines 
Participants enrolled in this study should be in good general health and therefore, should not 
be taking or using any other medication. 
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. 
6.5.3 
Prohibited Medicines 
No concomitant medication (with the exception of contraceptive in females) or over-the-
counter medication intake, including multivitamins, nutritional supplements and herbal 
products (e.g. St. John’s wort) will be permitted within 2 weeks or 5 half-lives, whatever is 
longer, prior to first study intervention administration and during the study until last PK 
sampling. 
If the administration of a non-permitted concomitant drug becomes necessary during the study, 
e.g. because of AEs, the Investigator and the Sponsor will decide if the participant’s 
withdrawal is necessary. 
Use of any investigational agent is not permitted within 6 months or prior to screening and 
during the whole study duration. 
6.5.4 
Other Interventions 
Not applicable. 
6.6 
Dose Selection and Modification 
Not applicable. See Section 4.3 (Justification for Dose). 
6.7 
Study Intervention after the End of the Study 
In this study of healthy participants, no further treatment is planned or required after the end 
of the study. 
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6.8 
Special Precautions 
Medical emergency and resuscitation equipment as well as agents (such as epinephrine, 
prednisolone equivalents, etc.) are to be available at the study site in case of severe allergic 
reactions. 
6.9 
Management of Adverse Events of Interest 
Healthy participants may be exposed to diarrhea, decreased appetite, nausea, vomiting and 
abdominal pain. These symptoms are almost always transient and occur early during therapy 
initiation and spontaneously resolve in most cases. If any of these AEs are observed, their 
severity should be defined based on clinical judgment of the Investigator and defined 
according to the Qualitative Toxicity Scale (See Appendix 5 (Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and Reporting)). 
 If adverse events (such as nausea, vomiting, diarrhea, abdominal pain, rash, etc.) occur 
after administration of metformin, it should be notified to the investigators immediately 
and the investigators should check for abnormalities through careful monitoring. 
 After administration of metformin, the shell of the tablets may come out through the 
stool, and this should be notified to participant that it is a normal phenomenon. 
 If blood glucose is lower than 60 mg/dL or hypoglycemic symptoms occur after 
administration of metformin, participants should take the sugar water containing 15g of 
sugar in 100 mL of water according to the judgment of the Principal Investigator (or 
delegated investigators). And if Principal Investigator (or delegated investigators) 
believes that the symptoms are severe, participants should receive an immediate 
treatment and have to move to emergency room to receive inpatient treatment. Blood 
Sugar Test is performed before blood collection at 3 and 4 hours after administration of 
each Period. 
 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1 
Discontinuation of Study Intervention 
If a clinically significant finding is identified (including changes from baseline in QT/QTc 
interval corrected using Bazett’s formula [QTcB]) after enrollment, the Investigator or 
qualified designee will determine if the participant can continue in the study and if any change 
in participant management is needed. This review of the ECG printed at the time of collection 
must be documented. Any new clinically relevant finding should be reported as an AE. 
The Section 1.3 (Schedule of Activities) specifies the data to collect at study intervention 
discontinuation and follow-up, and any additional evaluations that need to be completed. 
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7.1.1 
Temporary Discontinuation 
Not applicable.  
7.1.2 
Rechallenge 
Not applicable. 
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. 
 The participant may be withdrawn at any time at the discretion of the Investigator for 
safety, behavioral, compliance, or administrative reasons. 
 If Principal Investigator (or delegated investigators) decides that the study cannot be 
continued by occurrence of Adverse Events/ Adverse Drug Reaction/ Serious AE 
 If the participant arbitrarily takes any medication that is expected to affect the evaluation 
of safety and pharmacokinetic characteristics of the study intervention 
 If a serious violation of the protocol is found during the study that belongs to 
inclusion/exclusion criteria 
 If the Sponsor, MFDS or IRB requests suspension of the study 
 If protocol non-compliance is found during the study 
 The SoA specifies the data to collect at study discontinuation and follow-up, and any 
additional evaluations that need to be completed 
 The participant may be withdrawn if the participant has difficulties in collecting blood 
samples 
 The participant may be withdrawn if the participant vomits or has diarrhea during PK 
sampling periods 
 The participant will be withdrawn if the participant is pregnant 
 If the participant withdraws consent for future involvement in the study, any data 
collected up to that point may still be used, but no future data can be generated. Any 
biological samples collected until withdrawal shall be archived for a certain period, and 
pharmacokinetic analysis sample treatment of the withdrawn participants and other 
details regarding the disposal will follow SOP of the Analytical Facility. 
 A participant has the right at any time to request destruction of any biological samples 
taken. The investigator must document this in the site study records. 
 
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Details such as participant discontinuation date and specific reasons should be recorded in the 
source document and the electronic Case Report Form (eCRF). 
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; 2) if necessary, send a certified letter (or an equivalent local method) to 
the participant’s last known mailing address, and 3) if a participant has given the 
appropriate consent, contact the participant’s general practitioner for information. 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. 
8 
Study Assessments and Procedures 
 Study assessments and procedures and their timing are summarized in the Section 1.3 
(Schedule of Activities). 
 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 
study intervention. 
 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 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. 
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 A maximum of 203 mL of blood will be collected from each participant in the study. 
Repeat or unscheduled additional samples may be taken for any extra assessments that 
may be required or for safety reasons or for technical issues with the samples. 
The total blood sample amount collected for each participant is as follows. 
 
Assay 
Volume per 
 sample (mL) 
Total number of samp
les 
Total blood  
volume (mL) 
Screening 
(Clinical laboratory tests) 
16 mL 
1 time 
16 mL 
Admission day check 
8 mL 
2 times 
16 mL 
Safety confirmation test (including 
end of study) check) 
11 mL 
1 time 
11 mL 
Pharmacokinetics 
5 mL* 
32 times 
160 mL 
Total 
- 
36 times 
203 mL 
* Excludes the discarding 1 mL per each blood collection to completely remove the saline that is left in the 
collection set. 
8.1 
Efficacy Assessments and Procedures 
Not applicable. 
8.2 
Safety Assessments and Procedures 
The safety profile of the study intervention will be assessed through the recording, reporting 
and analysis of baseline medical conditions, adverse events (AEs), physical examination 
findings, vital signs, electrocardiograms, 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 (Time Period and Frequency for 
Collecting Adverse Event and Serious Adverse Event Information). 
8.2.1 
Adverse Events 
Principal Investigator (or delegated investigators) will assess all adverse events that occur 
during the bioequivalence study (from the obtainment of Informed Consent to the end of 
observation. See Section 8.3 (Adverse Events and Serious Adverse Events) and Appendix 5 
(Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting) for details of AE.  
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8.2.2 
Physical Examinations 
During screening and at the End of Study Visit, a complete physical examination is performed 
for all participants. Subsequently, participants will be interviewed, and a brief physical 
examination will be performed on admission day (Day-1) & Day 2: 
 A complete physical examination will include, at a minimum, assessments of the 
general condition, nutritional status, skin/ mucous membrane, eye (except decreased 
eyesight), nasopharyngeal system, thyroid, lung/ respiratory system, cardiovascular 
system, abdomen and digestive system, kidney/ genitourinary system, neuropsychiatric 
system, spine/ limbs/ tumor, peripheral circulation, lymphatic system and others. 
During screening, height and weight will also be measured and recorded. 
 A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, abdomen (liver and spleen), and the symptoms reported by the 
participant. 
 Investigators should pay special attention to clinical signs related to previous serious 
illnesses, particularly renal impairment and/or dehydration, vomiting, diarrhea. 
 Physical examination is assessed as normal, abnormal/ no clinical significance 
(Abnormal/ NCS) and abnormal/ clinical significance (Abnormal/ CS). 
8.2.3 
Vital Signs 
 Vital signs will be measured in a sitting position after 5 minutes of rest and will include 
tympanic temperature, systolic and diastolic blood pressure and pulse rate.  
 Measurement of tympanic temperature is performed only during the Screening and at 
the End of Study Visit or if deemed necessary by the Investigator or delegated 
Investigator. Preferably, automated device has to be used however, manual device can 
be used if necessary. The measurement results are evaluated by Principal Investigator 
(or delegated investigators).  
8.2.4 
Electrocardiograms 
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. 
The 12-lead ECG measurement will be performed while maintaining the lying posture without 
any sudden changes of body position. By combining the readings indicated by the algorithm 
within the examination instrument and the clinical findings from the reading physician, the 
examination outcome will be assessed as normal (Normal ECG), borderline, no clinical 
significance (Abnormal ECG / NCS) and clinical significance (Abnormal ECG / CS). 
8.2.5 
Clinical Safety Laboratory Assessments 
 Blood and urine samples will be collected for the clinical laboratory tests listed in 
Appendix 6 (Clinical Laboratory Tests), at the time points listed in the SoA. All samples 
should be clearly identified.  
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 Additional tests may be performed at any time during the study, as determined necessary 
by the Investigator or required by local regulations. 
 Clinical laboratory tests will be performed in the Department of Diagnostic Laboratory 
Medicine, Chungnam National University Hospital, which is a registered lab in the 
Korean Association of External Quality Assessment Service (Registered number: 0055) 
and is regularly certified for quality control. 
 The Sponsor must receive a list of the local laboratory normal ranges before shipment 
of study intervention(s). Any changes to the ranges during the study must be forwarded 
to the Sponsor. 
 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. 
 Clinical laboratory tests are assessed as normal, abnormal/ no clinical significance 
(Abnormal/ NCS) and abnormal/ clinical significance (Abnormal/ CS) depending on 
the deviation from the reference value. 
 Additional serum or highly sensitive urine pregnancy tests may be conducted, as 
determined necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the study. 
 
 
8.2.6 
Suicidal Risk Monitoring 
Not applicable. 
 
8.3 
Adverse Events and Serious Adverse Events 
The definitions of an Adverse Event (AE) and a Serious Adverse Event (SAE) are in 
Appendix 5. 
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 initially 
included in the study (date of first signature of first informed consent) and continues until the 
end of the observation. Beyond this reporting period, any new unsolicited SAEs that the 
Investigator spontaneously reports to the Sponsor will be collected and processed. 
Any SAE assessed as related to the study intervention must be recorded and reported, as 
indicated in Appendix 5, whenever it occurs, irrespective of the time elapsed since the last 
administration of study intervention. 
The method of recording, evaluating, and assessing causality of AEs (including SAEs) and 
the procedures for completing and transmitting SAE reports are in Appendix 5. All SAEs will 
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be recorded and reported to the Sponsor or designee immediately and under no circumstance 
will this exceed 24 hours, as indicated in Appendix 5 (Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting). The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available using the 
same procedure that was used for the initial report. 
Investigators are not obligated to actively solicit AEs or SAEs after the end of study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator will 
promptly notify the Sponsor. 
 
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 or her condition. During 
the reporting period, any unfavorable changes in the participant’s condition will be recorded 
as AEs, regardless if reported by the participant or observed by the Investigator. 
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 in the appropriate 
section of the eCRF. All SAEs must be additionally documented and reported using the 
appropriate report form as specified in Appendix 5 (Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting). 
Adverse events collected from the time of receipt of the Informed Consent Form to the end of 
participant observation shall be recorded in the "Adverse Events" sheet of the eCRF regardless 
of causal relationship with study intervention.  
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
AEs are recorded and assessed continuously throughout the study, as specified in Section 
8.3.1 (Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information) and are assessed for their outcome at the End of Study Visit. All AE/SAEs 
ongoing at the End of Study Visit must be monitored and followed up by the Investigator until 
stabilization or 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 also the responsibility of the Investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. Further information on follow-up 
procedures is given in Appendix 5 (Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting). 
If an adverse event due to the participation in the bioequivalence study has not recovered at 
the End of Study Visit, Principal Investigator (or delegated investigators) shall provide the 
required examinations and treatments, and the Principal Investigator shall follow-up until 
symptoms disappear. If all detrimental and unintended signs or symptoms have not 
disappeared, appropriate medical interventions such as first aid, outpatient records (additional 
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examination and medication) and consultation and referral to medical specialists, may be 
performed at the discretion of the Principal Investigator (or delegated investigators). 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
The Sponsor will send appropriate safety notifications to Health Authorities in accordance 
with applicable laws and regulations. 
Prompt notification by the Investigator to the Sponsor of an SAE (particularly life-threatening 
and deaths) is essential so that legal obligations and ethical responsibilities towards the safety 
of participants and the safety of a study intervention under clinical investigation are met. The 
Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving study participants to the IEC/IRB that 
approved the study. 
In accordance with ICH 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 line with respective 
regulations, the Sponsor/designee will inform the Investigator of AEs that are both serious 
and unexpected and considered to be related to the administered product (“suspected 
unexpected serious adverse reactions” or SUSARs). The Investigator should place copies of 
Safety Reports in the Investigator Site File. National regulations regarding Safety Report 
notifications to Investigators will be considered. 
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records 
of these notifications. When direct reporting 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/designee and of filing copies of all 
related correspondence in the Investigator Site File. 
8.3.5 
Pregnancy 
Only pregnancies the Investigator considers to be related to the study intervention (e.g., 
resulting from a drug interaction with a contraceptive method) are AEs. However, all 
pregnancies with an estimated conception date during the period defined in Section 8.3.1 
(Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information) must be recorded in the AE page/section of the eCRF for both pregnancies in 
female participants and 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 by the same process specified for SAE 
reporting in Appendix 5 (Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting), section on Reporting Serious Adverse Events. 
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the participants are withdrawn from the study. 
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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 (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) must be reported in an expedited manner, 
as specified in Section 8.3.1 (Time Period and Frequency for Collecting Adverse Event and 
Serious Event Information), while normal outcomes must be reported within 45 days after 
delivery. 
In the event of a pregnancy in a participant occurring during the study, the participant must 
be discontinued from the study intervention. The Sponsor/designee must be notified without 
delay and the participant must be followed as indicated above. 
8.4 
Treatment of Overdose 
For this study, any dose of study intervention greater than the highest daily dose included in 
the clinical study protocol within a 24-hour time period will be considered an overdose. 
Hypoglycemia has not been seen with metformin doses of up to 85 g, although lactic acidosis 
has occurred in such circumstances. High overdose or concomitant risks of metformin may 
lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. 
The most effective method to remove lactate and metformin is hemodialysis and may be used 
for an overdose. 
Even if it not associated with an AE or a SAE, any overdose is recorded in the eCRF and 
reported to drug safety in an expedited manner. Overdoses are reported on a SAE Report Form, 
following the procedure in Appendix 5 (Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting), section on Reporting Serious Adverse 
Events. 
In this study, metformin will be administered under medical supervision as 2 oral single doses 
of 500 mg separated by a 7-day wash-out. Overdosage is accordingly unlikely, however in 
case of overdose, close monitoring will be performed, and adequate medical care will be 
provided based on the clinical judgment of the Investigator. 
 
8.5 
Pharmacokinetics 
 The following PK parameters will be calculated, when appropriate:  
Parameters will be calculated from the metformin blood concentrations. 
 
Symbol 
Definition 
Measuring method 
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AUClast 
Area under the plasma concentration 
versus time data pairs, where last is 
the time of the last quantifiable 
concentration 
Linear trapezoidal method 
AUCinf 
Area under the plasma concentration 
versus time data pairs, with 
extrapolation to infinity 
AUClast + Clast / Kel 
Cmax 
Maximum plasma concentration 
Directly observed from the analysis 
data 
Tmax 
Time to maximum plasma 
concentration 
First observed time at which the 
maximum concentration is 
observed, directly observed from 
t1/2 
Elimination half-life 
The apparent terminal half-life, 
calculated according to the equation 
t1/2=Loge(2)/Kel 
Where Kel is the elimination rate 
constant Kel from the linear 
regression analysis on the log-linear 
plot of the portion corresponding to 
the terminal phase of the blood 
concentration-time curve 
AUClast/ 
AUCinf 
The ratio of AUClast to AUCinf 
AUClast/AUCinf 
 
 
The actual date and time (24-hour clock time) of each sample will be recorded to 
calculate actual time elapsed since the prior dose administration. 
Blood sample amount and aliquots per time points of pharmacokinetics are as follows. 
Part 1: Fasted state 
Collection time 
(h) 
0 
0.5 
1 
2 
2.5 
3 
3.5 
4 
5 
6 
7 
8 
10 12 24 32 
Sample 
amount (mL) 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
Aliquots 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
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Part 2: Fed state 
Collection time 
(h) 
0 
1 
2 
3 
4 
5 
5.5 
6 
6.5 
7 
8 
9 
10 12 24 32 
Sample 
amount (mL) 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
Aliquots 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
 
 The quantification of metformin in plasma will be performed using a validated analytical 
method (UPLC-MS/MS; LLOQ 20 ng/mL). Concentrations will be used to evaluate the 
PK of metformin.   
 Remaining samples collected for analyses of metformin concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study. 
 Details on processes for collection and shipment of these samples are in the SOP of Clinical 
Facility. Retention time and possible analyses of samples after the end of study are 
specified in the respective ICF. 
1) Blood Collection Method 
A normal saline-locked catheter will be inserted into the vein of arm or hand of the 
participants before dosing on Day 1 of each Period. 1 mL of the collected blood will be 
discarded to remove the saline left in the collection set and after that, collect blood into 
the EDTA(K2) treated collection tube. About 1 mL of physiological saline is injected 
into the catheter to prevent blood coagulation. 
2)  Place and Person for Blood Collection 
The collection site should be a place where about 60 people can be active, taking into 
consideration the space required for blood collection management and blood collection 
of 48 participants for Part 1 and 34 participants for Part 2. It is conducted within the 
Clinical Trial Center (
) of Chungnam 
National University Hospital, which is separated from general patients. 
Blood collection and management personnel include a Principal Investigator (or 
delegated investigator), a Clinical Trial Pharmacist, nurse(s), an assistant for the blood 
collection and a participant management personnel who is responsible for checking the 
randomization number of each participant and to arrange the order of blood samples 
collection. A total of more than 7 people are expected to be involved. 
3) Measures to Prevent Infections When Collect Blood Sample 
The collection of blood samples from participants will be done in a room with limited 
access to the public. Single use sterilized apparatus will be used to collect blood samples. 
The disposable blood collection apparatus will be disposed in a biohazard box. Needle-
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stick injury will be managed according to the Infection Management Procedure of 
Chungnam National University Hospital. 
4) Allowable Pharmacokinetics Blood Collection Time 
Every effort should be made to ensure that the pharmacokinetics blood sample is 
collected at nominal time following administration of the study interventions. The exact 
time of sample collection must be recorded in the source document and eCRF. The 
actual time of blood collection may be different from the nominal time, but the number 
of samples should remain the same. 
In the case of deviation of the blood sampling from the planned time point specified in 
this protocol, details such as the actual blood sampling time should be recorded in the 
eCRF. The acceptance range according to each sampling time point is as follows. 
Part 1: Fasted state 
Day 
(per period) 
Time (h) 
Deviation 
1 
0 
-1 h 
0.5 
±5 min 
1 
2 
2.5 
3 
3.5 
4 
5 
6 
7 
8 
10 
12 
±10 min 
2 
24 
32 
±30 min 
Part 2: Fed state 
Day 
(per period) 
Time (h) 
Deviation 
1 
0 
-1 h 
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1 
±5 min 
2 
3 
4 
5 
5.5 
6 
6.5 
7 
8 
9 
10 
12 
±10 min 
2 
24 
32 
±30 min 
Refer to ‘9. Statistical Considerations’ for details when performing statistical 
processing on primary variables. 
5) Plasma Storage for Pharmacokinetic Analysis 
Blood for pharmacokinetic analysis will be stored in an ice bath immediately after 
collection and centrifuged (
) within 30 minutes from the 
collection time to isolate the upper plasma. About 0.6 mL of the separated plasma will 
be transferred into 2 polypropylene tubes (one for analysis, one as back-up) and stored 
in a freezer set at 
 until they are ready to be transferred to the Analytical 
Facility. 
6) Transportation of Pharmacokinetic Samples 
Samples stored at 
 or below are transferred from the Clinical Facility to the 
Analytical Facility. At the Analytical Facility, continue to store the samples at
 
until the date of product approval by MFDS. Details of blood sample preparation, 
aliquot dispensing, sample storage and transportation shall be in accordance with 
Sample Treatment and Transfer Manual. The sample shall not be used for any purpose 
other than for this bioequivalence study and shall be discarded in consultation with the 
Sponsor after product approval. 
7) Analysis of Concentration of Metformin in Plasma 
Analysis of metformin in plasma is done by using ultraperformance liquid 
chromatography-tandem mass spectrometry (UPLC-MS/MS) (LLOQ: 20 ng/mL). After 
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validation of the analytical method is completed, the analytical method will be applied 
to the sample analysis. 
Method validation is performed in accordance with the “Guideline on Bioanalytical 
Method Validation” (MFDS, December 2013). 
Reanalysis should be completed before the pharmacokinetic analysis or statistical 
analysis. Sample reanalysis is performed only when the sample analysis result falls in 
the criteria specified in the 
 SOP titled “Reanalysis, Reinjection Analysis and 
Reintegration”. 
After the sample analysis is completed, Incurred Sample Reanalysis (ISR) is performed 
in accordance with ‘5. Incurred Sample Reanalysis’ of the “Guideline on Bioanalytical 
Method Validation” (MFDS, December 2013) and Standard Operating Procedure of 
 
8.6 
Pharmacodynamics 
Not applicable. 
8.10.1 
Screening 
 
Written informed consent is obtained from the participant. 
 
Demographic information (gender, age, height, weight and BMI) 
Height and weight will be measured to one decimal place, and BMI shall be 
rounded to 1 decimal from 2 decimal places.. 
 
Vital signs: Blood pressure (sitting position), pulse rate (measured after taking 
rest for more than 5 minutes), body temperature (eardrum) 
 
Interview: Drinking and smoking history, caffeine consumption, allergy, 
hypersensitivity, blood donation, etc. 
 
Previous medication 
 
Medical history:  
Liver biliary system, kidneys, digestive system, respiratory system, blood/ tumor 
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system, endocrine system, genitourinary system, neuropsychiatric system, 
musculoskeletal 
system, 
skin/ 
mucous 
membrane, 
immune 
system, 
nasopharyngeal system, ophthalmology system, cardiovascular system, operation, 
others, etc. are investigated. 
 
12-lead ECG 
 
Physical examination 
 
Clinical laboratory tests: blood and urine collection for clinical laboratory tests 
as listed in Appendix 6 after at least 4 hours of fasting 
 
Drug Screening (urine sample) 
 
Alcohol test (breath test) 
 
For female participants, pregnancy test (serum) 
 
Confirmation of inclusion and exclusion criteria 
8.10.2 
Clinic Day -1 (Period 1 and Period 2) 
Participants should admit to the Clinical Facility until about 3 to 5 pm on Day -1 of 
administration of study interventions and remain in the Clinical Facility until they are 
discharged at 32 hours post administration of each Period. After the admission of participants, 
the following activities are performed. 
 
Introduction of activities and schedule 
 
Recheck of inclusion and exclusion criteria 
 
Confirmation of prior medication use (Period 1), concomitant medication (Period 
2) and adverse events 
 
A brief physical examination 
 
Blood sample collection for admission day assessment (Clinical chemistry: 
AST(GOT), ALT(GPT), γ-GT, UN, Cr, eGFR with MDRD, Lactic acid). Based 
on the result of admission day assessments, participants that the Principal 
Investigator (or delegated investigators) considers to be ineligible for participation 
in the study are excluded from the study 
 
For female participants, serum sample collection for pregnancy test 
 
Drug Screening(urine sample) 
 
Alcohol test (breath test) 
Based on the results of the pregnancy, drug and alcohol tests, participants who do 
not fulfill eligibility criteria are excluded from the study 
 
Dinner at around 6 pm 
 
Randomization of Part 1 and 2 respectively according to admission day 
assessment result (only in Period 1) 
 
The fasting status is maintained for at least 10 hours before drug administration 
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to 4 hours after administration on the next day. (Part 1: Fasted state only) 
 
The fasting status is maintained for at least 10 hours before taking high-fat diet to 
4 hours after drug administration on the next day. (Part 2: Fed state only) 
 During admission period in the Clinical Facility, intake of food and beverages is 
limited except food and beverages provided by the Clinical Facility 
 Intake of xanthine-containing beverages (coffee, green tea, cola, black tea, 
chocolate, etc.) and grapefruit juice is restricted until the final blood sample 
collection of each Period is completed 
 Intake of alcohol is restricted until Period 2 has been completed 
 Strenuous physical activity (weight training, aerobics, long distance running, etc.) 
is to be avoided from 48 hours before admission for each Period to the final 
pharmacokinetics blood sample collection 
 Restrict smoking and the use of nicotine-containing products during admission 
period 
 
Sleep at around 10:00 pm 
8.10.3 
Clinic Day 1 (Period 1 and Period 2) 
After participants wakes up in the morning, the following procedures are carried out. 
 
Measure blood pressure and pulse rate 
 
Principal Investigator (or delegated investigators) interviews participants and if 
the participant is determined ineligible to participate in the study, the participant 
will be excluded from the study 
 
Confirmation of prior medications (prior to administration of Period 1), 
concomitant medication (after administration of Period 1 and Period 2) and 
adverse events 
 
Intravenous catheter insertion for blood sample collection 
 
Blood sample collection for pre-dose pharmacokinetics analysis 
 
Limit intake of water for 1 hour before and after administration. 
 
In the case of Part 2 Fed state, participants should take all of the high-fat breakfast 
of over 900 kcal and over 35% fat from around 07:30 am within 20 minutes. If a 
participant did not take all of diet within 20 minutes, the participant shall be 
dropped out at the discretion of the Principal Investigator (or delegated 
investigators). The difference of taking breakfast time between participants has to 
be about 1-minute interval considering the administration time 
 
Drug administration at about 08:00 am and in accordance to the description in 
‘6.4 Study Intervention Compliance’ 
 
Blood sample collection for pharmacokinetics analysis after drug administration 
- Part 1 (Fasted state): 0 (before administration), 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 
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10 and 12 hrs after administration 
- Part 2 (Fed state): 0 (before administration), 1, 2, 3, 4, 5, 5.5, 6, 6.5, 7, 8, 9, 10 
and 12 hrs after drug administration 
 
Blood Sugar Test (BST): Before blood collection at 3 and 4 hours after drug 
administration 
 
Confirmation of adverse events 
 
Lunch after blood sample collection at 4 hours after drug administration 
 
Dinner after blood sample collection at 10 hours after drug administration  
 
Sleep at around 10:00 pm 
8.10.4 
Clinic Day 2 (Period 1 and Period 2) 
After participants get up in the morning, the following procedures will be carried out. 
 
Measure blood pressure and pulse rate at 24 hours after drug administration 
 
Principal Investigator (or delegated investigators) performs physical examination 
of the participants. 
 
Confirmation of adverse events  
 
Confirmation of concomitant medication 
 
Pharmacokinetics blood sample collection at 24 hours post-drug administration 
 
Breakfast after blood sample collection at 24 hours after drug administration 
 
Lunch at around 12 pm 
 
Measure blood pressure and pulse rate at 32 hours after drug administration. 
 
Pharmacokinetics blood sample collection at 32 hours post-drug administration 
 
Return home 
- Remind participants they are prohibited from strenuous physical activity, drinking, 
restricted food and beverages intake and medication until the end of the study. 
Participant may stay at the Clinical Facility at the discretion of Principal 
Investigator (or delegated investigators) 
Observe individual participants' status throughout the study and record them in the electronic 
Case Report Form (eCRF). 
Between Period 1 and Period 2 drug administration, wash-out period of at least 7 days is set. 
Participants taking medication during the wash-out period cannot participate in the Period 2 
study. 
In the case of drop-outs, safety confirmation test may be conducted at a different schedule 
from study visits. 
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8.10.5 
End of Study Visit 
Participants will visit the Clinical Facility at 10 days ± 3 days from Day 1 of Period 2, and 
the following procedures is to be completed. 
 
Measure blood pressure, pulse rate, body temperature (eardrum) 
 
Physical examination 
 
12-lead ECG 
 
Checking for adverse events, if any. 
 
Confirmation of concomitant medication  
 
Blood and urine samples collection for clinical laboratory tests listed in 
Appendix 6 (Clinical Laboratory Tests) as part of safety confirmation test 
(serum pregnancy test for woman) 
 
9 
Statistical Considerations 
The detailed methodology for statistical analysis and summarization of the data collected in 
this study will be recorded in the Statistical Analyses Plan (SAP) that will be prepared and 
maintained by 
 
1) Demographic Information Analysis 
Demographic information such as gender, age, height, weight, and BMI of participants 
participating in the bioequivalence study will be analyzed by descriptive statistical method. 
2) Safety Evaluation Analysis 
For the participant safety evaluation, the results of the adverse events, concomitant 
medications, clinical laboratory tests, 12-lead ECG, vital signs, physical examination are 
continuously reviewed and analyzed by descriptive statistical method. 
3) 'SAS® (SAS Institute Inc. NC. USA: Ver. 9.4 or higher)' is used for the statistical 
processing of demographic information and safety evaluation analysis. 
4) Calculation of Pharmacokinetics Variables 
Using the Phoenix™ WinNonlin® 8.0 
 or higher version software, 
pharmacokinetic parameters are calculated from the data obtained by non-compartmental 
method. However, statistical processing for primary variables is performed as follows. 
 
To calculate the basic statistics, arithmetic mean is used. 
 
Average and standard deviation shall be indicated to three decimal places. 
 
If the concentration prior to administration is below the lower limit of quantification 
(BLQ), it is indicated as “0”. All other BLQ values are considered to be “blank” when 
calculating the geometric mean and “0” when calculating the arithmetic mean. 
When calculating the pharmacokinetic parameters, the concentration of BLQ in the 
curve of the rising section is entered as “0” and the concentration of BLQ in the 
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terminal phase is treated as “blank”. If the measured concentration is below the lower 
limit of quantitation, it is indicated as “BLQ (Below the limit of quantification)”. 
9.1 
Statistical Hypotheses 
The following null hypothesis for the ratio of the geometric means will be used to assess 
bioequivalence 
H0: 
µT/µR ≤ 0.8000 or 1.2500 ≤ µT/µR for at least one parameter (AUClast or Cmax) 
H1: 
0.8000 < µT/µR < 1.2500 for all parameters (AUClast and Cmax) 
where µT and µR are the geometric means for the test and reference treatment respectively. 
The test treatment is Glucophage® XR Reduced Mass tablet and reference is Glucophage® 
XR tablet both under fasting condition (Part 1) or fed condition (Part 2). 
1) The comparative evaluation parameters for the bioequivalence between the Test drug 
and the Reference drug are the area under the plasma concentration-time curve 
(AUClast) and maximum plasma concentration (Cmax). In this case, Cmax is actually 
measured values and AUClast is a calculated value by the trapezoidal rule. 
2) When log transformation and statistical evaluation on comparative parameters of the 
Reference and Test drug except Tmax are performed, the 90% confidence intervals for 
the difference in mean values between the Test and Reference should be within log 
0.8 to log 1.25.  
3) In the case of drop-outs, they are excluded from statistical analysis. 
4) Separate hospitalization 
For each study of Part 1 (Fasted state) and Part 2 (Fed state), if from the first administration 
of the first group to the first administration of second group is completed within 6 weeks, the 
effect of separate hospitalization is not considered. However, if it exceeds 6 weeks when 
separate hospitalization was arranged, the interaction by separate hospitalization has to be 
confirmed as follows. 
The interaction by separate hospitalization has to use a model that sets period, sequence, 
treatment, group and group*treatment as a fixed effect and sets participant nested within 
sequence as a random effect. 
At this time, if the group*treatment is not statistically significant (if it exceeds the significance 
level of 5%), the bioequivalence is evaluated by adding group as a fixed effect, and if the 
group*treatment is statistically significant, then the bioequivalence is evaluated by adding 
group and group*treatment as fixed effects. The cause of the interaction and the effect of the 
interaction on the evaluation of bioequivalence has to be closely checked. 
9.2 
Sample Size Determination 
9.2.1 
Sample Size 
82 Healthy adult participants (Part 1: 48 participants, Part 2: 34 participants) 
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9.2.2 
Sample Size Justification 
1) Part 1: Fasted state (N=48) 
Variability estimates were obtained from the preliminary PK data (
 
[fasted] and 
 [fed]) and intra-participant variability of the major 
pharmacokinetic parameters AUClast and Cmax of metformin were about 19.1 % and 25.0%, 
respectively. Assuming a within-participant variability CV%=25%, and with an assumed 
geometric mean ratio Test/Reference (GMR T/R) of 0.95, a one-sided alpha level of 0.05, 
38 evaluable participants will be needed to provide approximately 90% power to show 
bioequivalence. Considering the drop-out rate (about 20%) during the study, 24 
participants per sequence, totally 48 participants will be recruited. 
2) Part 2: Fed state (N=34) 
Variability estimates were obtained from the preliminary PK data (
 
[fasted] and 
 [fed]) and intra-participant variability of the major 
pharmacokinetic constants AUClast and Cmax of metformin were about 13.1% and 18.7%, 
respectively. Assuming a within-participant variability CV%=18.7%, and with an assumed 
geometric mean ratio Test/Reference (GMR T/R) of 0.95, a one-sided alpha level of 0.05, 
22 evaluable participants will be needed to provide approximately 90% power to show 
bioequivalence. Considering the drop-out rate (about 35%) during the study, 17 
participants per sequence, totally 34 participants will be recruited. 
9.2.3 
Replacement of Participant 
To be prepared for participant drop-outs which may occur due to the withdrawal of consent 
prior to drug administration in Period 1, some of the volunteers who met the inclusion/ 
exclusion criteria will be placed on the waiting list. If a participant who is scheduled to be 
administered with the study intervention in Period 1 is dropped out after the assignment of a 
randomization number but prior to the 1st administration of the study intervention, a 
participant in the waiting list will replace the participant who dropped out and will have the 
same randomization number (assigned to the same planned treatment sequence). For replaced 
participants, the participant number is given according to the ‘Blinding Method’ described 
under Section 6.3.1 (Study Intervention Assignment). Participants who drop-out after drug 
administration will not be replaced. 
9.3 
Populations for Analyses 
The analysis populations are specified below. The final decision to exclude participants from 
any analysis population will be made during a data review meeting prior to database lock. 
 
Analysis Set 
Description 
All Randomized 
Demographic Information is evaluated for those participants who participate in the 
bioequivalence study (i.e., all participants who were randomized). However, the 
participants who were replaced by the stand-by participants before the first 
administration of study interventions will be excluded from the analysis. 
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Analysis Set 
Description 
Safety 
Safety is evaluated for those participants who were administered at least one dose 
of the study interventions. 
PK 
Pharmacokinetics is evaluated for those participants whose pharmacokinetics 
evaluation is possible by the completion of all planned pharmacokinetics blood 
collection schedules according to the Protocol, who do not exhibit concentrations 
exceeding 5% of the maximum plasma concentration (Cmax) of the drug in the 
pharmacokinetics sample of prior to dosing and who have valid primary endpoints 
for both treatments. 
 
9.4 
Statistical Analyses 
Details on the statistical analysis will be presented in the statistical analysis plan (SAP) that 
will be finalized prior to database lock. 
The statistical analysis will not start until all data have been corrected and checked for 
plausibility and until all necessary coding and assessments have been completed. 
All data will be evaluated as observed; no imputation method for missing values will be used. 
 
9.4.1 
Efficacy Analyses 
Not applicable 
9.4.2 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis population. Safety will be 
analyzed in a descriptive way. 
After coding of AEs according to the Medical Dictionary for Regulatory Activities (MedDRA) 
classification (Version 23.0 or higher) and assignment to a system organ class (SOC), all AEs 
recorded during the course of the study will be listed by treatment and participant number and 
tabulated by MedDRA SOC and Preferred Term (PT). 
9.4.3 
Other Analyses 
9.4.3.1 
Analysis of Primary Endpoints 
Primary Variables: AUClast and Cmax of metformin 
 An analysis of variance (ANOVA) model will be fitted for the log-transformed PK 
parameters Cmax and AUClast based on the PK analysis set. The model will include 
treatment, period, sequence, and participant within sequence as fixed effects. Treatment 
differences on the log scale will be estimated for Cmax and AUClast together with their 90% 
CIs. Point estimates and CIs will be back-transformed to the original scale for the 
comparisons. 
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The comparison will be the test treatment (Glucophage® XR Reduced Mass tablet) vs the 
reference treatment (Glucophage® XR tablet) under fasting conditions in Part 1, and under 
fed conditions in Part 2. The null hypothesis for non-bioequivalence will be rejected if the 90% 
CI for the ratio of the GeoMean lies within the interval 0.8000 to 1.2500 for all primary 
pharmacokinetic parameters. 
The primary endpoints will be descriptively analyzed and graphical displays will be prepared.  
PK analyses will be specified in the Integrated Analysis Plan finalized before database lock. 
In principle, analysis of variance shall be used at α (significance level) = 0.05. 
9.4.3.2 
Analysis of Secondary Endpoints 
Secondary Variables: AUCinf (if data allows to calculate), AUClast/AUCinf (if data allows to 
calculate), t1/2 (if data allows to calculate) and Tmax of metformin. AUCinf will be analyzed in 
the same way as the primary PK parameters. 
The secondary endpoints will be descriptively analyzed and graphical displays will be also 
prepared where appropriate. 
9.4.3.3 
Analysis of Demographic Information 
Descriptive statistics like mean, standard deviation, etc. are analyzed for demographic 
information such as gender, age, height, weight, and BMI. 
9.4.3.4 
Sequence of Analyses 
Interim analysis of data is not allowed. 
 
10 
Comparative Dissolution Test Method  
The comparative dissolution test between the Test drug and the Reference drug using the same 
lot for the bioequivalence study shall be performed in accordance with the "Standard on 
Pharmaceutical Equivalence Study" or ‘Specification and Test Method’ of manufacturer of 
test drug. The comparative evaluation is made according to the "Standard on Pharmaceutical 
Equivalence Study". 
 
11 
References  
1) Idkaidek N, Arafat T, Melhim M, Alawneh J, Hakooz N (2011) Metformin IR versus XR 
Pharmacokinetics in Humans. J Bioequiv Availab 3: 233-235. 
2) “Standard on Pharmaceutical Equivalence Study” (MFDS Notification No. 1650, 14 
October 2020). 
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12 
Appendices 
 
 
 
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Appendix 1 
Abbreviations  
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT(GPT) 
Alanine Transaminase 
AST(GOT) 
Aspartate Transaminase 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
BP 
Blood Pressure 
(B)UN 
(Blood) Urea Nitrogen 
CTFG 
Clinical Trial Facilitation Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
ECG 
Electrocardiogram 
γ-GT 
Gamma Glutamyl Transpeptidase 
HBs Ag 
Hepatitis B Surface Antigen 
HCG 
Human Chorionic Gonadotropin 
HCV Ab 
Hepatitis C Virus Antibody 
Anti-HIV 
Human Immunodeficiency Virus Antibody 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
ISR 
Incurred Sample Reanalysis 
IRB 
Institutional Review Board 
KGCP 
Korea Good Clinical Practice 
PEAE 
Pre-Existing Adverse Event 
PK 
Pharmacokinetics 
LEU 
Leukocyte 
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MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFDS 
Ministry of Food and Drug Safety 
RBC 
Red Blood Cell 
RM 
Reduces Mass 
RPR Ab 
Rapid Plasma Reagin Antibody 
SAE 
Serious Adverse Event 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
T2DM 
Type 2 Diabetes Mellitus 
TEAE 
Treatment-Emergent Adverse Event 
Vent. Rate 
Ventricular Rate. The number of times the main pumping portion of 
the heart beats in a minute. 
WBC 
White Blood Cell 
WOCBP 
Women of Childbearing Potential 
XR 
Extended Release 
 
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Appendix 2 
Study Governance 
Financial Disclosure 
Principal Investigator and Sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information, as requested, for the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. This 
information is required during the study and for 1 year after completion of the study. 
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. 
 Participants or their legally authorized representative will be required to sign a 
statement of informed consent that meets all applicable requirements. 
 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. 
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 Following documents will be submitted for the protection of personal information.  
* Consent Form for Collection and Use of Personal Information (Fasted state) 
         * Consent Form for Collection and Use of Personal Information (Fed state) 
Study Administrative 
 The Principal Investigator listed on the title page represents all Investigators for decisions 
and discussions on this study, per ICH GCP and Korean Prime Minister Ordinance on 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. 
 The study will appear in the following clinical studies registries:  
o Korean Drug Regulating Authority (MFDS) Clinical Trials Database 
o ClinicalTrials.gov  
 Details of structures and associated procedures will be defined in a separate SOP of Clinical 
Facility. 
 Study monitoring, pharmacokinetic analysis, design and setting of eCRF, data management, 
statistical analysis and medical writing (Clinical Study Protocol & Report) are 
responsibilities of the CRO, 
, Ltd under the supervision of the Sponsor 
 Recruiting participants, management and administration of study interventions to 
participants, observation/ recording/ follow-up of AEs, blood sample collection for 
pharmacokinetics, clinical laboratory tests, ECG measurements and entry to the eCRF are 
the responsibilities of the clinic site, Clinical Trials Center of Chungnam National 
University Hospital. 
 Supply of the study interventions, drug safety reporting to Health Authorities and study 
oversight are responsibilities of the Sponsor. 
Non-Compliance of Protocol 
 Principal Investigator and sub-investigators should be fully acquainted with the protocol 
and implement it thoroughly enough to avoid non-compliance to the protocol. If a study 
protocol violation occurs inevitably, it should be reported to the IRB. 
 If the occurrence of protocol non-compliance is determined to have a significant effect 
on the interpretation of study result, the participant is excluded from the 
pharmacokinetics analysis in principle. However, it is not limited to the following 
reasons: 
 Medical history that may affect the evaluation of the pharmacokinetics was newly 
found during the study 
 Concomitant administration of prohibited medication(s) that can affect the 
pharmacokinetics properties of the study intervention 
 Wrong type, dosage or usage of the administered study intervention 
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 For minor protocol non-compliance that is not expected to affect the interpretation of 
study result, non-compliant action and its reasons are recorded in the source document. 
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 Good Clinical Practice (GCP) Guidelines 
 Annex 4 Good Clinical Practice “Regulation on Safety of Medicinal Products, etc.” 
(Ordinance of the Prime Minister No. 1650, 14 October 2020) 
 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 
ICH guidelines, the IRB/IEC, and all other applicable local regulations, i.e. Korean 
regulation for clinical studies 
 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. 
 Measures to Protect Safety of Participants: 
The Principal Investigator (or delegated investigators) is responsible for all medical 
decisions related to the bioequivalence study. The Principal Investigator should ensure that 
participants receive appropriate medical treatment for all adverse events that occurred 
during the bioequivalence study including clinically significant clinical laboratory 
abnormalities. If medical treatment is required for the participant's disease identified during 
the bioequivalence study, the Principal Investigator should notify it to the participant. The 
investigators should be well acquainted with the adverse events and precautions specified 
in the study protocol beforehand and should promptly report the Serious Adverse Events 
to the Principal Investigator when the Serious Adverse Events occur. The Principal 
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Investigator reports the occurrence of the Serious Adverse Events in accordance with the 
‘Appendix 4 (Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting)’. 
Emergency Medical Support 
 The Sponsor or designee will provide wristband 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 
the participant that may be needed to determine the course of medical treatment for the 
participant. The information on the wristbands may include the process for emergency 
unblinding (if applicable). 
 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. When the Investigator is not available, the Phase I 
facility will provide the appropriate means to contact a physician. This includes the 
provision of a 24-hour contact number at the facility, whereby the health care providers 
will be given access to an appropriate physician to assist with the medical emergency 
and to provide support for the potential unblinding of the participant concerned. The 
24-hour contact numbers of the Clinical Trials Center and PI are in the Informed 
Consent sheets; hence, the participants are informed of these numbers when they receive 
a copy of the Informed Consent. 
 During clinic days, PI or an Investigator or a physician is on-duty at the Clinical Trials 
Center for 24-hours and hence participants can contact him or her at any emergency 
case. If the Investigator is available when an event occurs, they will answer any 
questions. Any subsequent action (e.g., unblinding) will follow the standard process 
established for Investigators. 
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. 
The Sponsor will have clinical trial compensation insurance coverage for all participants 
before the start of the bioequivalence study and will compensate under the ‘Compensation 
Agreement for Victims’. 
Clinical Study Report 
After study completion, the Sponsor will write a clinical study report in consultation with 
the Principal Investigator.  
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.  
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 The Sponsor will comply with the requirements for publication of study results. Per 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by agreement. 
 Authorship will be determined by agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
Dissemination of Clinical Study Data 
 A summary of data will be provided to the MFDS Clinical Trials Database and 
ClinicalTrials.gov. 
 After completion of the study, a clinical study report will be written by the CRO under 
supervision of the Sponsor in consultation with the Principal Investigator following the 
guidance in ICH Topic E3 and will be submitted in accordance with local regulations. 
 Any and all scientific, commercial, and technical information disclosed by the Sponsor in 
this protocol or elsewhere should be considered the confidential and proprietary property 
of the Sponsor. The Investigator shall hold such information in confidence and shall not 
disclose the information to any third party except to such of the Investigator’s employees 
and staff who had been made aware that the information is confidential and who are bound 
to treat it as such and to whom disclosure is necessary to evaluate that information. The 
Investigator shall not use such information for any purpose other than for determining 
mutual interest in performing the study and, if the parties decide to proceed with the study, 
for the purpose of conducting the study. 
 The Investigator understands that the information developed from this clinical study will 
be used by the Sponsor in connection with the development of the study drug and therefore 
may be disclosed as required to other clinical investigators, to the US Food and Drug 
Administration, EMA, and to other government agencies. The Investigator also 
understands that, to allow for the use of the information derived from the clinical study, 
the Investigator has the obligation to provide the Sponsor with complete test results and all 
data developed in the study. No publication or disclosure of study results will be permitted 
except under the terms and conditions of a separate written agreement. 
 
Data Quality Assurance 
 All participant study data will be recorded on printed or electronic CRFs or transmitted 
to the Sponsor or designee electronically (e.g., laboratory data). The Investigator is 
responsible for verifying that data entries are complete, accurate, legible, and timely by 
physically or electronically signing the CRF. Details for managing CRFs are in the SOP 
of Clinical Facility. 
 The Investigator must maintain accurate documentation (source data) that supports the 
information in the CRF. 
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 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. 
 Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of non-
compliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are in the Project Management Plan. 
 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. PDF 
files of the CRFs will be provided to the Investigators at study completion. 
 Study monitors will perform ongoing source data verification to confirm that data in the 
CRF 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, the Korean Prime Minister 
ordinance on GCP, and all applicable regulatory requirements. 
 Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 15 years after study completion, unless local 
regulations, institutional policies, or the Sponsor requires a longer retention. 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. 
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 
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 Date that the participant left the study, including any reason for early withdrawal 
from the study or study intervention, 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/ EMR used for the procedure. As necessary, 
medical evaluation of these records should be performed, documented, signed and dated 
by the Investigator.  
 Data recorded on printed or electronic CRFs 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 and kept in the study file. 
 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. 
 Definition of what constitutes source data is found in Source Document Agreement. 
Study and Site Start and Closure 
First Act of Recruitment 
 The study start date is the date when the clinical study will be open for recruitment. 
 The first act of recruitment is announcement of applicants for bioequivalence study and 
will be the study start date. 
Study Closure and Site Termination 
 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 enough 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 
 If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
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organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The Investigator will promptly inform the 
participants and assure appropriate participant therapy and/or follow-up. 
 
 
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Appendix 3 
Data Management 
Records, Archives, Quality Control and Quality Assurance of Data 
To maintain the convenience and accuracy of data processing, the electronic Case Report 
Form (eCRF) from cubeCDMS®, the database system of CRScube Inc. will be used. 
The Sub-Investigators and participating researchers who are trained on the eCRF entry 
guideline can access the eCRF with their unique identification number (ID) and password 
according to the assigned eCRF access level. 
The Investigators shall accurately prepare, manage and complete the relevant documents of 
this study in accordance with KGCP (Korea Good Clinical Practice) and all relevant laws, 
regulations and rules of Korea. Bioequivalence study documents include all work logs, source 
documents, records by monitoring personnel and appointment schedules, correspondence 
between Sponsors and Investigators, and regulation documents (e.g, bioequivalence study 
protocol and its amendments, IRB correspondence, authorization/approval documents, signed 
informed consent, study interventions receipt/release records, etc.). The source document 
includes observational records, bioequivalence study activity record and all reports and 
records required for the evaluation and reconstitution of bioequivalence study. Therefore, the 
source document should include a record of treatments or similar records based on the 
bioequivalence study protocol. However, if the copy is exactly the same as the original and is 
clean and easy to read, if necessary, the copy can also be considered as a source document. 
Information on all participants is anonymized with English initials or participant numbers, 
and all participating investigators involved in this study should keep confidentiality of all 
source data and documents related to bioequivalence study results. The Principal Investigator 
keeps a copy of the participant's signed consent form and maintains a personal participant 
identification list, participant numbers with the corresponding participant names, to enable 
records to be identified. 
Entry to the eCRF should be conducted in accordance with the eCRF entry guideline (EDC 
Completion Guideline). The study data recorded in the source document are directly entered 
into the eCRF, with full audit trail for all inputs and modifications. For missing data, the 
appropriate reason should be documented. 
For the quality assurance of the bioequivalence study and for the confirmation that the 
collection, recording, and reporting of the bioequivalence study data complies with 
bioequivalence study management standards and related regulations, systematic audit shall be 
conducted. 
Details not specified in this Protocol are in accordance to 
 SOP and KGCP 
Data Management Plan 
A Data Management Plan (DMP) will be prepared. The DMP includes the description of the 
whole data management process, from the development of the eCRF, entry of bioequivalence 
study participant data, to query generation & resolution, and data locking. 
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Archive of Electronic Data 
After data management activities as described in the DMP is completed, the DM personnel 
from 
 will convert the eCRF data into PDF file format for each participant 
and delivers it to the Sponsor in a CD (or USB) format. The database containing data from 
the eCRF is backed-up according to the standards of CRScube Inc. and can only be accessed 
by the administrator. 
The data related to the study should be kept in the Clinical Facility by the archivist of the  
Clinical Facility for 15 years after the product is approved and after that, archiving and archive 
management is determined in consultation with the Sponsor. Data management activities in 
this bioequivalence study shall be conducted in accordance of the latest version of 
 
SOP. 
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Appendix 4 
Contraception 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile, as specified below. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before the first dose of study intervention, consider additional 
evaluation. 
A WOCBP is not: 
1. Premenarchal 
2. A premenopausal female with 1 of the following: 
Documented hysterectomy 
Documented bilateral salpingectomy 
Documented bilateral oophorectomy 
 
Documentation can come from the site personnel’s review of the female’s medical 
records, medical examination, or medical history interview. 
 
For a female with permanent infertility due to an alternate medical cause other than 
the above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion 
applies to determine study entry. 
3. A postmenopausal female 
A postmenopausal state 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 a female not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, more than 1 FSH measurement is 
required in the postmenopausal range. 
A female on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if she wishes 
to continue her HRT during the study. Otherwise, she must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
Contraception Guidance: 
 
 
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE: 
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Highly Effective Methods That Have Low User Dependency 
 
Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
 
Intrauterine device (IUD) 
 
Intrauterine hormone-releasing system (IUS) 
 
Bilateral tubal occlusion 
 
Vasectomized partner: a highly effective contraceptive method provided that the partner is the sole sexual 
partner of a WOCBP and the absence of sperm has been confirmed. Otherwise, use an additional highly 
effective method of contraception. The spermatogenesis cycle is approximately 90 days. 
Highly Effective Methods That Are User Dependent 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation 
 
Oral 
 
Intravaginal 
 
Transdermal 
 
Injectable 
Progestogen-only hormone contraception associated with inhibition of ovulation 
 
Oral 
 
Injectable 
Sexual abstinence: a highly effective method only if defined as refraining from intercourse during the entire 
period of risk associated with the study intervention. The reliability of sexual abstinence is evaluated in 
relation to the duration of the study. 
Acceptable Methods 
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of 
action 
 Male or female condom with or without spermicide.  Male condom and female condom cannot be used 
together (due to risk of failure with friction) 
 Cervical cap, diaphragm, or sponge with spermicide 
 A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-
barrier methods) 
Contraceptive use by men or women is consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies. 
Highly effective methods have a failure rate of <1% per year when used consistently and correctly. Typical 
use failure rates differ from those when used consistently and correctly. 
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
Acceptable methods are considered effective, but not highly effective (i.e., have a failure rate of ≥1% per 
year).  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of 
contraception. 
 
 
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Appendix 5 
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 study intervention. 
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. 
Adverse events that occurred from the time signed Informed Consent was obtained to prior 
to the administration of study interventions of Period 1 are collected as PEAE (Pre-existing 
Adverse Event) because there was no causal relationship with study interventions, and 
those that occurred after administration of study interventions are collected as TEAE 
(Treatment-Emergent Adverse Event). For TEAE (Treatment-Emergent Adverse Event), 
follow-up is performed until abnormal value of the test is normalized and symptoms are 
disappeared. 
 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 study 
intervention (including any other non-study interventions, radiation therapy, etc.) using the 
following definitions. Decisive factors for the assessment of causal relationship of an AE 
to the study intervention include, but may not be limited to, temporal relationship between 
the AE and the study intervention, known side effects of study intervention, medical history, 
concomitant medication, course of the underlying disease, and study procedures. 
Unrelated: 
Not reasonably related to the study intervention. AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention under 
study in this clinical study protocol. A reasonable alternative explanation 
must be available. 
Related: 
Reasonably related to the study intervention. AE could medically 
(pharmacologically/clinically) be attributed to the study intervention under 
study in this clinical study protocol.  
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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 study intervention discontinuation or are considered otherwise 
medically important by the Investigator. If a laboratory abnormality fulfills these criteria, 
the identified medical condition (e.g., anemia or increased ALT) 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 (Death itself is not a Serious Adverse Event, but the cause of death 
should be a Serious Adverse Event. The death should be recorded in the outcome.) 
 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 
(Hospitalization itself is not a serious adverse event, but the cause of hospitalization 
should be a serious adverse event. Hospitalization for scheduled surgery planned prior 
to bioequivalence study is not applicable (however, requires records of source 
document)) 
 Results in persistent or significant disability or incapacity (It does not necessarily mean 
only persistent. Includes situations in which daily life is impossible, such as having 
problems with walking or communicating. Even though it is mild, if it interferes with 
normal function persistently, it can be included.) 
 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 an 
study intervention is also considered an SAE, as specified below for reporting SAEs. 
Events that Do Not Meet the Definition of an SAE 
Elective hospitalizations to administer, or to simplify study intervention or procedures (e.g., 
an overnight stay to facilitate intravenous therapy) are not considered SAEs. However, all 
events leading to unplanned hospitalizations or unplanned prolongation of an elective 
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hospitalization (i.e., undesirable effects of any administered treatment) must be 
documented and reported as SAEs.  
Following cases are excluded from “Requires inpatient hospitalization or prolongs an 
existing hospitalization”. 
 Inpatient hospitalization or prolongation of existing hospitalization for diagnosis or to 
receive selective surgery for underlying disease 
 Inpatient hospitalization or prolongation of existing hospitalization to measure the 
efficacy of the bioequivalence study 
 Inpatient hospitalization or prolongation of existing hospitalization to have a scheduled 
treatment for the target disease of the bioequivalence study 
 In the case of visiting the emergency room, the case that it does not exceed 24 hours 
 Hospitalization for health checkup 
 Living environment related hospitalization that does not require medical/ surgical 
treatment 
Hospitalization 
Adverse event reported from the study in relation with the inpatient hospitalization or 
prolongation of existing hospitalization is considered to be serious. All initial 
hospitalization (though it is less than 24 hours) at the Clinical Facility meets this criteria. 
Hospitalization also includes transfer from hospital to Acute Ward/ Intensive Care Unit 
(e.g. from psychiatric ward to internal ward, from internal ward to cardiovascular intensive 
care unit, from neurology ward to tuberculosis ward). 
The followings are not classified as a hospitalization. 
 Rehabilitation facilities 
 Hospice facilities 
 Temporary protection (e.g. nurse replacement) 
 Skilled nursing facilities 
 Sanatorium 
 Regular emergency room hospitalization 
 Same-day surgery (the case surgery is performed by outpatient visit/ on the same day/ 
in a state walking is possible) 
Inpatient hospitalization or prolongation of existing hospitalization that is not related with 
clinical adverse events is not itself a serious adverse event. Examples include: 
  Hospitalization by the development of new adverse events or for the treatment of an 
existing disease that is not associated with worsening of existing disease (e.g. for the 
close examination of abnormal clinical laboratory tests values before having ongoing 
treatment) 
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 Administrative hospitalization (e.g. annual physical examination) 
 Hospitalization as specified in the protocol during the study (e.g. for the procedures 
required by the protocol) 
 Selective hospitalization not associated with sudden clinical adverse events (e.g. the 
case of selective plastic surgery) 
 Hospitalization for observation, without medical adverse events 
 Pre-planned treatment or surgical procedures should be recorded in the protocol and/ or 
individual participant document. 
 
 Events Not to Be Considered as AEs/SAEs 
Medical conditions present at the initial study visit that do not worsen in severity or 
frequency during the study are defined as baseline medical conditions, and are not to be 
considered AEs.  
Diagnostic and therapeutic noninvasive and invasive procedures such as surgery are not 
reported as adverse events. However, the medical condition for which the procedure was 
performed is reported as an adverse event if the definition of adverse events is met. For 
example, acute appendicitis that started during the reporting period of adverse events is 
reported as an adverse event and the resulted appendectomy is recorded as the treatment of 
the adverse event. 
 
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 study intervention administration time), its severity, its 
causal relationship with the study intervention, any other potential causal factors, any 
treatment given or other action taken, including dose modification or discontinuation of the 
study intervention, and its outcome. In addition, serious cases should be identified and the 
appropriate seriousness criteria documented.  
 
The Principal Investigator (or delegated investigators) has to follow-up the participant who 
developed adverse events until the symptoms disappear or the abnormal clinical laboratory 
tests are recovered into the reference range or medically sufficient explanation for the 
observed changes can be given. 
Specific guidance is in the e-CRF Completion and Monitoring Conventions provided by the 
Sponsor. Only the presence or absence of SAE is checked and recorded. There is no guidance 
for writing SAE report. 
Reporting Serious Adverse Events 
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Serious Adverse Events 
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform 
the Sponsor or its designee using the SAE report form (hard copy). 
Reporting of SAEs using a paper report form is required as a back-up method only for an EDC 
system failure. Names, addresses, and telephone and fax numbers will be included on the 
paper form. All information from the paper form must be transcribed into the electronic form 
as soon as the system becomes available. 
In exceptional circumstances, an SAE (or follow-up information) may be reported by 
telephone; in these cases, an electronic SAE report form must be completed immediately 
thereafter. 
Relevant pages from the CRF may be provided in parallel (e.g., medical history, concomitant 
drugs). Additional documents may be provided by the Investigator, if available (e.g., 
laboratory results, hospital report, autopsy report).  
The Investigator must respond to any request for follow-up information (e.g., additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for 
initial reports. This is necessary to ensure prompt assessment of the event by the Sponsor or 
designee and (as applicable) to allow the Sponsor to meet strict regulatory timelines associated 
with expedited safety reporting obligations. 
Requests for follow-up will usually be made via the study monitor, although in exceptional 
circumstances the drug safety department may contact the Investigator directly to obtain 
further information or to discuss the event. 
 
 
 
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Appendix 6 
Clinical Laboratory Tests 
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Table 1: 
Protocol-Required Clinical Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count 
WBC Count with Differential:  
 
Neutrophil (seg) (%) 
 
Lymphocyte (%) 
 
Monocyte (%) 
 
Eosinophil (%) 
 
Basophil (%) 
RBC 
Hemoglobin 
Hematocrit 
Biochemistry 
Blood Urea 
Nitrogen 
Potassium 
Aspartate Aminotransferase 
Total Bilirubin 
 
Creatinine 
Sodium 
Alanine Aminotransferase 
Total Protein 
 
Glucose 
Chloride 
Alkaline phosphatase 
Total Cholesterol 
Albumin 
Phosphorus 
Creatine Phosphokinase 
Lactic Dehydrogenase 
Uric Acid 
γ-GT 
eGFR with MDRD 
Lactic acid 
In the case of female, a pregnancy test of serum-HCG. (However, if menopause continued for 
more than 12 months or if it is infertility due to surgery, the pregnancy test can be omitted.) 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1 (Discontinuation of Study Intervention). 
Routine Urinalysis 
 
Specific gravity 
 
pH, glucose, protein, erythrocyte, ketones, bilirubin, urobilinogen, nitrite and leukocyte 
 
Color 
 
Turbidity and microscopic examination (if blood or protein is abnormal) 
Other Tests 
 
Serological tests: HBs Ag, Anti-HBc, HCV Ab, Anti-HIV 1&2 and RPR Ab 
 
Drug screening tests: THC(Tetrahydrocannabinol), OPI(Opiate), COC(Cocaine), 
MET(Methamphetamine), BAR(Barbiturates), BZO(Benzodiazepines) 
 For the Screening, all of the parameters in Table 1 will be tested. 
 For the Admission day check (Period 1 and Period 2), only clinical chemistry of 
AST(GOT), ALT(GPT), γ-GT, UN, Cr, eGFR with MDRD and Lactic acid will be tested. 
 For the Safety confirmation test of Post-Study Visit, all of the parameters in Table 1 except 
serological tests & Drug screening tests will be tested. 
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Appendix 7 
Pharmacokinetic Parameters 
 
Symbol 
Definition 
AUClast 
The area under the concentration-time curve (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. Calculated using the 
linear trapezoidal rule 
AUCinf 
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.      AUCinf = AUClast + 
Clast pred/ λz 
Cmax 
Maximum observed concentration 
λz 
Terminal first order (elimination) rate constant. Determined from the 
terminal slope of the log-transformed concentration curve using linear 
regression on terminal data points of the curve 
t1/2 
Apparent terminal half-life. t1/2  = ln (2)/λz 
tmax 
The time to reach the maximum observed concentration collected 
during a dosing interval (unless otherwise defined, take the 1st 
occurrence in case of multiple/identical Cmax values) 
AUClast/AUCinf 
The ratio of AUClast to AUCinf 
 
 
 
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Appendix 8 
Protocol Amendment History 
Protocol Version 2.0 (05-October-2020) 
This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union because it 
neither significantly impacts the safety or physical/mental integrity of participants nor the 
scientific value of the study. 
Overall Rationale for the Amendment 
Rationale Statement 
Section # and Name 
Description of Change 
Brief Rationale 
1.2 
Schema 
Sequence of Group 1 has been 
changed to RT and Group 2 to TR. 
Usual practice of site is having RT for 
Group 1and TR for Group 2.  
4.4 End of Study Definition 
“last participant last visit” has been 
changed to “ last participant last 
observation”  
To comply with KGCP requirements of 
MFDS according to the opinion of Site. 
5.1 Inclusion Criteria 
Coagulation test has been deleted 
To 
be 
consistent 
throughout 
the 
Protocol . 
5.1 Inclusion Criteria 
Added RPR Ab test. 
The site needs the participant to be 
syphilis negative. 
5.2 Exclusion Criteria 
Added 
“… 
or 
having 
other 
clinically 
relevant 
hypersensitivities.“ 
There can be other hypersensitivity in 
addition to the known hypersensitivity to 
ingredients of study interventions or 
Biguanides 
5.2 Exclusion Criteria 
“Diagnostic Assessments” has 
been moved to be located under 
“Medical Conditions” 
The site regards it would be more 
appropriate to locate it under Medical 
Conditions. 
5.3.1 Meals and Dietary 
Restrictions 
The 
phrase 
“provided 
drinks 
during high-fat meal” has been 
changed to “milk or juice in the 
course of high-fat meal”. 
The type of drinks was specified and it 
was clearly indicated that it was in the 
course of high-fat meal. 
6.1 
Study Intervention(s) 
Administration 
The 2nd and 3rd paragraphs in 
GCP Dispensing were deleted, 
and another sentence of “Detailed 
GCP Dispensing follows SOP of 
the Clinical Facility” was added 
instead. 
Detailed manual of the GCP Dispensing 
is not necessary to be presented in the 
protocol. 
6.3.1 Study Intervention 
Assignment 
Combined 
the 
sections 
[Participant 
identifier] 
and 
[Assignment 
to 
treatment 
sequence] into one section with 
content of the paragraphs remains 
the same. 
To be convenient to read. 
6.5.3 Prohibited Medicines 
Within 90 days has been changed 
to within 6 months. 
To be consistent with exclusion criterion 
14 
7.2 Participant 
Discontinuation/Withdrawal 
from the Study 
Treatment of samples from the 
withdrawn participant has been 
specified. 
Treatment 
of 
samples 
from 
the 
withdrawn participant has not been 
specified. 
8.2.3 Vital Signs 
Combined 2 phrases into 1. 
To simplify the repeated phrases. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.2.5 Clinical Safety 
Laboratory Assessments 
Detail of the Clinical Laboratory 
has been specified. 
To specify the Clinical Lab. 
8.10.2 Clinic Day -1 (Period 
1 and Period 2) 
Recheck 
of 
inclusion 
and 
exclusion criteria 
To be consistent with 1.3 Schedule of 
Activities. 
9.4.2 Safety Analyses 
From “over Version 23.0” to 
“Version 23.0 or higher” 
Current version is 23.0 and when FSFV 
takes place in December-2020, MedDRA 
will have 23.1. 
Appendix 6 Clinical 
Laboratory Tests 
Table 1 Protocol-Required 
Clinical 
Laboratory 
Assessments 
The unit of “WBC Count with 
Differential” of hematology tests 
has been simplified just to be %. 
To be consistent with the unit in the “Lab 
Normal 
Range” 
of 
the 
diagnostic 
laboratory of the site. 
2 years menopause has been 
revised to be more than 12 
months menopause 
To be consistent with Appendix 4, 
Contraception. 
Appendix 8 
Protocol 
Amendment History 
Addition of a new Appendix 8 
To follow mandatory template of the 
Sponsor. 
Protocol Version 3.0 (01-December-2020) 
This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union because it 
neither significantly impacts the safety or physical/mental integrity of participants nor the 
scientific value of the study. 
Overall Rationale for the Amendment 
Rationale Statement 
Section # and Name 
Description of Change 
Brief Rationale 
6.3.2 Blinding 
Modification according to the 
actual labelling method of the Site 
Modification according to the actual 
labelling method of the Site 
Appendix 6 Clinical 
Laboratory Tests 
Addition 
of 
“except 
Drug 
screening tests” in the “Safety 
confirmation test of Post-Study 
Visit”. 
Addition of a phrase for clarification 
Protocol Version 4.0 (08-December-2020) 
This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union because it 
neither significantly impacts the safety or physical/mental integrity of participants nor the 
scientific value of the study. 
Overall Rationale for the Amendment 
Rationale Statement 
Section # and Name 
Description of Change 
Brief Rationale 
4.1 Overall Design 
Addition of a phrase related to 
separate hospitalization 
Reflected the phrase for separate 
administration in case the recruitment of 
paticipants does not go smoothly. 
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6.4 Study Intervention 
Compliance 
Addition of a phrase related to 
participants who are subject to 
statistics 
for 
separate 
hospitalization. 
Reflected the criteria for the participants 
to whom additional statistics for separate 
hospitalization would be applied. 
Protocol Version 5.0 (04-January-2021) 
This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union because it 
neither significantly impacts the safety or physical/mental integrity of participants nor the 
scientific value of the study. 
Overall Rationale for the Amendment 
Rationale Statement 
Section # and Name 
Description of Change 
Brief Rationale 
5 Study Population 
Addition of a phrase of using 
external recruiting company by 
the request of the site. 
For smooth recruitment of participants 
using external recruiting company by the 
request of the site. 
Protocol Version 6.0 (08-July-2021) 
This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union because it 
neither significantly impacts the safety or physical/mental integrity of participants nor the 
scientific value of the study. 
Overall Rationale for the Amendment 
Rationale Statement 
Section # and Name 
Description of Change 
Brief Rationale 
4.2 Scientific Rationale for 
Study Design 
Correction of Error, Update of 
Ordinance of the Prime Minister 
No. and MFDS Notification No. 
Error Corrected. And reflected the latest 
Ordinance of the Prime Minister and 
MFDS Notification No. 
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9.1 Statistical Hypotheses 
Deletion 
of 
phrases 
due 
to 
updated 
“Standard 
on 
Pharmaceutical 
Equivalence 
Study” Notification 
Deleted the exceptions to follow the 
updated “Standard on Pharmaceutical 
Equivalence Study” Notification. 
10 Comparative Dissolution 
Test Method 
Deletion of a phrase due to 
updated 
“Standard 
on 
Pharmaceutical 
Equivalence 
Study” Notification 
Deleted the exceptions to follow the 
updated “Standard on Pharmaceutical 
Equivalence Study”  Notification. 
11 References 
Update of MFDS Notification No. 
Reflected the latest MFDS Notification 
No 
Appendix 
2 
Study 
Governance 
Update of Ordinance of the Prime 
Minister 
No. 
and 
MFDS 
Notification No. 
Reflected the latest Ordinance of the 
Prime Minister and MFDS Notification No 
Appendix 
11 
Analytical 
Project Manager Signature 
Page 
Change 
of 
Analytical 
Project 
Manager & Update of Ordinance 
of the Prime Minister No. and 
MFDS Notification No. 
Change 
according 
to 
the 
internal 
circumstances of the Analytical Facility. 
Reflected the latest Ordinance of the 
Prime Minister and MFDS Notification No 
 
 
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