Clinical trial NCT03467945
Conditions: Healthy
Keywords: Metformin Gliclazide Bioequivalence Drug-drug Interaction Pharmacokinetics
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2018-02-16; Completion date: 2018-04-29
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study investigated the bioequivalence and drug-drug interaction of Metformin/Gliclazide fixed combination tablet compared to co-administration of individual tablets of Metformin and Gliclazide.

Detailed description:

Arms: arm 1: Participants received single oral dose of metformin 1000 milligram (mg) and gliclazide 30 mg fixed combination tablet in treatment period 1 followed by concomitant oral dosing of metformin 1000 mg and gliclazide 30 mg in treatment period 2 followed by single oral dose of metformin 1000 mg in treatment period 3 and then a single oral dose of gliclazide 30 mg in treatment period 4. Each treatment period was separated by a 14-day wash-out period. arm 2: Participants received concomitant oral dosing of metformin 1000 mg and gliclazide 30 mg in treatment period 1 followed by single oral dose of gliclazide 30 mg in treatment period 2 followed by single oral dose of metformin 1000 mg and gliclazide 30 mg fixed combination tablet in treatment period 3 and then single oral dose of metformin 1000 mg in treatment period 4. Each treatment period was separated by a 14-day wash-out period. arm 3: Participants received single oral dose of metformin 1000 mg in treatment period 1 followed by single oral dose of metformin 1000 mg and gliclazide 30 mg fixed combination tablet in treatment period 2 followed by single oral dose of gliclazide 30 mg in treatment period 3 and then concomitant oral dosing of metformin 1000 mg and gliclazide 30 mg in treatment period 4. Each treatment period was separated by a 14-day wash-out period. arm 4: Participants received single oral dose of gliclazide 30 mg in treatment period 1 followed by single oral dose of metformin 1000 mg in treatment period 2 followed by concomitant oral dosing of metformin 1000 mg and gliclazide 30 mg in treatment period 3 and then single oral dose of metformin 1000 mg and gliclazide 30 mg fixed combination tablet in treatment period 4. Each treatment period was separated by a 14-day wash-out period.
Interventions: intervention 1: Metformin/Gliclazide Fixed Combination intervention 2: Metformin intervention 3: Gliclazide
Intervention descriptions: intervention 1: Participants received single oral dose of Metformin and Gliclazide fixed combination tablet in treatment period 1, 2, 3 or 4. intervention 2: Participants received single oral dose of Metformin tablet in treatment period 1, 2, 3 or 4. intervention 3: Participants received single oral dose of Gliclazide tablet in treatment period 1, 2, 3 or 4.

Protocol documents:
Prot_001.pdf: 
Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
1/79
Clinical Protocol
Protocol number
BD1412-62CEC
EMR200763-003
International non-proprietary 
name
Metformin/Gliclazide. 
Title
Randomized, Open label, Single Dose, 4 Treatment, 
4 Period, Crossover design (4 x 4) trial to evaluate the
Bioequivalence and Secondarily Drug -
Drug 
Interaction of Fixed Combination of Metformin 
Tablets 1000 mg/Gliclazide 30 mg MR, Compared 
with the Co-administration of Individual Tablets and 
Individual Administration of Each single tablet 
(Metformin 1000 mg XR and Gliclazide 30 mg MR) 
in Healthy Volunteers. 
Phase
Phase I (Bioequivalence, Drug - Drug Interaction). 
IND Number 
not applicable
EudraCT Number
not applicable
Principal Investigator
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor
Merck KGaA Darmstadt, Germany  
Address Frankfurter Strasse 250 64293 Darmstadt, 
Germany
Study Monitor
Date of elaboration and version
18/May/2017, version 1.0 
This document is property of Merck KGaA, Darmstadt, Germany, or one of its affiliates. It is for 
restricted use only and cannot - fully or partially - be transmitted, reproduced, published or used 
without express authorization of Merck KGaA, Darmstadt, Germany or its affiliate. Copyright © 
2014 by Merck KGaA, Darmstadt, Germany, or its affiliate. All rights reserved.
PPD
PPD








Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
5/79
Table of contents
Table of contents
5 
Abbreviations list 9 
1 
Summary.............................................................................................11 
Sample size calculation......................................................................................................14 
Analysis of PK parameters.................................................................................................15 
2 
Sponsor, Investigators and Study Administrative Staff......................16 
3 
Background.........................................................................................16 
3.1 
Metformin's Pharmacology.................................................................17 
3.1.1 
Metformin's Chemical Structure.........................................................17 
3.1.2 
Absorption ..........................................................................................17 
3.1.3 
Distribution.........................................................................................17 
3.1.4 
Metabolism .........................................................................................18 
3.1.5 
Excretion.............................................................................................18 
3.1.6 
Mechanism of action...........................................................................18 
3.1.7 
Pharmacological Properties ................................................................18 
3.1.8 
Adverse reactions................................................................................18 
3.2 
Gliclazide's Pharmacology .................................................................19 
3.2.1 
Gliclazide's Chemical Structure..........................................................19 
3.2.2 
Absorption ..........................................................................................20 
3.2.3 
Distribution.........................................................................................20 
3.2.4 
Metabolism .........................................................................................20 
3.2.5 
Excretion.............................................................................................20 
3.2.6 
Mechanism of action...........................................................................20 
3.2.7 
Pharmacological Properties ................................................................20 
3.2.8 
Adverse reactions................................................................................21 
4 
Adverse Reactions of the combination product 
(Metformin/Gliclazide).....................................................................22 
5 
Study Objectives.................................................................................24 
5.1 
Primary Objective...............................................................................24 
5.2 
Secondary Objectives: ........................................................................24 
6 
Statistical Hypothesis..........................................................................24 
7 
Investigational Plan ............................................................................25 


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
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7.1 
Experimental design and study plan...................................................25 
7.2 
Rationale for Study Design.................................................................26 
7.3 
Study population screening.................................................................27 
7.3.1 
Inclusion criteria:................................................................................27 
7.3.2 
Exclusion criteria:...............................................................................29 
7.3.3 
Criteria for Randomization.................................................................30 
7.3.4 
Criteria for Subject Withdrawal from trial: ........................................30 
7.4 
Start-up Criteria for Study Treatment.................................................31 
7.5 
Study Subject Withdrawal ..................................................................31 
7.5.1 
Withdrawal from the study.................................................................31 
7.6 
Study termination................................................................................32 
7.7 
End of Study Definition......................................................................32 
8 
Investigational Drug and Other Drugs Used in the Study..................33 
8.1 
Investigational Drug Description........................................................33 
8.2 
Dosage and administration .................................................................34 
8.3 
Randomization to treatment groups....................................................35 
8.4 
Selection and Dosing Schedule for Dosing for Each Subject.............35 
8.5 
Concomitant therapies and drugs........................................................36 
8.5.1 
Allowed Drugs....................................................................................36 
8.5.2 
Forbidden Drugs .................................................................................36 
8.5.3 
Other Interventions .............................................................................37 
8.5.4 
Special Warnings................................................................................37 
8.5.5 
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................37 
8.6 
Investigational Drug Packaging and Labelling...................................37 
8.7 
Preparation, Management and Storage of Study Drug .......................38 
8.8 
Study Drug Accountability.................................................................39 
8.9 
Assessment of Study Drug Compliance .............................................39 
8.10 
Method of Blinding.............................................................................39 
8.11 
Emergency Unblinding.......................................................................39 
8.12 
Overdose treatment.............................................................................40 
8.13 
Medical Care for Subjects Following the End of the Study...............42 
9 
Study Assessments and Procedures....................................................42 


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
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9.1.1 
Subjects screening ..............................................................................42 
9.1.2 
Study periods ......................................................................................43 
9.1.3 
Control of Meals and Liquid Intake....................................................44 
9.2 
Schedule of Assessments....................................................................44 
9.2.1 
First period of treatment .....................................................................45 
9.2.2 
Wash-out period..................................................................................47 
9.2.3 
Second period of treatment.................................................................47 
9.2.4 
Wash-out period..................................................................................47 
9.2.5 
Third period of treatment....................................................................47 
9.2.6 
Wash-out period..................................................................................47 
9.2.7 
Fourth period of treatment..................................................................47 
9.2.8 
End of Trial.........................................................................................48 
9.3 
Baseline demographic and other characteristics.................................48 
9.4 
Safety Assessments.............................................................................49 
9.4.1 
Adverse Event.....................................................................................49 
9.4.2 
Pregnancy and Exposure to Drugs in the Uterus................................55 
9.4.3 
Clinical Laboratory Assessments .......................................................57 
9.4.4 
Vital Signs, Physical Examinations and other Assessments ..............59 
9.5 
Pharmacokinetics................................................................................60 
9.5.1 
Body Fluids.........................................................................................61 
9.5.2 
Pharmacokinetic calculations .............................................................63 
9.6 
Statistics..............................................................................................63 
9.7 
Sample Size ........................................................................................63 
9.8 
Randomization....................................................................................64 
9.9 
Outcome variables ..............................................................................64 
9.9.1 
Main outcome variable .......................................................................64 
9.10 
Statistical Analyses Description .........................................................66 
9.11 
Extreme Values...................................................................................68 
10 
Ethical and Regulatory Issues.............................................................69 
10.1 
Principal Investigator's Responsibilities.............................................69 
10.2 
Information for the Subject and Informed Consent............................69 
10.3 
Subject's Identification and Confidentiality .......................................70 
10.4 
Medical Insurance and Subjects' Compensation.................................70 


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
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10.5 
Ethics and Investigation Committee and Investigational 
Committee...........................................................................................70 
10.6 
Health Authorities...............................................................................70 
11 
Study Management .............................................................................71 
11.1 
Case Report Form...............................................................................71 
11.2 
Source Document and Subject's Medical Chart..................................71 
11.3 
Site's File and Master File...................................................................72 
11.4 
Quality Management ..........................................................................72 
11.5 
Changes to the Protocol......................................................................72 
11.6 
Study Report and Publication Policy..................................................73 
11.6.1 
Clinical Study Report .........................................................................73 
11.6.2 
Publication..........................................................................................73 
12 
Deviations to the Protocol ..................................................................73 
13 
References...........................................................................................74 
14 
Appendices .........................................................................................76 
1. 
Appendix 1: Schedule of collecting blood samples from subjects 
and meals of the study ........................................................................77 
Appendix 2: 
Diet .....................................................................................................78 
Appendix 3: 
Drugs classification according to risks during pregnancy and 
breastfeeding (FDA) ...........................................................................79 
 


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
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Abbreviations list
A
Absorption
AE
Adverse Event
AMP
Adenosine monophosphate activated
ASA
Acetylsalicylic Acid
AUC
Area under the plasma/serum - concentration time curve
AUC0-f
Area under the plasma/serum concentration time curve from time 
zero to infinity
AUC0-t
Area under the plasma/serum concentration time curve from time 
zero to the last sampling time at which the concentration is at or 
above LLOQ
BC
Blood Chemistry
BMI
Body Mass Index
CARPERMOR
Grupo Diagnóstico Médico PROA, S.A. de C.V.
CBC
Complete Blood Count
CI
Confidence interval
Cmax
Maximum Plasma Concentration
CNFV
Mexican National Center of Pharmacovigilance
COFEPRIS
Federal Commission for the Protection against Sanitary Risks
CRF
Case Report Form
CV
Coefficient of variation
DBP
Diastolic Blood Pressure
dL
Deciliter
DPP4i
Inhibitors of dipeptidyl peptidase 4
E
Elimination
ECG
Electrocardiogram
EOT
End of Trial
FDA
Food and Drug Administration  
FDC
Fixed-dose combination  
g
Grams
GCP
Good Clinical Practice
GLP-1-RA
Glucagon like peptide-1 receptor agonists
h
Hour


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
10/79
HAV
Hepatitis A virus
HBs
Hepatitis B surface
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Conference of Harmonization
IPP
Prescribing information
ITESM
Instituto Tecnológico de Estudios Superiores de Monterrey
IUPAC
International Union of Pure and Applied Chemistry 
IV
Intravenous 
Ke
Elimination Rate Constant
L
Litre
mg
Milligram
min
Minute
mL
Milliliter
MR
Modified release
MRT
Mean Residence Time
ng
Nanogramm
pC
Plasma Concentration
PI
Principal Investigator (Study Coordinator, Clinical Unit)
PK
Pharmacokinetics
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SD
Standard Deviation
SGPT
Serum glutamic pyruvic transaminase
SOPs
Standard Operating Procedures
SUR1
Sulphonylureas receptor
t
Time
t½
Elimination Half Time
tmax
Time of peak plasma concentration
UA
Urinalysis
WOCBP
Women of childbearing potential


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
11/79
1
Summary
Protocol number 
EMR200763-003
Title
Randomized, Open label, Single Dose, 4 
Treatment, 4 Period, Crossover design (4 x 4) trial 
to evaluate the Bioequivalence and Secondarily 
Drug - Drug Interaction of Fixed Combination of 
Metformin Tablets 1000 mg/Gliclazide 30 mg 
MR, Compared with the Co-administration of 
Individual Tablets and Individual Administration 
of Each Single Tablet (Metformin 1000 mg XR 
and Gliclazide 30 mg MR) in Healthy Volunteers.
Phase 
Phase 
I 
(Bioequivalence, 
Drug 
-
Drug 
Interaction). 
IND Number 
NA
IND study 
No
Number EudraCT
NA
Principal Investigator
Sponsor
Merck KGaA 
Sponsor's legal representative at the 
European Union
Merck KGaA 
Sites/Countries
Not applicable
Scheduled study period (first subject 
and last subject)
Not applicable
Trial Registry
COFEPRIS
Objectives: 
Primary objectives
x
Demonstrate bioequivalence of the new fixed dose modified release combination for 
Metformin 1000 mg plus Gliclazide 30 mg MR compared to the concomitant 
administration of single tablets of Metformin 1000 mg XR and Gliclazide 30 mg MR.
x
Demonstrate the absence of drug interaction between the combination and the
administration of each single tablet.
Secondary objective is Clinical safety and tolerability will also be assessed.
Methodology: A randomized, open label, single dose, 4 periods, 4 treatments crossover design 
will be used with 40 subjects in fasting state with a 14-day wash-out period along 4 study 
stages.
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
12/79
Planned number of subjects: 40 healthy subjects; 20 female and 20 male
Primary endpoints:
-
To demonstrate bioequivalence of the fixed combination of Metformin tablets 1000 mg 
XR plus Gliclazide 30 mg MR compared to the co-administration of the individual 
tablets of Metformin 1000 mg XR and Gliclazide 30 mg MR, given as single dose to 
healthy volunteers in fasting state. Primary endpoints will be AUC0-t, AUC0-∞and Cmax
for Metformin and Gliclazide.
-
To demonstrate the lack of an effect of Gliclazide on the PK of Metformin by 
comparing the Metformin PK following administration of the fixed combination tablet 
Metformin/Gliclazide and Metformin alone (AUC0-t, AUC0-∞and Cmax of Metformin).
-
To demonstrate the absence of an effect of Metformin on the PK of Gliclazide by 
comparing the Gliclazide PK following administration of the fixed combination tablet 
Metformin/Gliclazide and Gliclazide alone (AUC0-t, AUC0-∞and Cmax of Gliclazide).
Secondary endpoints:
-
The secondary endpoints variable are volume of distribution Ke, half-life elimination, 
clearance, and median residence time all these parameters will be presented only for 
informative reasons for both medications.
-
To compare the safety and tolerability of all the experimental treatments.
Pharmacokinetic parameters: 
Primary endpoints will be AUC0-t, AUC0-∞and Cmax for Metformin and Gliclazide.
Other assessments: To assess clinical safety (vital signs, ECGs, lab data, physical 
examinations) and tolerability for all experimental treatments through adverse event report and 
the effect of Metformin on Gliclazide PK and vice versa.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
13/79
Diagnoses and key inclusion and exclusion criteria:  
Inclusion criteria:
1. Subject has given written informed consent before any study-related activities are 
carried out
2. Ethnic origin: Mexicans (e.g. Caucasians, Indigenous peoples and Mestizos)
3. Age between 18 and 55 years old, inclusive.
4. Female and male subjects (at least 30% of each gender).
5. Weight between 55 and 95 kg.
6. Body mass index between 18.5 and 27 kg/m2.
7. Not smoking more than 5 cigarettes or 1 cigar or 1 pipe per day (or non smokers).
8. Good physical and mental health status, determined on the basis of the medical history 
and physical examination.
9. Vital signs (blood pressure and pulse) in supine position within the normal range or 
showing no clinically relevant deviation as judged by the Investigator.
10.Electrocardiogram recording (12-lead) without signs of clinically relevant pathology in 
particular QTc (Bazett) <450 ms.
11. All values for biochemistry and hematology tests of blood and urine within the normal 
range or showing no clinically relevant deviation as judged by the Investigator.
12. All women of childbearing potential (WOCBP) are not nursing, are not pregnant, and 
are using highly effective methods of birth control (defined as those, alone or in 
combination, that result in a low failure rate (i.e., less than 1 percent per year) when 
used consistently and correctly) for a period of at least one month before and after 
dosing. Standard birth control methods are considered to be: barrier methods and 
intra-uterine devices. Female volunteers may also be enrolled if they are 
postmenopausal (i.e. at least 12 consecutive months of amenorrhea after the last 
menstrual period) or surgically sterilized/ hysterectomized at least 6 months prior to 
study participation.
13.All women of childbearing potential must have negative tests for pregnancy (qualitative 
and quantitative) at screening, and at day -1 for each treatment period and at EOT as 
described in section 9.4.3.
14.Negative screen for alcohol and drugs of abuse (opiate class, barbiturates, cocaine and 
metabolites, 
amphetamines, 
cannabinoids, 
benzodiazepines 
and 
tricyclic 
antidepressants) at Screening and on each admission.
15.Negative screen for HBs antigens, HCV antibodies, HAV antibodies and HIV 1 and 2 
antibodies.
Exclusion criteria:
Subjects are not eligible for this study if they fulfill one or more of the following exclusion 
criteria:
1. Participation in a clinical trial within 90 days prior to first drug administration.
2. Subjects who have donated more than 500 mL of blood or who have lost significantly 
(more than 450 mL) blood within 90 days prior to first drug of administration.
3. Any surgical or medical condition, including findings in the medical history or in the 
pre-study assessments, or any other significant disease, that in the opinion of the 


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
14/79
investigator, constitutes a risk or a contraindication for the participation of the subject 
in the study or that could interfere with the study objectives, conduct or evaluation.
4. History of surgery of the gastrointestinal tract which could influence the gastrointestinal 
absorption and/or motility according to the Investigator’s opinion.
5. Allergy: ascertained or presumptive hypersensitivity to the active drug substance and/or 
formulations’ ingredients; history of anaphylaxis to drugs or allergic reactions in 
general, which the Investigator considers may affect the outcome of the trial.
6. Receipt of any prescription or non-prescription medication within 2 weeks before the 
first study drug administration, including multivitamins and herbal products (e.g. St 
John’s Wort), including ASA, and hormonal contraceptives in females.
7. Renal failure or renal dysfunction (creatinine clearance <80 mL/min) as assessed by 
using the estimated measure with the Cockcroft-Gault formula.
8. Known lack of subject compliance or inability to communicate or cooperate with the 
Investigator (e.g. language problem, poor mental status).
9. Considerable diet deviations from normal nutritional patterns.
10. Consumption of large quantities of methylxanthine-containing beverages (more than 
600 mg caffeine / day: one cup (240 mL) of coffee contains approx. 100 mg of caffeine, 
one cup of tea ~ 30 mg and one glass of cola ~ 20 mg caffeine).
11. Consumption of grapefruit, orange, cranberry or juices of these fruits, 14 days prior to 
drug administration and during the study.
12. Legal incapacity or limited legal capacity.
13. Subjects kept in detention.
Study drug: dosage/route/dosing schedule: 
Treatment 1: dosing of fixed combination of Metformin 1000 mg and Gliclazide 30 mg MR 
(single oral dose of one tablet).
Reference drug: dosage/route/dosing schedule: 
Treatment 2: concomitant oral dosing of one tablet of Metformin 1000 mg XR and one tablet 
of Gliclazide 30 mg MR 
Treatment 3: single oral administration of one tablet of Metformin 1000 mg XR                         
Treatment 4: single oral administration of one tablet of Gliclazide 30 mg MR.
Study duration: approximately 18 weeks: eight weeks for screening phase, eight weeks 
approximately for conduct phase, 14 days for washout period between our periods, followed 
by 2 weeks of clinical follow-up.
Duration per subject: approximately 80 days (up to 30 days SCR, 3 periods a 14 days and 8 
days for EOS).
Statistical methods (includes sample size calculation):
Sample size calculation
The sample size estimation is based on the CVintrasubject variability of both drugs. Because 
the pharmacokinetic and drug-drug interaction, evaluates changes in the bioavailability, the 
propose is the use the same determination for both aims. 
The sample size is determined by the greatest variability under fasting conditions, AUC0-t of 
Metformin (CV=23%). Assuming a mean treatment ratio of 0.95, and aiming at a power of 
90% for the individual test, alpha=0.05 one-sided, 32 evaluable subjects are needed to
demonstrate bioequivalence.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
15/79
The same arguments can be applied to evaluate the absence of an effect of Gliclazide on the 
PK of Metformin, whereas the power for the third test is close to 100% with 32 subjects, due 
to the low variability of Gliclazide PK. Therefore, the overall power is still greater than 80% 
with 32 evaluable subjects. Considering a drop-out rate of approximately 20%, 40 subjects 
should be randomized.
Analysis of PK parameters
Bioequivalence test methodology will be used in all 3 steps:
Bioequivalence in step1:
A mixed model will be applied to log-transformed Cmax, AUC0-t and AUC0-∞(both analytes) 
with treatment, period and sequence as fixed effects, and subject (sequence) as a random effect.
Based on the residual error term 90% confidence intervals will be computed for the estimated
differences Test – Reference, resulting in 90% confidence intervals for the Test/Reference 
ratios after back-transformation. 
Drug-rug interaction in steps 2 and 3:
A mixed model will be applied to log-transformed Cmax, AUC0-t and AUC0-∞(one analyte) 
with treatment as fixed effect, and subject as a random effect. Based on the residual error term 
90% confidence intervals will be computed for the estimated differences Test – Reference, 
resulting in 90% confidence intervals for the Test/Reference ratios after back-transformation. 
1.
Bioequivalence will be concluded, if all six 90% CIs for all six primary endpoints 
reside within the acceptance range [0.80 – 1.25]
2.
Absence of an effect of Gliclazide on the PK of Metformin will be concluded, if all
three 90% CIs for Metformin endpoints reside within the range [0.80 – 1.25]
3.
Absence of an effect of Metformin on the PK of Gliclazide will be concluded, if all  
three 90% CIs for Gliclazide endpoints reside within the range [0.80 – 1.25]
Additionally, the primary endpoints will be descriptively analyzed and graphical displays 
(Box-whiskers-plots) will be prepared.
All other PK endpoints will be analyzed using descriptive methods. Graphical displays will be 
also prepared where appropriate (Concentration-time profiles individual and average will be 
display for each drug).
Analysis of safety parameters
All safety parameters will be analyzed descriptively.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
16/79
2
Sponsor, Investigators and Study Administrative Staff 
The study will be sponsored by: 
x Merck KGaA. Address Frankfurter Strasse 250 64293 Darmstadt, Germany
The study will be conducted in one single site, 
.
Principal Investigator, 
 from the
, represents all investigators with regards to decisions and 
discussions related to the study according to International Conference on Harmonization (ICH), 
topic E6 from the Good Clinical Practice (GCP, referred as ICH GCP in the following.) The
Principal Investigator will provide expert physicians and advice with regards to the trial design 
and conduct. She is responsible for review and approval of the clinical study report. 
This protocol meets requirements of current clinical research regulations, including: ICH GCP, 
ethical principles for clinical research in human beings from the Declaration of Helsinki issued in 
the 64th General Assembly from the World Medical Association, Fortaleza, Brazil, October 2013; 
General Health Act and General Health Act Regulations in the field of Health Research.  
The study will be listed in the following registries for clinical trials: National Registry for Clinical 
Trials from the Mexican Ministry of Health through the Federal Commission for the Protection 
against Sanitary Risks.
x Study Monitor: 
3
Background
This study will be conducted according to the provisions stated in NOM 177-SSA1-2013 which 
states that "tests and procedures to prove that the drug is interchangeable as well as the 
requirements which authorized third parties, performing tests, should adhere", including the Good 
Clinical Practice (GCPs), ICH and all other applicable regulations. 
According to the General Health Act Regulations in the field of health research, second title, 
chapter I, article 17, section III which was published on the Official Gazette on April 2nd, 2014 
this study is considered an investigational study with risk higher than minimum.  
Based on the non-clinical and clinical data available so far, the conduct of the trial specified in this 
clinical protocol is justified.
PPD
PPD
PPD
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
17/79
3.1
Metformin's Pharmacology
3.1.1
Metformin's Chemical Structure
Systematic name as per IUPAC for Metformin is N,N-dimethylmidodicarbonimidicyl Diamide. 
Metformin empiric formula is: C4H11N5. Metformin's molecular weight is 129.164 g/mol and 
Metformin hydrochloride is 165.63 g/mol (Pubchem, 2015.)
Figure 1. – Metformin
3.1.2
Absorption
Metformin's apparent distribution volume (V/F) following oral single dose of Metformin 
hydrochloride 850 mg tablets averaged 654 ± 358 L. Metformin is negligibly bound to plasma 
proteins in contrast to sulphonylureas which are more than 90 % to protein bound. Erythrocytes 
seem to represent the secondary distribution compartment. At usual clinical doses of Metformin 
hydrochloride, plasma concentration in steady state is achieved within 24 - 48 h and generally are 
< 1 mg/mL (Green and Feinglos, 2008, Cho, 2002). After an oral dose of Metformin XR 500 mg 
tablet, the Tmax was 7 hours and Cmax 645 (115) ng/mL.
3.1.3
Distribution
Maximum concentrations are lower in blood than in plasma and are achieved approximately 
simultaneously. Erythrocytes seem to represent the secondary distribution compartment. Mean 
distribution volume is between 63 a 276 L. 
It is quickly distributed to tissues and peripheral body fluids. It is slowly distributed in erythrocytes 
and in a deep tissue compartment (Pentikainen et al., 1979).


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
18/79
3.1.4
Metabolism
Metformin does not undergo liver metabolism; however, following i.v. dosing, 20 % of dose is not 
recovered in urine. Therefore, some kind of transformation is suggested but no metabolites or 
conjugated compounds have been identified; although, hydroxylation might be a route, as in case 
of phenformin (Green and Feinglos, 2008).
3.1.5
Excretion
Metformin renal clearance is > 400 mL/min, which shows that Metformin is cleared by glomerular 
filtration and tubular secretion. Following oral dosing, elimination half-life is approximately 6.5 h 
(Green and Feinglos, 2008; Zhong et al., 2005).
3.1.6
Mechanism of action
Metformin reduces blood glucose concentrations by means of two mechanisms; the first one 
reduces glucose output by liver and the second one increases insulin effects on muscle and fat. At 
a molecular level, these actions are partially mediated by AMP activated protein kinase (AMP 
kinase) cellular activation. Mechanisms by means Metformin reduces glucose concentrations are 
controversial; but most of the data indicate that it reduces gluconeogenesis.  
Another mechanism is reduction of glucose absorption from gut, but it does not seem to have 
clinical significance (Goodarzi et al., 2005; Hundal and Inzuchi, 2003; Ristic et al., 2007).  
3.1.7
Pharmacological Properties
Throughout Metformin's chronic treatment, vitamin B12, folates and calcium supplements 
intestinal absorption revert Metformin's effects on vitamin B12. Maximum effective dose is 2.5 g 
a day. 
Metformin reduces A1c hemoglobin approximately by 2 %, much the same as sulphonylureas. It 
does not promote weight gain and reduces triglycerides concentrations between 15 % and 20 %. 
There is a consensus about reduction of microvascular complications by A1c hemoglobin 
reduction with any therapy (insulin or oral agents); however, only Metformin has shown to reduce 
cardiovascular events in Type 2 Diabetes Mellitus (Turner et al., 1999; Galeone et al., 1998).
3.1.8
Adverse reactions 
Following adverse reaction may occur with Metformin treatment: taste impairment (dysgeusia), 
nausea, vomiting, diarrhea, anorexia, abdominal pain and loss of appetite (CCSI V7 for Metformin 
hydrochloride).
The following definitions apply to the frequency terminology used hereafter: Very common (≥ 
1/10); Common (≥ 1/100, < 1/10); Uncommon (≥ 1/1,000, < 1/100); Rare (≥ 1/10,000, < 1/1,000) 
Very rare (< 1/10,000).


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
19/79
Gastrointestinal disorders
Very common: Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and 
loss of appetite. These undesirable effects occur most frequently during initiation of therapy and 
resolve spontaneously in most cases. A slow increase of the dose may also improve gastrointestinal 
tolerability.
Skin and subcutaneous tissue disorders
Very rare: Skin reactions such as erythema, pruritus, or urticaria.
Metabolism and nutrition disorders
Very rare: Lactic acidosis.
Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of 
Metformin. Consideration of such an etiology is recommended if a patient presents with
megaloblastic anaemia.
Hepatobiliary disorders
Very rare: Liver function tests abnormalities or hepatitis resolving upon Metformin
discontinuation.
Metformin is classified as category "B", for use during pregnancy and breastfeeding according to 
the FDA (FDA, 2015).
3.2
Gliclazide's Pharmacology
3.2.1
Gliclazide's Chemical Structure
Systematic name according to the IUPAC for Gliclazide is 1-(3,3a,4,5,6,6a-hexahydro-1H-
cyclopenta[c]pyrrol-2-yl)-3-(4-methylphenyl). 
Gliclazide's empiric formula is: C15H21N3O3S. Gliclazide's molecular weight is 323.412 g/mol.
Figure 2. - Gliclazide


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
20/79
3.2.2
Absorption
It is quickly absorbed. After oral administration of Gliclazide, plasma concentrations increase 
progressively until the 6th hour, reaching plateau between the 6th and 12th hour (IPP Diamicron 
MR, 2013). Gliclazide is fully absorbed. 
3.2.3
Distribution
Gliclazide is distributed in the extracellular fluid, which causes high concentrations in the liver, 
kidneys, skin, lungs, musculoskeletal, intestines, and cardiac tissue when given to animals. 
Significant absorption in the central nervous system is unlikely. Gliclazide also crosses the
placental barrier and travels in the fetal blood stream. A low apparent distribution volume is likely 
seen in the high binding degree to proteins (approximately 94 % of a plasma concentration of 8 
mcg/mL) (Sarkar et al., 2011).  
3.2.4
Metabolism
Gliclazide is metabolized widely in the liver. Less than 1 % of given oral dose appears unchanged 
in urine. Metabolites are oxidative and hydroxylated byproducts, as well as glucuronic acid 
conjugates, enzymes involved are Cytochrome P450 2C9, Cytochrome P450 2C19. No active 
metabolites have been detected in plasma (Sarkar et al., 2011). 
3.2.5
Excretion
Approximately 70 % of the given dose is slowly cleared in urine, achieving its maximum within 7 
to 10 hours following dosing. Metabolites are detectable in urine until 120 h following dosing
(Ings et al., 1986).
Fecal clearance is approximately 11 % of the administered dose (Ings et al., 1986). Gliclazide is 
generally fully cleared 144 h following the last dose.  (Sarkar et al., 2011). Gliclazide's elimination 
half-life ranges between 12 and 20 hours (IPP Diamicron MR, 2013).
3.2.6
Mechanism of action
Gliclazide binds to the β cells (SUR1) sulphonylureas' receptor, blocking subsequently sensitive 
potassium channels ATP. Channels closure outcomes lead to the reduction in the potassium flow 
which causes β cells depolarization. This opens β cells voltage dependent calcium channels; which 
in turns, results in the calmodulin activation then leading insulin's exocytosis containing granules 
secretion (Hoich et al., 1986).      
3.2.7
Pharmacological Properties
Gliclazide is a hypoglycemic sulphonylurea, oral anti-diabetic drug which has a nitrogen 
heterocyclic ring which differentiate it from other drugs of this type. 


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
21/79
It stimulates insulin secretion from islets of Langerhans β cells. Increase of postprandial insulin 
secretion and C-peptide persists 2 years following therapy (Ristic et al., 2007).
Besides its metabolic properties, Gliclazide has hemovascular properties.
• Effect on the insulin release: In type 2 diabetes patients, Gliclazide repairs early peak of insulin 
secretion upon presence of glucose and increases the second phase of that secretion. There is a 
significant increase in the insulin's response following stimulation induced by food or glucose. 
• Hemovascular properties: Gliclazide reduces microthrombosis process by means of two 
mechanisms which might be implied in Diabetes complications:
a) Partial inhibition of platelet aggregation and adhesion with a reduction of platelet activation 
markers (beta-thromboglobulin, thromboxane B2).  
b) An effect on a vascular endothelium's fibrinolytic activity with an increase of the t-PA 
activity.  
3.2.8
Adverse reactions
They depend on the administered dose; they are transient and respond to the therapy's reduction 
and stop. 
As any other sulphonylureas, Gliclazide therapy may cause hypoglycemia. 
Possible hypoglycemic symptoms are: headache, increase appetite, nausea, vomit, tiredness, 
drowsiness, sleep disorders, restlessness, aggressiveness, reduced concentration, wakefulness and 
reaction; depression, confusion; visual and speech disorders; aphasia; tremors, paresis, sensory 
disorders, dizziness, helplessness feeling, lack of self-control, delirium, seizures, shallow 
breathing, bradycardia, drowsiness, syncope which might lead to coma and death.   
In addition, the following symptoms might be seen: sweating, anxiety, tachycardia, hypertension, 
palpitations, angina pectoris and cardiac arrhythmias.   
Gastrointestinal disorders have been reported, including abdominal pain, nausea, vomit, dyspepsia, 
diarrhea and constipation; these might be avoided if tablet is taken in fasting state. 
The following adverse reaction have been reported less frequently:
• Skin rash - mucosal sore: rash, pruritus, hives, maculopapular rash, and blisters. 
• Blood disorders: they are rare, anemia, leukopenia, thrombocytopenia, and granulocytopenia. 
These are generally reverted upon therapy stop.
• Hepatobiliary disorders: liver enzymes elevation (AST [SGOT], ALT [SGPT], and alkaline 
phosphatase), or hepatitis (isolated cases.) Therapy should be interrupted if cholestatic jaundice 
occurs. These symptoms usually disappear following treatment stop.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
22/79
• Eye disorders: visual transient discomforts may occur specially at the beginning of treatment due 
to glycemic changes. 
Gliclazide is classified as category "C", for use during pregnancy and breastfeeding according to 
the FDA (FDA, 2015).
4
Adverse 
Reactions 
of 
the 
combination 
product 
(Metformin/Gliclazide)
Hypoglycaemia
As for other sulphonylureas, Gliclazide can cause hypoglycaemia, if mealtimes are irregular and, 
in particular, if meals are skipped. Possible symptoms of hypoglycaemia are: headache, intense 
hunger, nausea, vomiting, lassitude, sleep disorders, agitation, aggression, poor concentration, 
reduced awareness and slowed reactions, depression, confusion, visual and speech disorders, 
aphasia tremor, paresis, sensory disorders, dizziness, feeling of powerlessness, loss of self-control, 
delirium, convulsions, shallow respiration, bradycardia, drowsiness and loss of consciousness, 
possibly resulting in coma and lethal outcome.
In addition, signs of adrenergic counter-regulation may be observed: sweating, clammy skin, 
anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmia.
Usually, symptoms disappear after intake of carbohydrates (sugar). However, artificial sweeteners 
have no effect. Experience with other sulphonylureas shows that hypoglycaemia can recur even 
when measures prove effective initially. If a hypoglycaemic episode is severe or prolonged, and 
even if it is temporarily controlled by intake of sugar, immediate medical treatment or even 
hospitalisation is required.
The following definitions apply to the frequency terminology used hereafter: Very common (≥ 
1/10); Common (≥ 1/100, < 1/10); Uncommon (≥ 1/1,000, < 1/100); Rare (≥ 1/10,000, < 1/1,000) 
Very rare (< 1/10,000).
Blood and lymphatic system disorders
Rare: Hematologic disturbances which may include anaemia, leucopenia, thrombocytopenia, 
granulocytopenia. These are in general reversible upon discontinuation of medication.
Metabolism and nutrition disorders
Very rare: Lactic acidosis. Decrease of vitamin B12 absorption with decrease of serum levels 
during long-term use of the fixed dose combination (Metformin/Gliclazide). Consideration of such 
etiology is recommended if a patient presents with megaloblastic anaemia.
Frequency not known: Hypoglycaemia.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
23/79
Nervous system disorders
Common: Taste disturbance.
Eye disorders 
Frequency not known: Transient visual disturbances may occur especially on initiation of 
treatment, due to changes in blood glucose levels. 
Gastrointestinal disorders
Very common: Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain, 
and loss of appetite.
Frequency not known: Constipation and dyspepsia.
These undesirable effects can be avoided or minimized if dose is increased slowly and is taken 
with breakfast.
Hepatobiliary disorders
Very rare: Liver function tests abnormalities or hepatitis resolving upon treatment discontinuation.
Discontinue treatment if cholestatic jaundice appears.
Skin and subcutaneous tissue disorders
Very rare: Skin reactions such as erythema, pruritus, or urticaria.
Frequency not known: Angioedema, maculopapular rashes, and bullous reactions (such as 
Stevens-Johnson syndrome and toxic epidermal necrolysis).
Related to sulphonylureas
Class attribution effects:
As one of the active ingredients in the fixed dose combination of Metformin and Gliclazide belongs 
to sulphonylureas, the following adverse events have been observed: cases of erythrocytopenia, 
agranulocytosis, haemolytic anaemia, pancytopenia, allergic vasculitis, hyponatremia.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
24/79
5
Study Objectives
5.1
Primary Objective
To demonstrate the bioequivalence of Metformin/Gliclazide fixed dose combination tablet 
(1000 mg /30 mg MR) compared with the co-administration of the individual tablets 
(Metformin 1000 mg XR and Gliclazide 30 mg MR), administered as single dose in fasting 
condition to healthy volunteers.
To demonstrate the absence of an effect of Gliclazide on the PK of Metformin by 
comparing the Metformin PK following administration of the fixed combination tablet 
Metformin/Gliclazide and Metformin alone (AUC0-t, AUC0-∞and Cmax of Metformin).
To demonstrate the absence of an effect of Metformin on the PK of Gliclazide by 
comparing the Gliclazide PK following administration of the fixed combination tablet 
Metformin/Gliclazide and Gliclazide alone (AUC0-t, AUC0-∞and Cmax of Gliclazide).
5.2
Secondary Objectives:
To assess clinical safety and tolerability for all experimental treatments.
6
Statistical Hypothesis 
1. Test bioequivalence of fixed combination and separate tablets
H0: μT / μR ≤ 0.8 or 1.25 ≤ μT / μR for Metformin and/or Gliclazide AUC0-t, AUC0-∞or Cmax,
or for all
H1: 0.8 < μT / μR < 1.25 for all Metformin and Gliclazide primary endpoints (i.e. AUC0-t,
AUC0-∞or Cmax)
μT and μR being the means under Test and Reference treatment, respectively.
Test treatment: 
Metformin/Gliclazide fixed dose combination tablet (1000 mg /30 mg MR).
Reference treatment:
co-administration of the individual tablets (Metformin 1000 mg XR and 
Gliclazide 30 mg MR).
Bioequivalence is confirmed if all six 90% CIs for all six primary endpoints reside within the 
acceptance range [0.80 – 1.25].


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
25/79
2. Test absence of an effect of Gliclazide on the PK of Metformin
H0: μT / μR ≤ 0.8 or 1.25 ≤ μT / μR for Metformin AUC0-t, AUC0-∞or Cmax, or for all 
H1: 0.8 < μT / μR < 1.25 for all Metformin primary endpoints (i.e. AUC0-t, AUC0-∞or Cmax)
μT and μR being the means under Test and Reference treatment, respectively.
Test treatment: 
Metformin/Gliclazide fixed dose combination tablet (1000 mg /30 mg MR).
Reference treatment:
Single administration of Metformin 1000 mg XR 
Absence of an effect of Gliclazide on the PK of Metformin will be concluded, if all three 90% CIs 
for Metformin endpoints reside within the range [0.80 – 1.25]
3. Test absence of an effect of Metformin on the PK of Gliclazide
H0: μT / μR ≤ 0.8 or 1.25 ≤ μT / μR for Gliclazide AUC0-t, AUC0-∞or Cmax, or for all 
H1: 0.8 < μT / μR < 1.25 for all Gliclazide primary endpoints (i.e. AUC0-t, AUC0-∞or Cmax)
μT and μR being the means under Test and Reference treatment, respectively.
Test treatment: 
Metformin/Gliclazide fixed dose combination tablet (1000 mg /30 mg MR).
Reference treatment:
single administration of Gliclazide 30 mg MR
Absence of an effect of Metformin on the PK of Gliclazide will be concluded, if all three 90% CIs 
for Gliclazide endpoints reside within the range [0.80 – 1.25]
7
Investigational Plan
7.1
Experimental design and study plan
This randomized, open-label, single dose, four-treatment, four period crossover design (4x4) trial
with a 14-day wash-out period along 4 study stages will investigate the bioequivalence (primary 
endpoints are AUC0-t, AUC0-∞or Cmax for Metformin and Gliclazide) of a Metformin/Gliclazide 
fixed combination tablet (1000 mg /30 mg MR) compared with the co-administration of the 
individual tablets (Metformin 1000 mg and Gliclazide 30 mg MR) and the drug-drug interaction 
between the Metformin/Gliclazide fixed combination and the administration of each single tablet,
administered in fasted condition in 40 healthy volunteers. Secondarily, safety and tolerability will 
be also investigated in every case.
The subjects will be randomized to one of the 4 treatment sequences (see table below). Ten subjects 
will be randomized to each treatment sequence with a minimum proportion of 30% for each sex 
in each treatment sequence.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
26/79
Sequence
Period 1
Wash-
out 
period
Period 2
Wash-
out 
period 
Period 3
Wash-
out 
period 
Period 4
1
Fixed 
combination 
Metformin + 
Gliclazide
Metformin
Gliclazide
2
Metformin + 
Gliclazide 
Gliclazide 
Fixed 
combination 
Metformin
3
Metformin
Fixed 
combination 
Gliclazide 
Metformin + 
Gliclazide 
4
Gliclazide
Metformin
Metformin + 
Gliclazide
Fixed 
combination 
7.2
Rationale for Study Design
As per international clinical guidelines about Type 2 Diabetes management (Diabetes Care, 2014), 
Metformin, if there are no contraindications and if this is tolerated, is the drug of choice for Type 
2 Diabetes. In the event Metformin monotherapy at the maximum tolerated dose does not maintain 
hemoglobin A1c under 7% as target for more than 3 moths, then it will be necessary to add a 
second oral agent from another pharmacological family, such as sulphonylureas, thiazolidine, 
DPP4i or GLP-1-RA. Gliclazide is a second generation sulphonylurea which offers a 
complementary mechanism of action for Metformin. 
On the other hand, there is wide experience about Metformin’s and Gliclazide's association and it 
is particularly recommended for some clinical guidelines (Treatment Algorithm for Type 2 
Diabetes, 2014) when Metformin's monotherapy is not enough to achieve treatment objectives. 
Therefore, a fix dose combination has been developed as second line therapy, in cases when 
Metformin's monotherapy has not shown satisfactory benefit/risk.  
Fixed dose combination for Metformin and Gliclazide is a generic for the existent concomitant 
administration of these two active ingredients which use is already generalized. Fixed dose 
combination has the potential advantage of making easier the therapy by reducing the number of 
individual dosage units to be taken by the patient. This simplifies therapy and may improve 
patient's compliance (Diabetes Care, 2014; Treatment Algorithm for Type 2 Diabetes, 2014.)  
In case of combinations which contain the active ingredients (as proposed in this study) and with 
a replacement indication (i.e., use in adequately controlled patients with individual products 
administered simultaneously, at the same dosage level than in the combination, but in different 
tablets), bioequivalence should be proven between free formulations combination and marketing 
formulation (fixed combination) (EMA, 2009).


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
27/79
On the other hand, international guidelines recommend that in case of new fixed combinations, it 
is necessary to assess the degree which drugs affect mutually the appropriate pharmacokinetic 
pattern (drug - drug interaction) (EMA, 2009). 
Likewise, in Mexico, the committee to assess the marketing approval for new molecules (New 
Molecules' Committee) in case of new fixed dose combinations requests evidence about the lack 
of interaction between compounds making up the combination (drug - drug interaction) 
(COFEPRIS, 2013).  
Clinical trial herein proposed is designed to achieve objectives stated by international guidelines 
as Mexico's Health Authorities in the field of bioequivalence and interactions. Although both 
objectives could be studied in two separate clinical trials (bioequivalence crossover design 2 x 2 
and a cross interaction design 3 x 3), it is deemed more efficient to combine them in a single study. 
This reduces the number of subjects exposed as well as the minimization of time and costs. 
Therefore, the purpose of this clinical trial is mainly demonstrating bioequivalence and the drug-
drug interaction of the new fixed dose combination for Metformin 1000 mg plus Gliclazide 30 mg 
MR compared to the concomitant dosage of individual tablets of Metformin 1000 mg XR and 
Gliclazide 30 mg MR. As secondary objective clinical safety and tolerability for all treatments 
used will be assessed.
7.3
Study population screening 
Only those subjects who meet all inclusion criteria and none of the exclusion criteria will be 
recruited as study subjects. Before performing any study specific assessment which is not part of 
the subject's routine health care, the Principal Investigator will make sure that the subject has 
provided his/her written consent form according to the procedure described in section 10.2, 
Subject's information and informed consent form.  
Recruitment by invitation by means of an open announcement. 
Inclusion of 40 subjects in study as per protocol's criteria.
Female and male subjects (at least 30% of each gender per treatment sequence).
7.3.1
Inclusion criteria: 
For study inclusion, all of the following criteria must be fulfilled:
1. Subject has given written informed consent before any study-related activities are carried out 
2. Ethnicity origin: Mexicans (e.g., Caucasian, Indigenous people and mestizos [mixed race]) 
3. Gender: male and female (at least 30% of each gender)
4. Age between 18 and 55 years old, inclusive.
5. Weight between 55 and 95 kg.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
28/79
6. Body mass index between 18.5 and 27 kg/m2.
7. Not smoking more than 5 cigarettes or 1 cigar or 1 pipe per day (or non smokers).
8. Good physical and mental health, determined on the basis of the medical history and a physical 
examination.
9. All results from blood chemistry, hematology, and urinalysis should be within normal ranges 
or without clinically significant deviations as per Principal Investigator's judgment.
9 Hematology complete blood count [CBC]: hematocrit and hemoglobin must be above the 
lower limit; upper limit may range up to 15 %. Remaining results, including white blood 
cells may range ± 15 %, if subject is asymptomatic.  
9 Liver Function Test (LFT), including: direct and indirect bilirubin, glutamic oxaloacetic 
transaminase (aspartate aminotransferase) and SGPT (ALT), total proteins, albumin, 
globulin and albumin/globulin ratio. Total bilirubin from 0.00 to 1.6 mg/dL, direct 
bilirubin from 0.0 to 0.4 mg/dL and indirect bilirubin from 0.0 to 1.2 mg/dL. They may 
range up to 15 % the enzyme's upper limit. Lower limit has no restriction for subjects' 
inclusion.
9 Blood chemistry (BC) including at least: glucose, urea, creatinine and uric acid. 
Asymptomatic subjects without family history of Diabetes or renal failure may be 
included with values ranging ± 15 %. 
9 Lipids panel including total cholesterol and triglycerides. Asymptomatic subjects without 
family history of dyslipidemia may be included with values ranging ± 15 %. Lower limit 
does not have restriction for subject’s inclusion. 
9 Urinalysis (UA): asymptomatic subjects without history of renal failure may be included 
with values of urinary density ranging ± 1 %. pH should be within 5 and 7. They can be 
included with albumin trace.
10. Electrocardiogram recording (12-lead) without signs of clinically relevant pathology in 
particular QTc (Bazett) <450 ms.
11. Vital signs (blood pressure and pulse) in supine position within normal ranges or showing no 
clinically relevant deviation as judged by the medical Investigator.
9 Heart rate between 50 and 100 beats per minute.
9 Respiratory rate between 12 and 20 per minute.
9 Systolic blood pressure between 80 and 129 mmHg.
9 Diastolic blood pressure between 50 and 89 mmHg.
9 Temperature between 36.0 and 37.0 °C. 


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
29/79
12. All women of child bearing potential who are not pregnant or breastfeeding and who are using
a highly effective contraceptive method (defined as those, alone or combined, which failure 
rate is low, i.e., less than 1 % a year, when used continuously and correctly) for at least one 
month before and following dosing. Barrier methods and intrauterine device are considered 
standard contraceptive methods. Hormonal methods will not be included. Post-menopausal 
women can be included (i.e., those with at least 12 consecutive months of amenorrhea 
following their last menstruation period) or surgically sterile/hysterectomy for at least 6 
months before their participation in the study. 
13. All women of childbearing potential must have negative tests for pregnancy (qualitative and 
quantitative) at screening, and at day -1 for each treatment period and at EOT as described in 
section 9.4.3
14. Negative result for oral alcohol screening at the beginning of each visit (day -1 for treatment 
period) and illegal drugs abuse (opioids, barbiturates, cocaine and its metabolites, 
amphetamines, metamphetamines, morphine, cannabinoids, benzodiazepines and tricyclic 
antidepressants), throughout the screening period and start of each one of the visits (day -1 for 
each treatment period).  
15. Serology tests negative for human immunodeficiency virus (HIV1 and HIV2 antibodies), 
hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV) and VDRL test screening. Valid for 
3 months.
7.3.2
Exclusion criteria:  
1. Participation in a clinical trial within 90 days prior to first drug administration.
2. Subjects who have donated more than 500 mL of blood or who have lost significantly 
(more than 450 mL) blood within 90 days prior to first drug of administration.
3. Any surgical or medical condition, including findings in the medical history or in the pre-
study assessments, or any other significant disease, that in the opinion of the investigator, 
constitutes a risk or a contraindication for the participation of the subject in the study or 
that could interfere with the study objectives, conduct or evaluation.
4. History of surgery of the gastrointestinal tract which could influence the gastrointestinal 
absorption and/or motility according to the Investigator’s opinion.
5. Allergy: ascertained or presumptive hypersensitivity to the active drug substance and/or 
formulations’ ingredients; history of anaphylaxis to drugs or allergic reactions in general, 
which the Investigator considers may affect the outcome of the trial.
6. Receipt of any prescription or non-prescription medication within 2 weeks before the first 
study drug administration, including multivitamins and herbal products (e.g. St John’s 
Wort), including ASA, and hormonal contraceptives in females.
7. Renal failure or renal dysfunction (creatinine clearance <80 mL/min) as assessed by using 
the estimated measure with the Cockcroft-Gault formula.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
30/79
8. Known lack of subject compliance or inability to communicate or cooperate with the 
Investigator (e.g. language problem, poor mental status).
9. Considerable diet deviations from normal nutritional patterns.
10. Consumption of large quantities of methylxanthine-containing beverages (more than 600 
mg caffeine / day: one cup (240 mL) of coffee contains approx. 100 mg of caffeine, one 
cup of tea ~ 30 mg and one glass of cola ~ 20 mg caffeine).
11. Consumption of grapefruit, orange, cranberry or juices of these fruits, 14 days prior to drug 
administration and during the study.
12. Legal incapacity or limited legal capacity.
13. Subjects kept in detention.
7.3.3
Criteria for Randomization
Eligible subjects will be rechecked at the time of admission to the study center (Day -1).
Results of the procedures performed on Day -1 as detailed Section 9.1.1, must be available prior 
to randomization. All inclusion and exclusion criteria will undergo a final verification before 
randomization.
7.3.4
Criteria for Subject Withdrawal from trial:
Subjects can be withdrawn from the study, as per the Principal Investigator's judgment, for the 
following reasons:
In case continuous participation in the trial is detrimental for subject's health, as per Investigator's 
judgment.
1. Hypertension signs and symptoms which require pharmacological treatment. 
2. Syncope or shock.
3. Severe adverse reaction.
4. Serious Adverse Event.
5. Concurrent diseases or concomitant treatments not allowed by the protocol.
6. Lack of discipline.
7. Lack of compliance with the diet.
8. Lost of two samples within absorption period or near to the Cmax.
9. If vomit occurs within therapeutic dosing interval, research subject should be withdrawn 
from the study and removed from the statistical analysis.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
31/79
10. .If any of the participant subject, during wash-out period, takes alcoholic beverages, 
smokes tobacco, has xanthines containing beverages or food (coffee, tea, cacao, chocolate, 
mate, coke drinks, etc.) grapefruit, grapes or citrus, or grilled food (charcoal) within 24 h 
prior to the recruitment in the admission phase, or using any drug known by affecting the 
study.   
11. Subjects with positive results to the drugs screening such as: amphetamines, 
benzodiazepines, cocaine, metamphetamines, morphine and tetrahydrocannabinoids.
12. Positive pregnancy test (qualitative or quantitative) following the study drug dosing.
13. All cases where the Principal Investigator judges as lack of compliance to the protocol or 
which may risk final results.
7.4
Start-up Criteria for Study Treatment 

All women of childbearing potential should test negative for pregnancy qualitative and
quantitative test at day -1 of each treatment period.

All subjects must have negative result for oral alcohol screening at SCR and at the
beginning of each visit (day -1 for treatment period) and drugs of abuse (opioids, 
barbiturates, cocaine and its metabolites, amphetamines, metamphetamines, morphine, 
cannabinoids, benzodiazepines and tricyclic antidepressants), throughout the screening 
period and start of each one of the visits (day -1 for each treatment period).
7.5
Study Subject Withdrawal
Participant subjects in the study are free to withdraw from the study at any time and they will only 
be asked to give the reason of their withdrawal. An end of study examination must be performed 
if the subject has received at least one active drug as describe in section 8.2.7. Withdrawal reason 
should be documented in the medical chart in the case report form, if known. Study drug assigned 
to the dropped subject cannot be assigned to another subject. Subjects who withdraw after at least 
one IMP administration will not be replaced. 
7.5.1
Withdrawal from the study 
A subject must be withdrawn from the study for any event which might risk subject's safety. In the 
event pregnancy tests during subjects' admission are positive, their participation will be stopped
immediately (for further procedure in case of pregnancy see section 8.5.2).
A subject should be withdrawn from the study in case of any of the following:
x
Voluntary subject's withdrawal.
x
Lost to follow-up.
x
Participation in another investigational study.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
32/79
7.6
Study termination
The clinical study can be finished or stopped early as per health authorities' request, in case of new 
safety or efficacy information posing a unfavorable risk - benefit for study subjects. The Sponsor 
may end the study in case it is no longer justified from the medical or ethical point of view; due to 
poor enrollment, due to the stop of the study drug's clinical development, withdrawal of the study 
drug or comparator from the market due to safety reasons.   
Health Authorities, Independent Ethics Committee (IEC) and Investigational Committee (IC) will 
be informed about this cancellation as per the applicable regulations.
This study can be stopped temporarily or definitively as per the Sponsor, Principal 
Investigator, or Ethics and Investigational Committee according the Ministry of Health's 
guidelines. 
Reasons can be several, among others, frequency and type of adverse events which lead to 
a considerable number of subjects to abandon the study; new information about the drug 
which affect directly subjects' safety or study conduct; or based on the Ethics and 
Investigational Committee, Investigational Committee and Ministry of Health's decision.
In case of temporal or early termination, research subjects will be immediately informed 
and an appointment will be schedule to let them know the definitive decision about the 
study course. In case of definitive termination, the Principal Investigator will inform the 
study subjects about this decision and will determine the withdrawal procedures to be 
performed.
If termination is due to the Sponsor or Principal Investigator's decision, decision between 
both of them should be documented in writing, providing the Ethics and Investigational 
Committee, the Investigational Committee and Ministry of Health with a detailed 
explanation about the temporary or definitive termination. 
Study drugs will be secured and kept, and will be disposed (return or storage) as agreed 
with the Sponsor.
7.7
End of Study Definition
The end of the trial is defined by the last contact with the last subject who participated in the trial 
(last subject last visit).


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
33/79
8
Investigational Drug and Other Drugs Used in the Study 
1. Test drug: Fixed combination for Metformin/Gliclazide.
2. Reference drug: Concomitant dosing of Metformin + Gliclazide
3. Reference drug: Dosing of Metformin alone.
4. Reference drug: Dosing of Gliclazide alone.
8.1
Investigational Drug Description
Study Sponsor will provide drugs to be administered to the subjects in each of the study visits.
International non-proprietary name: Metformin/Gliclazide.
Reference drug: Dabex® XR.
o
Dosage form: tablets
o
Quali-Quantitative Formula: each tablet contains 1000 mg of Metformin hydrochloride.
o
Manufacturer: Merck KGaA
o
Distributor: MERCK, S. A. de C. V.
o
Marketing Holder: MERCK, S. A. de C. V.
Reference drug: Diamicron MR®.
o
Dosage form: extended release tablets
o
Quali-Quantitative Formula: Each tablet contains 30 mg of Gliclazide.
o
Manufacturer: Les Laboratoires Servier Industrie
o
Distributor: Beckman Laboratories de México, S. A. de C. V. 
o
Marketing Holder: Beckman Laboratories de México, S. A. de C. V. 
Test drug: Metformin 1000 mg/Gliclazide 30 mg MR.
o
Dosage form: tablets
o
Quali-Quantitative Formula: Each tablet contains Metformin 1000 mg/Gliclazide 
30 mg MR.
o
Manufacturer: Merck, SA, Brazil.
o
Distributor: Merck, SA, Brazil. 
o
Marketing Holder: Merck, SA, Brazil. 
Dosage: Metformin 1000 mg/Gliclazide 30 mg MR. 
x
Treatment 1: dosing of fixed combination of Metformin 1000 mg/Gliclazide 30 mg MR 
(one tablet). 


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
34/79
x
Treatment 2: concomitant dosing of Metformin 1000 mg/Gliclazide 30 mg (two tablet.) 
x
Treatment 3: dosing of Metformin 1000 mg (one tablet.) 
x
Treatment 4: dosing of Gliclazide 30 mg (one tablet.)
Test drug should be imported as per the following quantities and specifications: 
Description: Fixed combination tablet of Metformin 1000 mg/Gliclazide 30 mg. 
Quantity required for each stage of the research: 11 tablets.
60 tablets for the study.
220 tablets for the finished product analysis and dissolution profile:
60 tablets as retention sample.
Manufacturer: Merck KGaA
Products importer:
Merck S.A. de C.V.
Merck LATAM 
8.2
Dosage and administration
After 10 hours of fasting conditions the dose to be used in the study will be the fixed Metformin 
XR 1000 mg/Gliclazide MR 30 mg combination as single dose of the test product or the individual 
reference products as appropriate for each period. 
PPD
PPD
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
35/79
8.3
Randomization to treatment groups 
Once it is confirmed that all inclusion criteria and none exclusion criteria have been met, subjects 
will be randomized to one of four treatment sequences. Randomization of each subject to a 
treatment sequence will occur prior to dosing on Day 1. The Investigator or delegate will allocate 
from the treatment kit stock (numbered 101-140 the next available treatment kit in a sequential, 
chronological order starting with the lowest number. Randomization will be based on a unique 
randomization list.
The Principal Investigator will perform the randomization list before the Day 1, the list will be 
generated from the Web Site Randomization.com ۦhttp://www.randomization.comۧ. Once 
obtained, the format 
"Treatment Sequence" will be developed which will 
review Quality Management according to the standard operation procedure, code: 
, 
randomizing a clinical study of interchangeability and comparability
An additional set of 12 treatment kits for possible replacers will be provided. There will be 3 
treatment kits per treatment sequence. Replacement kit numbers will be 987 to 999.The pharmacist 
will assign the open-label replacement kit according to the treatment sequence of the originally 
assigned kit.
8.4
Selection and Dosing Schedule for Dosing for Each Subject 
Forty male and female subjects will be included in this trial. Both sexes will be included with a 
minimum proportion of 30% for each sex at least 12 females and at least 12 males. 
Ten subjects will be randomized to each treatment sequence with a minimum proportion of 30% 
for each sex in each treatment sequence.
The administration of the test or reference drug will be held at morning (about 08:00 h) after the 
fasting period (minimum eight hours) and follow the randomization list. It shall be recorded in the 
Case Report Form the current time of drug administration
During each period one of the four treatments will be dosed for all subjects from 08:00 till 08:14 
h, in 8 groups of 5 subjects, with a 2-minute gap among each group for dosing and each one of the 
activities. Group’s distribution can be changed due to operational reasons, as long as there is no 
impact in the study results.
Group’s distribution, subjects and dose schedules are shown in the following table.
PPD
PPD




Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
37/79
8.5.3
Other Interventions 
Subjects who have been exposed to agents known as inducers or inhibitors of liver enzymatic 
systems, who have taken drugs potentially toxic within 30 days prior to the study start-up, who 
require any drug throughout the study, who have history of gastrointestinal tract surgery which 
might affect gastrointestinal absorption and/or motility are not allowed to participate in the study. 
8.5.4
Special Warnings  
In case of adverse events, medical staff will provide medical care required depending on the 
adverse event occurred. In case of severe eventuality, which requires hospital admission, the 
Principal Investigator or medical staff on due will request the transfer of the subject to the agreed 
hospital and will contact the external ambulance service, according to the standard operating 
procedure, code: 
Management of clinical eventualities.
8.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions 
In case of adverse events, medical staff will provide immediate medical care required depending 
on the adverse event occurred. The Principal Investigator will decide the subsequent management, 
according to the standard operating procedure, code: 
Management of clinical 
eventualities.
8.6
Investigational Drug Packaging and Labelling 
Diabex XR ® de Merck, S.A. de C.V., México
Reference drug will be provided by the Sponsor, in commercial dosage form (original primary and 
secondary packaging).
Drug will be stored in a closed package, identified with an external label containing study code 
and, if applicable, an internal label containing the study code, batch number and expiry date as 
minimum. Drug will be stored according to the product’s needs.
Reference product will be given orally at a dose of 1000 mg (one tablet) of Metformin XR, given 
with 250 mL of water. Single dose.
Diamicron® MR, Laboratorios Servier México
Reference drug will be provided by the Sponsor, in commercial dosage form (original primary and 
secondary packaging or prototype).
Drug will be stored in a closed package, identified with an external label containing study code 
and, if applicable, an internal label containing the study code, batch number and expiry date as 
minimum. Drug will be stored according to the product’s needs.
PPD
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
38/79
Reference product will be given orally at a dose of 30 mg (one table) of Gliclazide XR, given with 
250 mL of water. Single dose.
Fixed dose combination of MR Metformin 1000 mg and Gliclazide 30 mg from 
Merck, S.A., Brazil 
Reference drug will be provided by the Sponsor, in commercial dosage form (original primary and 
secondary packaging or prototype).
Drug will be stored in a closed package, identified with an external label containing study code 
and, if applicable, an internal label containing the study code, batch number and expiry date as 
minimum. Drug will be stored according to the product’s needs.
Test product will be given orally at a dose of Metformin 1000 mg/Gliclazide 30 mg (one tablet)
with 250 mL of water. Single dose.
All study drugs will be packaged and labeled according to the applicable standards and directives 
from Good Manufacturing Practices.
8.7
Preparation, Management and Storage of Study Drug 
Test and reference drugs will be received at the 
. by the Pharmacy Responsible or by the designated staff, as per 
the standard operating procedures, code: 
Receipt, use, balance and final disposition 
of the study drug. Once drugs have been identified, they will be kept by the clinical unit until they 
are administered to the subjects.
Acceptance criteria for test and reference drugs.
Complete documentation:
9 Certificate of Analysis.
o
Dosage units.
o
Content assessment.
9 Letter of Good Manufacturing Practice compliance for test and reference drug.
9 Copy of the invoice for the reference drug. 
Test drug with label compliant with the minimum requirements from NOM-072-SSA1-
2012, Labelling of Drugs and Herbal Remedies.
Enough quantity of test and reference drug.  
PPD
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
39/79
Expiry date not due at the moment of use in the clinical study.
Test and reference drug in good physical conditions.
Rejection criteria for test and reference drugs.
Blister which have been tampered.
Drug received out of the storage or transportation specifications. 
In case primary package is damaged.
Drug should be stored in a safe, dry, and locked cabinet at a temperature not higher than 25 °C 
according to the label information. 
8.8
Study Drug Accountability 
The Sponsor will ship enough quantities of the test and reference product to conduct the study and 
keep some as "retention samples" to the 
The Principal Investigator, Pharmacy Responsible or designated staff at the 
 
 will be in charge of dispensing the 
number of required doses the day of the study as well as of keeping an inventory of used and stored 
doses as retention samples, according to the standard operating procedure, code: 
Receipt, use, balance and final disposition of the study drug.
8.9
Assessment of Study Drug Compliance 
Throughout dosing period, dose, full intake and time will be checked and recorded in the 
appropriate forms, according to the standard operating procedure, code: 
Preparation 
and administration of drugs in clinical trials of interchangeability and biocomparability;
Randomization in an interchangeability and biocomparability clinical study
A subject is compliant with the treatment only if he/she completes all study periods.
8.10
Method of Blinding
Not applicable, this is an open-label trial.
8.11
Emergency Unblinding 
Not applicable, this is an open-label trial.
PPD
PPD
PPD
PPD
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
40/79
8.12
Overdose treatment 
Overdose is defined as any dose higher than the highest daily dose included in the clinical protocol 
or foreseen for a subject recruited in the study.
Even though this does not meet criteria for serious adverse event, any overdose should be recorded 
in the study drug section of the CRF and medical chart. It should be reported to the National Center 
of Pharmacovigilance (CNFV) from the Federal Commission for the Protection Against Sanitary 
Risks (COFEPRIS), according to the standard operating procedures, code: 
Adverse 
event reporting in clinical and bioavailability studies and the Mexican Official Standard for 
Setting-up and Operations of Pharmacovigilance in Mexico, NOM-220-SA1-2012 and following 
procedure listed in section 8.5.1. If the overdose caused a SAE, it has to be reported immediately 
the sponsor according to the section 10.1.1.2.
The study medication will be prepared and administered under the supervision of the Principal 
Investigator, once administered the study drug, the drug will secure again in the area of pharmacy,
which will be restricted for access.
Gliclazide overdose:
Study drug overdose may lead hypoglycemia.
Moderate symptoms of hypoglycemia without unconsciousness or neurological sign should be 
fully corrected by means of glucose administration. Observation and strict control should continue 
until the Principal Investigator is sure that the subject is not at risk anymore.
Severe hypoglycemic reactions such as coma, seizures and other neurological disorders are 
possible and they should be managed as a medical emergency which requires immediate hospital 
admission.
During the study all subjects will have their finger stick blood glucose measured (see section 8.5) 
and will be given 10 mL of concentrated glucose solution (20 to 30 %) within 1 or 2 hours 
following the dose. Glucose solution charges are not limited to these two occasions. If
hypoglycemia symptoms occur, additional glucose solution can be given. The concentrated 
glucose solution (20 to 30 %) should be given slowly, preferably through a small bore needle into 
a large vein, to minimize venous irritation.
Subject should be closely controlled, based on his condition following that episode and the 
Principal Investigator will make a decision whether subsequent control is necessary.
Metformin overdose:
Hypoglycaemia has not been seen with Metformin doses of up to 85 g, although lactic acidosis has 
occurred in such circumstances. 
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
41/79
High overdose of Metformin or concomitant risks 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 haemodialysis.
Symptoms and Management of overdose of the combination drug product (Metformin and 
Gliclazide):
Symptoms
No data are available with regard to overdose of the fixed-dose combination product.
Symptoms of a Metformin overdose
High overdose of metformin or concomitant risks may lead to lactic acidosis. Lactic acidosis is a 
medical emergency and must be treated in hospital.
Symptoms of a Gliclazide overdose
An overdose of sulphonylureas may cause hypoglycaemia.
Management
Management of a Metformin overdose:
The most effective method to remove lactate and Metformin is haemodialysis.
Management of a Gliclazide overdose:
Moderate symptoms of hypoglycaemia, without any loss of consciousness or neurological signs, 
must be corrected by carbohydrate intake, dose adjustment and/or change of diet.
If hypoglycaemia coma is diagnosed or suspected, the patient should be given a rapid i.v. injection 
of 50 mL of concentrated glucose solution (20 to 30 %). This should be followed by continuous
infusion of a more dilute glucose solution (10 %) at a rate that will maintain blood glucose levels 
above 1 g/L. Patients should be monitored closely and, depending on the patient's condition after 
this time, the doctor will decide if further monitoring is necessary.
Gliclazide is not dialyzable due to its strong binding to proteins.
 
Hypoglycaemia has not been seen with Metformin doses of up to 85 g, although lactic acidosis has
occurred in such circumstances. High overdose of Metformin or concomitant risks 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 haemodialysis (CCDS Metformin V7).


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
42/79
8.13
Medical Care for Subjects Following the End of the Study 
Subjects will sign a consent, which states that they will receive an economical compensation for 
their participation in the study. The Sponsor will pay treatment (or compensation, if applicable) 
resulting from injuries or diseases caused by their participation in the study until their resolution 
as per the clinical criteria. The Sponsor will not pay injuries caused by subject's negligence, 
irresponsible behavior or medical reasons no related to the study. 
External follow-up will be given to all subjects recruited in the study. As per the last dose of the 
drug, free appointment or telephone contact will be available as per the Principal Investigator's 
judgment, for a period equivalent to the established wash-out period.
9
Study Assessments and Procedures 
9.1.1
Subjects screening 
Screening of the subjects will take place within 30 days prior to the first administration of the trial 
medication and comprises the following:
x
Informed consent for participation in the trial,
x
Inclusion/exclusion criteria checked.
x
Demographics (including nicotine consumption, smoking history, alcohol consumption, 
intake of caffeine or xanthine-containing beverages, intake of grapefruit, orange, cranberry 
or juices of these three fruits and diet as described in Section 6.3.2)
x
Medical history and history of medications
x
Vital signs (body temperature [tympanic], as well as blood pressure (BP) and pulse rate 
after at least 5 minutes rest in supine position),
x
Physical examination (including measurement of weight and height),
x
Safety laboratory: biochemistry tests, hematological tests and urinalysis孯季宦oagulation and 
virology,季
x
A urine drug screen and alcohol breath test,
x
Serum pregnancy test (WOCBP only),
x
12-lead standard ECG (after 5 minutes rest in supine position),
AEs, concomitant medications and procedures will be continuously assessed from signature of 
informed consent to the end-of-trial examination.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
43/79
If no clinically relevant finding is made at screening and the subject satisfies all of the protocol 
inclusion criteria and none of the exclusion criteria, he/she will be considered as eligible and will 
be enrolled into the clinical trial.
Subjects who fail to meet the protocol specified criteria for dosing or who withdraw their consent 
in the screening period are considered screening failures. The following data will be recorded for 
these subjects: demographics (including age, sex, weight and height), AEs, concomitant 
medications and reason for screening failure.
9.1.2
Study periods 
At the beginning of each period, a clinical assessment consisting of an examination by apparatus 
and systems will be made in order to check if the subject remains eligible for the study. Blood will 
be taken for pregnancy tests for women of childbearing potential and urine samples for drug 
screening. Oral alcohol test will also be performed.
Subjects should inform the medical staff in charge of the study conduct about any symptom they 
might have. Likewise, medical staff will question the subjects in every study period about 
symptoms occurred since recruitment in the first period, prior and following dosing. In case they 
report any, they will be provided with care and notes will made in the appropriate documents.
During admission, subjects will be continuously monitored and an electrocardiogram will be 
performed pre-dose, during each discharge (48 h post-dose) and during the last outpatient sampling 
(168 h post-dose) at each visit. 
During each admission, blood and urine samples will be taken from subjects for safety laboratory 
tests such as hematology, blood chemistry, prothrombin time (PT) and partial thromboplastin time 
(PTT) and urinalysis. Samples will be taken pre-dose (following 10-h fasting) and at discharge (48 
h post-dose).  
Glucose measurements will be performed: at each pre-dose and 4, 12, 24, and 32 h post-dose. 
Finger stick glucose measurement (Hematoglucotest) will be made at each pre-dose and 2, 4, 8, 12 
and 24 h post-dose. 
At the end of each period and at the last outpatient sample (sample 168.00 h post-dose) a clinical 
assessment will be made. It will consist of an interview, physical examination (oral cavity 
examination, lungs, heart, abdomen and other organs, if necessary in case of symptoms), vital signs 
measurement and follow-up of adverse events. Blood and urine samples will be taken for safety 
laboratory tests such as hematology; blood chemistry, prothrombin time (PT) and partial 
thromboplastin time (PTT); and urinalysis.  
At the last visit for outpatient sampling (168.00 h post-dose) a clinical assessment will be 
performed consisting of an interview, physical examination (oral cavity examination, lungs, heart, 
abdomen and other organs, if necessary in case of symptoms). 


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
44/79
Weight and height, and vital signs will be measured; and electrocardiogram and adverse events 
follow-up will carried out. Blood samples will be taken for pregnancy tests for women of 
childbearing potential. 
For post-menopausal women (amenorrhoeic for at least one year), post-menopausal condition will 
be confirmed by means of follicle-stimulating hormone level during screening period only.
Due to operational issues, the Principal Investigator may modify start of the study (starting as per 
the dosing of study drug) for one hour, as long as there is no impact on the study results.
9.1.3
Control of Meals and Liquid Intake 
During study conduct, subjects should fast for at least 10 hours before the dosing and at least for 
4 hours following the dosing. Water is allowed ad libitum, except for the period between one hour 
prior to dosing and the first meal. 
During confinement, meals will be served as shown below. Forty five minutes (45) will be allowed 
for having meals; water consumption will not be subject to this period.
Feeding time
MEALS
DAY 0, 14, 28 
and 42
DAY 1, 15, 29 and 43
Breakfast
-----
As from 12:00 h
Lunch
-----
As from 16:00 h
Dinner
21:00 h
As from 21:00 h
Groups will be outdated by two 2 minutes between each (after dosing) for food delivery for the 
order and interval of drug administration. Food and Liquids that were not intake completely must 
be described as protocol deviation.
9.2
Schedule of Assessments 
Prior any study assessment, the Principal Investigator or designated person will obtain written 
informed consent.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
45/79
9.2.1
First period of treatment
Day- 1:
Admission the day prior to the visit for assuring 10-h fasting period.
Dinner at least 10 h before the dosing.
Subject’s eligibility will be checked again before catheter insertion and drug's dosing.
Catheter insertion (by choice, only women).
Day 1:
At 5:00 h, grooming and intake of 250 mL of water.
Between 05:20 and 06:30 h, electrocardiogram will be performed.
Post electrocardiogram the following activities will be done
x
Catheter insertion (control or "0" sampling).
x
vital signs will be measured
x
Safety laboratory tests.
x
Blood glucose determination
x
Finger stick glucose
x
Adverse events and previous medication
Randomization for the first period of treatment only
At 08:00 h, oral administration of test or reference drug with 250 mL of water at room 
temperature p.o., according to the standard operating procedure, code: 
PREPARATION AND ADMINISTRATION OF DRUGS IN INTERCHANGEABILITY 
AND BIOCOMPARABILITY CLINICAL STUDIES.
From 08:30 to 00:00 h, sampling as per the sampling schedule.
At 8:00 h, 0.5 PK sampling
At 9:00 h, 1 PK sampling
x
At 10:00 h, 2 PK sampling and Finger stick glucose
At 11:00 h, 3 PK sampling
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
46/79
At 12:00 h, 4 PK sampling and Finger stick glucose, Blood glucose determination and vital 
signs
As from 12:00 h, breakfast.
At 13:00 h, 5 PK sampling
At 14:00 h, 6 PK sampling
At 15:00 h, 7 PK sampling
At 16:00 h, 8 PK sampling and Finger stick glucose and vital signs
As from 16:00 h, lunch.
At 18:00 h, 10 PK sampling
At 20:00 h, 12 PK sampling and Finger stick glucose, Blood glucose determination and 
vital signs
As from 21:00 h, dinner.
Day 2:
At 00:00 h, 16 PK sampling
At 8:00 h, 24.0-h PK sampling, Finger stick glucose, Blood glucose determination and vital 
signs.
At 12:00 h, 28.0-h PK sampling.
At 16:00 h, 32.0-h PK sampling, Blood glucose determination and vital signs.
Day 3:
At 8:00 h, 48.0-h PK sampling, physical examination, vital signs, electrocardiogram and 
Safety laboratory
Approximately at 10:00 h, temporary discharge from the clinical unit.
Day 4
At 8:00 h, 72.0-h PK sampling.
Day 5
At 8:00 h, 96.0-h PK sampling.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
47/79
Day 6
At 8:00 h, 120.0-h PK sampling.
Day 7
At 8:00 h, 144.0-h PK sampling.
Day 8
At 8:00 h, 168.0-h PK sampling.
Approximately at 10:00 h, temporary discharge and free appointment.
9.2.2
Wash-out period
Wash-out period lasts for 14 days after administration in each period. It is intended to clear the 
prior dose before administering the next one and to fulfill with the NOM-177-SSA1-2013 criterion 
about having a period of at least 7 half-lives for the study drug.  
9.2.3
Second period of treatment
Like the First period of treatment but after 14 days
9.2.4
Wash-out period
Wash-out period lasts for 14 days after administration in each period. It is intended to clear the 
prior dose before administering the next one and to fulfill with the NOM-177-SSA1-2013 criterion 
about having a period of at least 7 half-lives for the study drug.  
9.2.5
Third period of treatment
Like the First period of treatment but after 28 days
9.2.6
Wash-out period
Wash-out period lasts for 14 days after administration in each period. It is intended to clear the 
prior dose before administering the next one and to fulfill with the NOM-177-SSA1-2013 criterion 
about having a period of at least 7 half-lives for the study drug.  
9.2.7
Fourth period of treatment
Like the First period of treatment but after 42 days


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
48/79
9.2.8
End of Trial
At 8:00 h, 168.0-h PK sampling.
interview, physical examination (oral cavity examination, lungs, heart, abdomen and other 
organs, if necessary in case of symptoms), 
Vital signs measurement and follow-up of adverse events.
Safety laboratory tests.
Weight and height will be measured;
Electrocardiogram. 
Blood samples will be taken for pregnancy tests for women of childbearing potential. 
9.3
Baseline demographic and other characteristics 
At screening, the following demographic data will be collected: date of birth, sex (gender), race, 
ethnicity
Specify any additional critical variables to be assessed such as:
x Information about previous and concomitant medications 
x Medical history data 
x Previous medication
x Weight, height and BMI
x Special diets
x For women, menstrual status, date of last menstrual period, and serum pregnancy test.
x Month prior to drug administration, nicotine consumption 
x Smoking history 
x Alcohol consumption 
x Caffeine or xanthine consumption -containing beverages, intake of grapefruit, orange, 
cranberry or juices of these three fruits, intake of food containing xanthine and usual diet.
x Physical examination, and serum virology
x Safety laboratory
x
ECG
x Vital signs 


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
49/79
9.4
Safety Assessments
Clinical safety will be assessed by means of a complete physical examination (before the study 
and 48 and 168 h post-dose). On the other hand, throughout the study, subjects will be continuously 
monitored, including vital signs measurement (baseline and 4, 8, 12, 24, 32, 48 and 168 h post-
dose) and an electrocardiogram will be performed (baseline, 48 and 168 h post-dose).
Safety by means of laboratory will be assessed by means of full laboratory tests (baseline and 48 
h post-dose in every period). In blood analyses besides glucose (baseline, 4, 12, 24, and 32 post-
dose), finger-stick glucose (Hematoglucotest) will be monitored (baseline, 2, 4, 8, 12 and 24 h 
post-dose).
Investigational drugs' safety profile will be assessed by means of the record, report and analysis of 
baseline medical conditions, including the use of drugs, smoking habits and alcohol use, adverse 
events, findings in the physical examination, including vital signs, drug abuse screening, 
pregnancy test and laboratory tests. 
Comprehensive assessment for any apparent toxicity experience by any subject should be carried 
out since informed consent signature and throughout the study. The Principal Investigator will 
report any adverse event, observed by him/her or the assigned medical staff or reported by the 
subject (see section 9.5.1.2). Reporting period for adverse events is described in section 8.4.1.3.
9.4.1
Adverse Event 
9.4.1.1
Adverse Event Definitions
Adverse Event
An adverse event is any untoward medical occurrence which may occur during drug's clinical 
research stage but which do not necessarily has a causal relation with the drug.   Therefore, an 
adverse event can be any untoward sign and symptom (including any abnormal finding in the 
laboratory tests), or condition temporarily related to the use of the drug (investigational), whether 
related or not to that product.
Adverse events associated to the use of drugs in humans, related or not to the drug, include the 
following: 
Any adverse event occurring during the use of the drug in the professional practice. 
An adverse event, which occurs because of the abuse of drug products or substances.
An adverse event, which occur following the stop of drug's intake. 
An adverse event where there is a reasonable possibility that the event occurred only as a 
consequence of the subject's participation in the study (e.g., adverse event or serious 


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
50/79
adverse event due to the stop of anti-hypertensive drugs during wash-out phase) should be 
reported as an adverse event even though this is not related to the investigational product.  
Clinical onset on any failure of the expected pharmacological action. 
In case the event meets the criteria for "serious" adverse event, it should be recorded and reported 
as that.
9.4.1.2
Adverse Event's Causality with the Investigational Product 
Adverse events' causality with study drug is a clinical decision based on all available information
at the moment of the adverse event onset.
Adverse reactions are classified according to the causality according to the following probabilistic 
categories:
A causality assessment would include:
Certain. It consists of an event (clinical onset or an abnormal result of laboratory test) 
which occurs within a reasonable period of time following the drug's administration and 
which cannot be explained by the natural condition's evolution, by any concomitant 
pathology or by other drugs dosing. Response to drug's stop should be clearly evident.
Probable. It consists of an event (clinical onset or an abnormal result of laboratory test) 
which follows a reasonable period of time following the drug's administration and which 
can hardly be related to the natural condition's evolution, concomitant pathologies or to 
other drugs dosing. A clinically reasonable response is obtained upon stop of other(s) 
drug(s).
Possible. It consists of an event (clinical onset or an abnormal result of laboratory test) 
which follows a reasonable period of time following the drug's administration and which
can hardly be related to the natural condition's evolution, concomitant pathologies or to 
other drugs dosing. There is no information available related to the suspect drug's dosing 
or this is not clear.
Suspect. It consists of a an event (clinical onset or abnormal laboratory test) which follows 
a reasonable sequence of time following the drug's dosing which makes causality unlikely 
(but not impossible). It might be explained in a reasonable way since it is part of the natural 
evolution of the condition, or it is due to the presence of concomitant pathologies or other 
drugs dosing.
Conditional - Unclassifiable It consists of an event (clinical onset or abnormal laboratory 
test result) which cannot be properly assessed since more data are required or because
additional data are still being analyzed. 


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
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Not evaluable - Unclassifiable It consists of a report which suggest that there is an adverse 
reaction which cannot be assessed since collected information is not enough or 
inconsistent. The report cannot be completed or checked.
Other factors to be considered for adverse event's causality assessment with the study drug are:
Recovery or discontinuation, relapse or rechallenge: Subject's response following stopping 
the drug or subject's response following rechallenge should be considered based on the 
usual clinical course of the corresponding event.
Response pattern known for this type of drug: Clinical/Pre-clinical
Exposure to physical and/or mental stress: Exposure to stress may produce adverse changes 
in the receptor and provide a rationale and a better explanation for the event.
Test drug's pharmacology and pharmacokinetics: Test drug's pharmacokinetic properties 
(absorption, distribution, metabolism and excretion) as well as the subject's individual 
pharmacodynamics should be considered.  
9.4.1.3
Adverse Event's Severity 
The following classification should be used.
Adverse events intensity or severity should be classified as follows:
Mild. They occur with easily tolerated signs and symptoms. They do not require treatment
or extend hospitalization, and do not necessarily require drug's discontinuation.
Moderate. They interfere with usual activities (may cause work or school absenteeism) 
without affecting patient's life directly.  They require pharmacological therapy and do not 
necessarily require the discontinuation of the drug which caused the event, reaction, or 
suspect adverse reaction. 
Severe. They interfere with usual activities (may cause work or school absenteeism).  They 
require pharmacological therapy and the discontinuation of the drug which caused the 
event, reaction, or suspect reaction.
9.4.1.4
Laboratory Abnormal Findings and other Abnormal Findings 
throughout the Study 
Abnormal laboratory findings and other abnormal findings during the study (e.g., ECG trace) 
should not reported as serious adverse events, unless they are related to clinical signs and 
symptoms, which cause treatment's discontinuation or, in the other hand, they are considered 
clinically important by the Principal Investigator. In the event laboratory abnormality meets these 
criteria, identified medical condition (for instance, anemia, and high ALT) should be reported as 
an adverse event instead of the abnormal value by itself. 


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
52/79
9.4.1.5
Unexpected Adverse Event 
An unexpected adverse event is any adverse event which specificity or severity are not foreseen in 
the most recent product's information (Investigator's Brochure - or package insert for marketed 
products). Likewise, reports which provide important information about specificity or severity of 
a known adverse event, already documented, constitute unexpected adverse events. For instance, 
any event more specific or more severe than those described in the Investigator's Brochure should 
be considered "unexpected".
9.4.1.6
Serious Adverse Event 
A serious adverse event is any unexpected medical occurrence which at any dose: 
Results in death.
It is life-threatening.
Requires hospitalization or prolongs the existing hospitalization.
Results in persistent or important disability or incapacity.
It is a congenital abnormality or birth defect.
It is clinically important event.
Some clinically important events, although they do not lead to death, are not life-threatening or 
require hospitalization, may be considered serious adverse events based on the appropriate medical 
judgment and the need of medical or surgical care to avoid the events previously mentioned in this 
definition. Examples of those medical events include: allergic bronchospam which require 
intensive care in the emergency room or at home, blood dyscrasias or seizures which require 
hospitalization, or the development of drug's dependence or abuse. 
Life-threatening means that the subject was in danger, as per Investigator's judgment, immediate 
risk of death due to the reaction when it occurred.
9.4.1.7
Adverse Event of Special Interest
Hypoglycemia is a condition characterized by abnormally low blood glucose (blood sugar) levels, 
usually less than 70 mg/dl and may be associated with the following symptoms: headache, increase 
appetite, nausea, vomit, tiredness, drowsiness, sleep disorders, restlessness, aggressiveness, 
reduced concentration, wakefulness and reaction; depression, confusion; visual and speech 
disorders; aphasia; tremors, paresis, sensory disorders, dizziness, helplessness feeling, lack of self-
control, delirium, seizures, shallow breathing, bradycardia, drowsiness, syncope which might lead 
to coma and death. Subjects will be monitored closely.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
53/79
In the event of a non-serious AESI, the investigator will complete the AESI Report Form and send 
it to the Sponsor. Names, addresses, and telephone and fax numbers for AESI reporting will be 
included on the Report Form. Serious AESIs have to be reported in an expedited manner as SAEs 
as outlined above.
9.4.1.8
Recording Methods and Adverse Events Assessment 
Any adverse event occurring during the study period should be recorded in the medical chart as 
well as in the case report form for each subject.
Documentation should be supported by a record into the subject's medical chart. Any abnormality 
in laboratory tests, considered clinically relevant, for instance, those which lead to the subject's 
withdrawal from the study, require treatment, cause evident clinical onset in the subject, considered 
relevant by the Investigator, should be reported as an adverse event. All adverse events should be 
described in details, including subject's identity (name, age and gender), adverse event, suspected 
drug, reporter's data, onset and end date for the event, event's name and treatment, generic and 
brand name, dosage, route of administration, reason of prescription,  event's consequences and 
relevant data in the medical history.  
9.4.1.9
Definition of Reporting Period for Adverse Events
Report of adverse events will start as per the informed consent form signature and until and 
continues through the trial tart as per the informed consent form signature and until end-of-trial 
examination (last contact with the subject).季
9.4.1.10
Procedure for Reporting Adverse Events and Serious Adverse 
Events 
Report of adverse events will be the responsibility of the 
 and it will be made according to the ICH GCP and the standard 
operating procedure, code: 
 REPORT OF CLINICAL AND BIOAVAILABILITY 
STUDIES 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 in writing. All written reports should be transmitted using the SAE Report 
Form, which must be completed by the Investigator following specific completion instructions.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, a written report must be sent immediately thereafter by fax or e-mail. Names, 
addresses, and telephone and fax numbers for SAE reporting will be included in the trial-specific
SAE Report Form.
PPD
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
54/79
Relevant pages from the CRF may be provided in parallel (for example, medical history, 
concomitant drugs). Additional documents may be provided by the Investigator, if available (for 
example, laboratory results, hospital report, autopsy report). In all cases, the information provided 
on the SAE Report Form must be consistent with the data about the event recorded in the CRF.
The Investigator must respond to any request for follow-up information (for example, 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 responsible Monitor, although in exceptional 
circumstances the Global Drug Safety department may contact the Investigator directly to obtain 
further information or to discuss the event.
Report of adverse events will be made according to the ICH GCP and the standard operating 
procedure, code: 
 REPORT OF CLINICAL AND BIOAVAILABILITY STUDIES 
ADVERSE EVENTS and the Mexican Official Standard for the Setting-up and Operations of 
Pharmacovigilance in Mexico, NOM-220-SA1-2012. Therefore, any serious adverse event or 
suspect serious adverse reaction should be notified to the National Center of Pharmacovigilance 
(CNFV) from the Federal Commission for the Protection Against Sanitary Risks (COFEPRIS) as 
well as to the Sponsor within the first 24 h following the Investigator is aware of it. A supplemental 
report, as detailed as possible and including all information collected, should be sent within 15 
days.   Report to the CNFV will be made by the Pharmacovigilance Officer at the 
 
 To comply with NOM-220-SSA1-
2012, mild or moderate, expected and unexpected adverse reactions should be reported by the 
study Principal Investigator at the 
. along with the clinical stage report to the CNFV.  
The reports to Merck shall be sent in English using the Merck SAE form via fax or email within 
24 hours.
PPD
PPD
PPD
PPD
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
55/79
9.4.1.11
Report of Safety Information to the Health Authorities, Ethics 
and Investigation Committee and Investigational Committee  
According to local law and regulation, all serious and non-serious adverse events should be 
reported to the appropriate Ethics and Investigation Committee, Investigational Committee and to 
the Health Authorities. This will be carried out according to the ICH GCP and the standard 
operating procedure, code: 
Report of clinical and bioavailability studies adverse 
events
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving trial subjects to the IEC/IRB that approved the 
trial.
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of “findings that 
could adversely affect the safety of subjects, impact the conduct of the trial or alter the IEC’s/IRB’s 
approval/favorable opinion to continue the trial.” In particular and in line with respective 
regulations, the Sponsor/designee will inform the Investigator of AEs that are both serious and 
unexpected and are considered to be related to the administered product (“suspected unexpected 
serious adverse reactions” or SUSARs). The Investigator should place copies of Safety Reports in 
the Investigator Site File. National regulations with regard to Safety Report notifications to 
Investigators will be taken into account.
9.4.1.12
Monitoring of Subjects with Adverse Events 
Adverse events are recorded and assessed on an ongoing basis throughout the study, and they will 
be assessed for the final outcome in the 14-day follow-up following the last dose of the drug.  All 
ongoing adverse events, including the follow-up period, should be watched and followed-up by 
the Investigator until they are stable or until their outcome is known; unless it is documented that 
the subject is "lost to follow-up". All reasonable efforts should be made to collect information and 
these should be documented. It is also the Principal Investigator's responsibility to ensure that all 
additional and necessary therapeutic measures are taken as well as the follow-up procedures.  
9.4.2
Pregnancy and Exposure to Drugs in the Uterus  
All pregnancies, with a conception date estimated during the period defined in section 9.5.1.3. will
be recorded as AE in the appropriate CRF page/section. For female subjects and male subjects' 
female partners as AE or SAE depending on the outcome of the pregnancy. The Principal 
Investigator should inform immediately the Sponsor or designated person about any pregnancy 
using a Pregnancy Report Form which should be submitted according to the same procedure for 
SAE referred in section 9.4.1.10.
The Principal Investigator or designated person should follow-up, document and report all 
pregnancies outcomes, even if subjects were withdrawn from the study.
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
56/79
The Principal Investigator should inform the Sponsor or designated person about the outcome 
using the Pregnancy Report Form. In case of an abnormal outcome, the SAE Report Form will be 
used. In case subject, child/fetus experienced an event, the Parent-Child/Fetus Adverse Event 
Report Form will be used.
Any abnormal outcome should be reported immediately as described in section 8.4.1.4. All 
abnormal outcomes should be reported (the observation period comprises 45 days following the 
delivery).
In case of pregnancy during the study, the subject should be withdrawn and no further IMP has to 
be given. Sponsor or designated person should be immediately informed and follow-up should be 
made as aforementioned. 
Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased 
congenital abnormalities and perinatal mortality. The use of the combination drug Metformin and 
Gliclazide has not been studied in pregnant women.
A limited amount of data from the use of Metformin in pregnant women does not indicate an 
increased risk of congenital abnormalities. Animal studies with Metformin do not indicate harmful 
effects with respect to pregnancy, embryonic or fetal development, parturition or postnatal 
development. 
With Gliclazide no teratogenic effects have been shown in animal studies, but lower fetal body 
weight was observed in animals receiving doses 25 fold higher than the maximum recommended 
dose in humans. No impairment of fertility was seen in a study with male and female rats.
When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes 
is not treated with Gliclazide, but insulin should be used to maintain blood glucose levels as close 
to normal as possible.
Pregnancy occurring during a patient’s participation in a clinical trial, although not typically
considered an SAE, must be notified to the sponsor within the same timelines as an SAE (within 
one working day) on a Pregnancy Monitoring Form. The outcome of a pregnancy should be 
followed up carefully and any abnormal outcome of the mother or the child should be reported. 
This also applies to pregnancies following the administration of the investigational product to the 
father prior to sexual intercourse.
Based on the outcome and the timing of the delivery, the pregnancies during the clinical trial can 
be categorized into the followings:
Female is study participant and becomes pregnant during study participation:
1.
Normal outcome before end of study
2.
Abnormal outcome before end of study
3.
Normal outcome after end of study
4.
Abnormal outcome after end of study


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
57/79
Female is partner of study participation and becomes pregnant during study:
5. Normal outcome before or after end of study
6. Abnormal outcome before or after end of study
In all of these situations, the Pregnancy Monitoring Form should always be filled out. However, 
only for situation #2, a SAE needs to be reported.
9.4.3
Clinical Laboratory Assessments 
Blood samples for hematology:
1.
Two (2) blood samples will be collected per period at times established in the schedule. Test 
tubes with EDTA K2, specifically designed for venipuncture, will be used.
2.
Each sample will be 4 mL. Blood withdrawn to clean catheter should be disposed prior to 
the blood sample collection (purge).
3.
A ± 1 minute window is allowed for sampling.
4.
Samples should be maintained at room temperature (between 20 and 25 °C [68 °F to 77 °C).
5.
Blood tubes will be labelled with Study No. (##), Case No. (C##), Sample No. (S##) and 
Visit No. (V#) according to the SOP, code 
Pre organization for conducting a study 
of interchangeability and biocomparability;
Processing and packaging of biological 
samples for studies interchangeability and biocomparability. They will be kept at room 
temperature until their delivery to the clinical laboratory.
Samples for blood chemistry and glucose determination:
1. Two (2) blood samples for blood chemistry and 5 samples for glucose determination will 
be collected per period at times established in the schedule and in test tubes without 
anticoagulant specifically designed for venipuncture.
2. Each sample will contain 6 mL for blood chemistry and 3 mL for glucose determination. 
Blood withdrawn to clean catheter should be disposed prior to the blood sample collection 
(purge).
3. A ± 1 minute window is allowed for sampling.
4. Samples should be maintained at room temperature (between 20 and 25 °C [68 °F to 77 °C).
5. Blood tubes will be labelled with Study No. (##), Case No. (C##), Sample No. (S##) and 
Visit No. (V#) according to the SOP, code, 
Pre organization for conducting 
a study of interchangeability and biocomparability;
Processing and 
packaging of biological samples for studies interchangeability and biocomparability. They 
will be kept at room temperature until their delivery to the clinical laboratory.
PPD
PPD
PPD
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
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Blood samples for coagulation:
1. Two (2) blood samples will be collected per period at times established in the schedule in 
test tubes with sodium citrate specifically designed for venipuncture.
2. Each sample will be 3 mL. Blood withdrawn to clean catheter should be disposed prior to 
the blood sample collection (purge).
3. A ± 1 minute window is allowed for sampling.
4. Samples should be maintained at room temperature (between 20 and 25 °C [68 °F to 77 °C).
5. Blood tubes will be labelled with Study No. (##), Case No. (C##), Sample No. (S##) and 
Visit No. (V#) according to the SOP, code, 
Pre organization for conducting 
a study of interchangeability and biocomparability;
Processing and 
packaging of biological samples for studies interchangeability and biocomparability They 
will be kept at room temperature until their delivery to the clinical laboratory.
Urine samples for urinalysis/ microscopic analysis / sediment:
1. Two (2) urine samples will be collected per period at the times established in the schedule.
2. Samples should be maintained at room temperature (between 20 and 25 °C [68 °F to 77 °C).
3. Urine containers will be labelled with Study No. (##), Case No. (C##), Sample No. (S##) 
and Visit No. (V#) and will be kept at room temperature until their delivery to the clinical 
laboratory.
Urine samples will be taken from fresh, spontaneous urine from each subject. The following 
parameters will be evaluated by Aution max 4280 Urine analyzer:
pH, specific gravity
Proteins*, glucose, ketones, nitrites*, bilirubine, urobilinogen, blood*, leucocytes*
* if positive, a microscopic examination (urine sediment) will be performed.
Urine sample from these subjects should be kept in the fridge.
Containers will be labeled with Study No. (##), Case No. (C##), Sample No. (S##) and Visit No. 
(V#) according to the SOP, code, 
Sampling for clinical laboratory for subjects' 
screening in interchangeability and biocomparability studies. They will be kept in the fridge until 
their delivery to the clinical laboratory.
PPD
PPD
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
59/79

Pregnancy test:
For all women of childbearing potential one blood sample per period will be collected for
pregnancy tests (qualitative and quantitative) at day -1 of each treatment period in test tubes 
specifically designed for venipuncture without anticoagulant.
5 mL of blood will be collected and processed as follows:
Each sample will be centrifuged at 2500 x g for 15 minutes at 4 °C [39.2 °F] (± 2 °C [35.6 
°F]) to obtain at least 1 mL of plasma.
Samples should be maintained at room temperature (between 20 and 25 °C [68 °F to 77 °C).
Blood tubes will be labeled with Study No. (##), Sample No. (S##) and Visit No. (V#) 
according to the SOP, code, 
Tubes labeling and distribution in racks; BE-
PNO-009
Collection 
of 
multiple 
blood 
samples 
for 
interchangeability 
and 
biocomparability studies. They will be kept at room temperature until their delivery to the 
clinical laboratory.
Pregnancy qualitative test will be performed in the clinical unit with the One Step HCG 
insta test trip (serum), for In-Vitro diagnostic.
Pregnancy quantitative test will be performed in the clinical laboratory with the architect i 
2000 analyzer by Chemiluminescence.
The Sponsor should receive a list of laboratory normal ranges before shipping the study drug. Any 
change to the study laboratory normal ranges should be submitted to the Sponsor.
9.4.4
Vital Signs, Physical Examinations and other Assessments 
At Screening and prior to each dosing, blood pressure, pulse, respiratory rate and temperature 
(subjects should be in rest and in supine position at least 10 minutes before vital signs 
measurement; and they should be in rest and in supine position during the vital signs 
measurements) will be measured.
In case it is necessary to be measured vital signs for some adverse event and coincide with the
scheduled signs, the vital signs will be measured according to the current subject's condition until 
they are resolved, then the scheduled vital signs will be measured.
These values should be within the normal range (SBP between 80 and 129 mmHg and DBP 
between 50 and 89 mmHg, heart rate between 50 and 100 beats per minute) in order the subject is 
allowed to keep on participating in the study. Same measurements will be made during all shifts 
following dosing at each one of the visits. Vital signs will be measured as shown in the following:
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
60/79
Record of Vital Signs
First Visit
Second Visit
Third Visit
Fourth Visit
Admission
Admission
Admission
Admission
Pre-dose
Pre-dose
Pre-dose
Pre-dose
Morning shift 
(approximately 4 h post-
dose)
Morning shift 
(approximately 4 h 
post-dose)
Morning shift 
(approximately 4 h 
post-dose)
Morning shift 
(approximately 4 h post-
dose)
Evening shift 
(approximately 8 h post-
dose)
Evening shift 
(approximately 8 h 
post-dose)
Evening shift 
(approximately 8 h 
post-dose)
Evening shift 
(approximately 8 h post-
dose)
Night shift 
(approximately 12 h 
post-dose)
Night shift 
(approximately 12 h 
post-dose)
Night shift 
(approximately 12 h 
post-dose)
Night shift 
(approximately 12 h 
post-dose)
24 and 32 h post-dose
24 and 32 h post-dose
24 and 32 h post-dose
24 and 32 h post-dose
Discharge (48 h post-
dose)
Discharge (48 h post-
dose)
Discharge (48 h post-
dose)
Discharge (48 h post-
dose)
Ambulatory samples (72, 
96, 120, 144 and 168 h 
post-dose)
Ambulatory samples 
(72, 96, 120, 144 and 
168 h post-dose)
Ambulatory samples 
(72, 96, 120, 144 and 
168 h post-dose)
Ambulatory samples (72, 
96, 120, 144 and 168 h 
post-dose)
In the event any subject has clinically significant changes out of normal ranges for blood pressure 
and pulse during confinement post-dose, he/she will be observed by the medical staff. Supportive 
measures, as appropriate, will be taken according to the current subject's condition until they are 
resolved. If change persists, continuation in the study will be considered by the Principal 
Investigator.
9.5
Pharmacokinetics 
Twenty two (22) 10-mL samples of venous blood will be taken per period with catheter or 
venipuncture for the measurement of drug's plasma concentration:  0.00 (Pre-dose, control), 0.5, 
1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 
and 168.0 h following administration.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
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9.5.1
Body Fluids
Pharmacokinetics Blood Samples
One blood sample will be collected per period at times established in the schedule. Test 
tubes with sodium heparin, specifically designed for venipuncture, will be used.
Each sample will be 10 mL. Blood withdrawn to clean catheter should be disposed prior to 
the blood sample collection (purge). Blood volume to be withdrawn by visit will be of 220 
mL approximately (440 mL a month), 880 mL of blood in total at the end of the study. 
A ± 1 minute window is allowed for sampling during absorption and distribution phase, 
and up to ± 3 minutes during the excretion phase.   
Each sample will be centrifuged at 2450 x g for 5 minutes at 4 °C [39.2 °F] (± 2 °C 
[35.6 °F]). 
Resulting plasma volume will be transferred into 1.5 or 2 mL cryotubes each.  
Plasma tubes will be perfectly identified with Study No. (##), Case No. (C##), Sample No. 
(S##) and Visit No. (V#). They will be kept deep frozen at a temperature lower than or 
equal to - 40 °C or lower, according to the standard operating procedures, code: 
Early organization for the conduct of an interchangeability and biocomparability 
study; and 
Processing and shipment of biological samples for 
interchangeability and biocomparability studies, 
Samples transportation 
from the clinical unit to the analytical unit; until their delivery at the analytical unit.
Samples Shipment 
To ensure transportation conditions of biological samples from the laboratory, where they were 
processed for freezing and storage, to the analytical unit do not affect samples' stability, it is 
essential to comply with the following guidelines:
The Study Principal Investigator or the Sub-Investigator will define shipment's date and 
time in accordance with the analytical unit, as well as the transportation to be used and 
approximate time for itinerary.  
Mechanism of control and security for samples shipment will be defined by the person in 
charge of transportation in agreement with the Principal Investigator or Sub-Investigator.
Samples Processing Responsible or designated person will sign a list of material to be 
shipped, with a detailed description by subject for tubes quantity and codes.
An internal temperature reading system will be available in the fridge. A reading will be 
made at least every 30 minutes with its appropriate record. 
PPD
PPD
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
62/79
In addition, reading at the moment of departure of the material from the samples processing
area, as well as a reading at the reception at the analytical unit will be made.
Samples transportation is the responsibility of the clinical unit where samples collection 
and processing took place.  
Delivery will be made personally, by a member of the Clinical Unit.
Samples should arrive deep frozen (- 20 °C [- 4.0 °F] as maximum) at the moment of the 
container bags check.
A temperature log will be included in the trial master file.
Samples Receipt, Check and Storage by the Analytical Unit 
Person responsible for the study or designated person from the analytical area will receive 
samples (along with documentation) and check 100 % with the assistance from analysts 
and Quality Assurance. They will record any remarks on the appropriate form.  Once 
review is finished the person responsible for the study or designated person will store 
samples in the ultra-freezer documenting it on the equipment's notebook.
Quality Assurance will confirm accuracy and reliability of operations.
Samples which do not meet acceptance criteria will be rejected. In addition to those which don't 
have documentation along with them. In such instances, the clinical unit should be informed about 
the reason why samples were rejected. Rejected biological specimens will be kept at the analytical 
unit meanwhile the analytical unit and the clinical unit make an agreement about their disposition.
Handling of Biological Specimens by the Analytical Unit
Biological specimens will be handled and processed as described in the appropriate analytical 
technique.
Biological Specimens Disposition
As agreed with the Sponsor or 30 calendar days following the final report, samples will be removed 
from the ultra-freezer and will be stored in a transient warehouse for infectious biological hazard 
residues until they are collected for their final disposition by an authorized designated company. 
Ultra-frozen Samples Labelling 
Cryotubes will be identified with labels according to the standard operating procedure, code: 
, Early organization for the conduct of an interchangeability and biocomparability study.
Each cryotube will state the study number, subject's number, period and number of samples 
specified in the protocol. Labels will be digitally designed and printed using thermal printer.  
PP
D


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
63/79
Label and printing type will ensure that that printing and adhesion resist several freezing and thaw 
cycles.
9.5.2
Pharmacokinetic calculations
Bioanalysis will be performed by analytical unit from the 
.
PK parameters of Metformin and Gliclazide's plasma concentrations will be calculated and 
evaluated by the analytical unit from the 
, according to their standard operating procedures and in accordance with the 
NOM-177-SSA1-2013.
Non-compartmental computation of PK parameters as well as descriptive statistical analysis for 
PK primary and secondary endpoints will be performed using Phoenix WinNonlin 6.3 software.
The primary PK variables will be calculated and listed for all subjects who provided sufficient 
concentration-time data. 
9.6
Statistics
9.7
Sample Size 
The sample size estimation is based on the CV intrasubject variability of both drugs. Because the 
pharmacokinetic and drug-drug interaction, evaluates changes in the bioavailability, the propose 
is the use the same determination for both aims. 
The sample size is determined by the primary endpoint with the greatest variability under fasting 
conditions, AUC0-t of Metformin (CV=23%). Assuming a mean treatment ratio of 0.95, and aiming 
at a power of 90% for the individual test, alpha=0.05 one-sided, 32 evaluable subjects are sufficient 
to demonstrate bioequivalence in the first step. The same arguments can be applied to the second 
step: Test absence of an effect of Gliclazide on the PK of Metformin, whereas the power for the 
third test is close to 100% with 32 subjects, due to the low variability of Gliclazide PK. Therefore, 
the overall power is still greater than 80% with 32 evaluable subjects. Considering a drop-out rate 
of approximately 20%, 40 subjects should be randomized.
According to NOM-177-SSA1-2013, this sample determination was realized with Chow & Wang 
(2001) equation  
PPD
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
64/79
Where:
t(alfa, 2n-2) and  t(beta, 2n-2) considered the error alfa and beta respectively 
CVintra: intra subject variability for crossover (or replicate crossover) study.
Tetha: 0.95:  the target ratio in average BA between the two formulations expressed in percentage 
of the average reference 
0.8: the least statistical power to detect (1-Power) differences between the Test and the Reference 
formulation (in this case the power expected is 90%)
9.8
Randomization
Forty male and female subjects will be included in this trial. Both sexes will be included with a 
minimum proportion of 30% for each sex at least 12 females and at least 12 males. Subjects will 
be randomly assigned to one of the 4 treatment sequences. Randomization of each subject to a 
treatment sequence will occur immediately before dosing on Day 1 of the first treatment period. 
The randomization list will be generated by the CRO based on the 
 internal procedures and in compliance with the Mexican 
Official Standard NOM-177-SSA1-2013 using software in website www.randomization.com, in 
agreement with the sponsorures and in compliance with the Mexican Off drop-out before any drug 
administration, the new subject will be allocated the same randomization number. Subjects leaving 
the trial after they have received any of the drugs at least once might be replaced if the drop-out 
rate is higher than expected after discussion with the sponsor.
9.9
Outcome variables 
9.9.1
Main outcome variable
To demonstrate Metformin/Gliclazide combination's bioequivalence at fixed dose as tablets (1.000 
mg / 30 mg MR) compared to the concomitant administration of individual products (Metformin's 
tablet 1000 mg XR and Gliclazide tablets 30 mg MR), given as single dose to healthy volunteers
in fasting state. The primary endpoints are AUC0-t, AUC0-∞and Cmax for Metformin and Gliclazide.
9.9.2
Secondary outcome variables
The secondary outcome variable are volume of distribution Ke, half-life elimination, clearance, 
and median residence time all these parameters will be presented only for informative reasons for 
both medications.
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
65/79
9.9.3
PK Analysis Set
The PK Analysis Set will include all subjects who have completed the trial with adequate trial 
medication compliance, without any relevant protocol violations with respect to factors likely to 
affect the comparability of PK results, and with sufficient evaluable data to determine primary 
endpoints (AUC0-t, AUC0-∞and Cmax) for both analytes. If subjects received concomitant 
medication for the treatment of an AE, their inclusion in the PK population needs to be discussed 
on a case-by-case basis.
All PK analyses will be based on this Analysis Set.
9.9.4
Safety Analysis Set
All the deviations must be justified with statistical or scientific evidence and any change to the 
original statistical plan must be reported, in the master file of the study and in the statistical 
pharmacokinetic report and final report of the study
Subject data will not be replaced, any data missing will be considered as a non-existing data and 
likewise data cannot be eliminated from the statistical analysis, except in the following cases:
Research subjects with pre-dose plasma concentrations in the biological 
matrix.
If the pre-dose concentration is lower than 5% of the Cmax value in a subject, the subject´s data can 
be included without adjustment in all measurements and pharmacokinetic calculations. In the cases 
where the pre-dose value is greater than 5% of Cmax, the research subject must be eliminated from 
all study evaluations.
Data elimination due to vomiting or diarrhea
Data from research subjects who experimented vomiting or diarrhea during the course of a clinical
study for immediate release products can be eliminated from the statistical analysis if the vomiting 
or diarrhea occurred before 2 times the median of Tmax or 2 times the value of Tmax obtained in the 
research subject during a given period.
A research subject with very low plasma concentrations for study drugs
As established by the Mexican Official STANDARD NOM-177-SSA1-2013, also research 
subjects that in a crossover design do not provide assessable data, both from test drug and reference 
drug, should not be included in the statistical analysis.
A research subject is considered to have very low concentrations if the AUC is lower than 5% of 
the geometrical mean of the reference medication AUC (must be calculated without inclusion of 
data of the research subject with of atypical values).


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
66/79
Data exclusion due to this reason will only be accepted under scientific justification and previous 
review of the case by the Federal Commission for the Protection against Sanitary Risks (Comisión 
Federal para la Protección contra Riesgos Sanitarios, COFEPRIS).
9.10
Statistical Analyses Description 
9.10.1
General Considerations
Statistical analysis and analysis of PK parameters will be performed using Phoenix WinNonlin 
software Version 6.3 (
).
Descriptive statistical methods will be used to summarize demographic characteristics, 
pharmacokinetics parameters and adverse events. After the data base closing
Individual plasma concentration-time will be tabulated and plotted. Primary pharmacokinetics 
parameters, AUC and Cmax, will be tabulated and plotted by subject. Likewise, differences and odd 
ratios for test/reference will be tabulated for each subject for those parameters. Plasma 
concentration - time graphs will be made using arithmetic and semi-logarithmic scale. All de 
calculations will be determinated in concordance with NOM-177-SSA1-2013
A complete description of the analyses will be given in the statistical analysis plan (SAP) into the
protocol.
Statistical Analysis
9.10.2
Analysis of primary and secondary endpoints
The following sequential testing of a priori ordered hypotheses will be applied, as shown below. 
Bioequivalence test methodology will be used in all 3 steps:
1. Test bioequivalence of fixed combination and separate tablets
2. Test absence of an effect of Gliclazide on the PK of Metformin
3. Test absence of an effect of Metformin on the PK of Gliclazide
Bioequivalence in step1:
A mixed model will be applied to log-transformed Cmax, AUC0-t and AUC0-∞(both analytes) with 
treatment, period and sequence as fixed effects, and subject (sequence) as a random effect. Based 
on the residual error term 90% confidence intervals will be computed for the estimated differences 
Test – Reference, resulting in 90% confidence intervals for the Test/Reference ratios after back-
transformation. 
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
67/79
Drug-drug interaction in steps 2 and 3:
A mixed model will be applied to log-transformed Cmax, AUC0-t and AUC0-∞(one analyte) with 
treatment as fixed effect, and subject as a random effect. Based on the residual error term 90%
confidence intervals will be computed for the estimated differences Test – Reference, resulting in 
90% confidence intervals for the Test/Reference ratios after back-transformation. 
1.
Bioequivalence will be concluded, if all six 90% CIs for all six primary endpoints reside 
within the acceptance range [0.80 – 1.25]
2.
Absence of an effect of Gliclazide on the PK of Metformin will be concluded, if all three 
90% CIs for Metformin endpoints reside within the range [0.80 – 1.25]
3.
Absence of an effect of Metformin on the PK of Gliclazide will be concluded, if all three 
90% CIs for Gliclazide endpoints reside within the range [0.80 – 1.25]
Additionally, the primary endpoints will be descriptively analyzed and graphical displays (Box-
whiskers-plots) will be prepared.
Statistical model in the variance analysis of mixed effects should be applied for log-transformed 
parameters Cmax, AUC0-t and AUC0-∞(one analyte) with TREATMENT as fixed effect and 
SUBJECT as randomized effect. Based on residual errors, confidence interval of 90 % will be built 
for estimated differences for test - reference, resulting in a confidence interval of 90 % for the 
test/reference ratio following transformation.
Using minimum mean squares for AUC and Cmax, two-side t test will be performed (Schuirmann's 
test) by constructing confidence intervals of 90 % for test/reference ratios. If and only if intervals 
are within interval (80, 125), bioequivalence will be proven for both drugs.
Bioequivalence is concluded if 6 confidence intervals for the analytes are included into the 
bioequivalence limits.
8.11.4 Analysis of secondary endpoints
All other PK endpoints will be analyzed using descriptive methods. Graphical displays will be also 
prepared where appropriate.
9.10.3
Safety Analyses
All safety endpoints will be analyzed descriptively.
Vital signs measurements and ECG recordings will be individually listed by subject number,
treatment and time point and flagged according to reference ranges. All variables will be presented 
by descriptive statistics by treatment and time point for the values obtained during the treatment 
periods and overall and by treatment sequence at screening and the end of study visit.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
68/79
All hematology and biochemistry parameters, including hematoglucotest (HGT) results, will be
listed and summarized using descriptive statistics on observed values by treatment and time point 
for the values obtained during the treatment periods and overall and by treatment sequence at 
screening and end of study visit. Urinalysis will be summarized in frequency tables.
In addition, shift tables for laboratory tests based on a classification of values as low, normal, or
high with respect to the reference range could be summarized and presented by time point.
After coding of AEs according to the Medical Dictionary for Regulatory Activities (MedDRA) 
classification (current version) and assignment to a system organ class (SOC), all AEs recorded
during the course of the trial will be listed by treatment and subject number and tabulated by
MedDRA SOC and Preferred Term (PT).
The frequency of treatment-emergent AEs (TEAEs) will be summarized using the frequency of
events and the number of subjects experiencing these events per treatment, PT, and SOC.
In addition, all TEAEs will be tabulated by intensity and relationship to drug per treatment.
An AE will be tabulated by intensity since the first investigational product administration of each 
period or if it occurred before administration and worsened during the period. The results will be 
presented as a frequency proportions or histograms.
9.10.4
Analysis of Further Endpoints
Individual concentrations of Metformin and Gliclazide in plasma will be listed and summarized 
by treatment. Individual plasma concentration-time profiles (linear and semi-logarithmic scales) 
will be plotted by treatment (showing all subjects simultaneously) and by subject (showing all 
treatments for a subject). Mean plasma concentrations will be plotted by treatment with SD using 
scheduled time points (linear and semi-logarithmic scales).
Demographic parameters (such as ethnic group, sex, age, height, weight, BMI) and other baseline 
characteristics (such as smoking history, diet, previous medications taken prior to screening visit, 
nicotine consumption, alcohol consumption, intake of caffeine or xanthine containing beverages) 
will be summarized by means of tabulated descriptive statistics for all subjects overall and by 
treatment sequence.
9.11
Extreme Values 
According to the Mexican Official Standard, NOM-177-SSA1-2013, there are several statistical 
tests to identify extreme values. Most of them start by calculating the student residual absolute 
value. Likewise, it is stated that «since studies are generally crossed designed, the most important 
extreme values is the extreme value for the subject». An adequate method for estimating extreme 
values allows to increase reliability of the study conclusion.  An analysis to identify outliers 
(extreme) values based on the student residual estimation among subjects will be performed 
according to lineal mixed model in Excel.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
69/79
Criterion: extreme values are those data which degree is higher than ± 2 standardized residuals 
intra-subject.  
10
Ethical and Regulatory Issues
10.1
Principal Investigator's Responsibilities 
The Principal Investigator is responsible for the study conduct at the site. He/she will make sure 
that the study is conducted according to the clinical protocol, ethical principles established in the 
Declaration of Helsinki, ICH, GCP and established regulation NOM-177-SSA1-2012, which states 
tests and procedures to show that a drug is interchangeable as well as the requirements which 
Authorized Third-Parties should fulfill to perform the tests. The Investigator should ensure that 
only subjects who have provided their informed consent are included in the study.
10.2
Information for the Subject and Informed Consent 
An additional requirement for each subject before their participation in the study, is to have a 
written informed consent, which should be given before any study-related activity is carried out. 
Therefore, the Principal Investigator or designated personnel should provide appropriate 
information before obtaining informed consent. 
Subject's Information Sheet should be elaborated in Spanish, according to the ICH GCP and will 
be provided by the Sponsor with the purpose to get informed consent.  Besides providing written 
information to the potential subject, Investigator or designated person will inform them verbally 
all relevant aspects of the study, using language chosen so that information can be fully and easily 
understood by the subjects.  Subject will be given enough time to read the information and ask 
questions and request additional information and explanations.
After providing information to the subject, informed consent form should be signed and dated by 
the subject, the Principal Investigator and two witnesses.
The dated and signed informed consent will be kept in the study site and should be securely filed 
so that files can be retrieved at any moment for monitoring, auditing and inspection purposes.  A 
copy of the signed and dated informed consent form should be provided to the subject before their 
participation in the study.
Whenever new relevant information arises for the informed consent, the Investigator will revise 
subject's information and any other written information to be provided to the subjects which should 
be submitted to the Committees for review and approval.  
Revised and approved version of the written information will be used. The Principal Investigator 
or designated personnel will explain each subject all changes made to the previous version and 
will obtain a new written consent to continue his participation in the study.  Subject will be given 
enough time to read the information and ask questions, and request additional information and 
explanations about changes.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
70/79
10.3
Subject's Identification and Confidentiality 
A unique number will be assigned to each subject following information consent has been 
obtained. This number will be used as subject's identification in the study, as well as in the clinical 
study database. All data collected from study subjects will be recorded in appropriate charts. Only 
the Investigator will be able to link the test's data for a subject by means of an identification list 
will be located at the site.  For each subject, clinical data will be available for verification purposes 
by the monitor, audits and regulatory inspections, but subject's confidentiality will be strictly kept. 
Data protection and confidentiality will be kept during data entry, processing, submission and 
storage. Subjects will be informed about it and they will be requested to provide their consent for 
data management according to the national regulations.
The Ministry of Health, Ethics and Investigation Committee and the Investigational Committee 
will be the only authorized bodies for reviewing study documentation, (which includes participant 
subject's identity data) and documents considered confidential by clinical unit at the 
 
 and by the analytical unit from 
Merck.
10.4
Medical Insurance and Subjects' Compensation 
Subjects will sign a consent which states that they will receive an economical compensation for 
their participation in the study. The Sponsor will pay treatment (or compensation, if applicable) 
resulting from injuries or diseases caused by their participation in the study until their resolution 
as per the clinical criteria. The Sponsor will not pay injuries caused by subject's negligence, 
irresponsible behavior or medical reasons not related to the study.
10.5
Ethics and Investigation Committee and Investigational 
Committee 
Before study start-up, approval from the Ethics and Investigation Committee and from the 
Investigational Committee will be obtained. They should provide a list of the members who 
compose it, as per request from the Study Sponsor or Principal Investigator. If necessary due to 
amendments to the clinical protocol, case report form or informed consent form, a new approval 
should be got from both Committees.
10.6
Health Authorities 
The clinical protocol as well as the appropriate documents will be submitted to the health 
authorities, according to the local and national applicable regulations.
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
71/79
11
Study Management
11.1
Case Report Form 
Case Report Forms will be completed by authorized medical staff according to the standard 
operating procedure, code: 
Good documentation practices, with legible letter and 
without amendments. 
Paper CRF will be fully and legibly completed, using blue ink appropriate for use in official 
documents.  Necessary amendments or corrections should be made, dated and confirmed by the 
Investigator or designated personnel. Whenever corrections are made to data, original entries 
should remain legible, and should not be deleted or corrected. Investigator or designated personnel 
should state reasons of corrections of relevant data. For any missing information or comments, 
blanks should be voided to avoid unnecessary follow-up queries.  CRF's are essential documents 
which should be available for regulatory inspections and submissions.  
11.2
Source Document and Subject's Medical Chart 
The Principal Investigator should keep a paper or electronic file (medical file, and original medical 
records) for each subject in the study. It should be possible to identify each subject by means of 
this file. This file will contain the following subject's demographic and medical information and 
should be as complete as possible.
x
Subject's complete name, date of birth, sex, height and weight.
x
Medical history. 
x
Previous concomitant therapies (including changes during the study).
x
Study identification; i.e., subject's number.  
x
Study recruitment dates (informed consent) and visits to the site.
x
Any medical exam and pre-defined clinical findings in this clinical protocol.
x
All adverse events.
x
Date when the subject withdraw his/her consent, including any reason for withdrawal.
All documents which contain source data should be shown, including but not limited to, 
electrocardiograms and laboratory tests results.  These documents should have subject's number 
and date of procedure. If possible, this information should be printed by the equipment used to 
perform the assessment or measurement. As necessary, medical assessment should be conducted; 
all assessments should be documented, signed and dated by the Principal Investigator. 
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
72/79
11.3
Site's File and Master File 
At the beginning of the study, the Principal Investigator will receive a master file for the site which 
contains all necessary study documents to be completed throughout the study and which will be 
updated as necessary.  Master file should be available for Monitor's review, Sponsor's audits and 
Health Authorities' inspection during and following study. It should be securely filed for at least 
15 year (or more, according to the local needs or otherwise stated by the Sponsor) following study 
completion. Documents to be filed include the subject's identification list and the signed informed 
consent by the subject.  In the even the master file cannot be kept at the site anymore, Principal 
Investigator should inform the Sponsor/designated person.
All subjects' source documents (medical charts) should be stored at the site as long as possible, as 
allowed by applicable guidelines and/or according to the ICH GCP guidelines, whatever is longer.  
In any case, the Principal Investigator should ensure that no destruction of medical charts is done 
without written approval form the Sponsor. 
11.4
Quality Management 
Quality assurance is performed by means of follow-up to the standard operating procedures, codes: 
Elaboration of quality assurance report for clinical trials;
First 
stage of quality control and quality assurance review during clinical studies conduct;
Second stage of quality control and quality assurance review during clinical studies conduct;
and 
Third stage of quality assurance review during clinical studies conduct.
Quality Management follows up the conduct of the study by means of quality control monitoring 
for the review of compliance with the clinical protocol, internal standard operating procedures, 
and applicable guidelines according to the GCP (ICH E6R1). Discrepancies and areas of 
improvement identified are followed up according to the standard operating procedure, code: 
, Discrepancies identification and follow-up, potential causes of discrepancies and 
continuing improvement. All information collected is analyzed for the preparation and issue of the 
Quality Assurance report.
11.5
Changes to the Protocol 
Protocol amendments can be issued by the Principal Investigator and agreed with the Sponsor or 
vice-versa. Substantial changes have to approve by the Ethics and Investigation Committee and by 
the Investigational Committee. Administrative changes (non substantial changes) which do not 
affect the study will be agreed with and approved by the Sponsor, the analytical unit and by the 
Principal Investigator. They will also be notified to the Ethics and Investigation Committee and to 
the Investigational Committee. 
PPD
PPD
PPD
PPD
PPD


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
73/79
11.6
Study Report and Publication Policy 
11.6.1
Clinical Study Report 
After study completion, the Principal Investigator with Sponsor's advice will prepare the clinical 
study report according to the Mexican Official Standard which states tests and procedures to show 
that drug is interchangeable. Requirements which authorized third parties should fulfill for 
interchangeability tests. Requirements for performing biocomparability studies. Requirements 
which authorized third parties, investigational sites and hospitals conducting biocomparability 
tests should fulfill (NOM-177-SSA1-2013) and applicable guidelines. 
11.6.2
Publication
All data and results, and all intellectual property rights for data and outcomes from the study will 
be property of Merck KGaA, which may use data for different purposes such as, submission to 
government health authorities or submission to other investigators. 
The Investigator, although is free to use data derived from the study for scientific purposes, but
has to discuss any publication with Merck in advance and obtain Sponsor's written consent for the 
pursued publication.
The Sponsor acknowledges the Investigator's right to publish outcome once the study is completed. 
Anyway, the Investigator should submit a draft of the paper or summary to be published to Merck 
30 days before submitting the final version for publication.
It will be reviewed soon and approval will not be unnecessarily delayed. In case of controversies 
between the Sponsor and the Investigators, publication content will be discussed in order to find a 
satisfactory solution for both parties.
12
Deviations to the Protocol 
Deviations to the research protocol which occur during study conduct should be documented. The 
Principal Investigator, the Study Sponsor have to be informed immediately. Ethics and 
Investigation Committed and to the Investigational Committee.
When a protocol deviation occurs during the clinical stage, the Principal Investigator should assess 
it and consider if study subject's continuation may affect protocol's outcome. Sponsor will be 
informed and jointly they will make a decision about subject's continuation in the study.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
74/79
13
References 
American Diabetes Association. Standards of Medical Care in Diabetes 2014. Diabetes 
Care 2014;37(Supp.1).
Cho HY, Moon JD, Lee YB. Bioequivalence of Glycomin Tablet to Glucophage Tablet 
(Metformin HCl 500mg). J Kor Pharm Sci. 2002; 32: 223-229 (in Korean).
Chow, S.C. and Wang, H. (2001). On sample size calculation in bioequivalence trials. 
Journal of Pharmacokinetics and Pharmacodynamics, 28, 155-169.
Cryer PE, Davis SN, Shamoon H: Hypoglycemia in diabetes. Diabetes Care 26:1902–1912, 
2003.
DIAMICRON MR: gliclazida. Responsável Técnico: Patrícia Kasesky de Avellar. Rio de 
Janeiro: Laboratórios Servier do Brasil Ltda. [2013]. Bula de medicamento.
Drugs classification according to risks during pregnancy and breastfeeding (FDA) obtained 
at http://www.drugs.com/pro/glucophage.html.
Ethical Principles for Medical Research in Humans contained in the Declaration of 
Helsinki, published on the 64th General Assembly from the Worldwide Medical 
Association, Fortaleza, Brazil; October 2013.
European Medicines Agency. CHMP/EWP/240/95 Rev. 1 Guideline on clinical 
development of fixed combination medicinal products. London, 2009.
Fuhr U. Tobacco smoking, alcohol, and special diet in drug trials: exclusion criteria or 
target of specific investigations? International Journal of Clinical Pharmacology and 
Therapeutics, Nov 1998; 36(11): 604 – 606.
Galeone F, Fiore G, Arcangeli A, et al. Gliclazide and Metformin combination in patients 
with Type 2 diabetes. Preliminary data. Minerva Endocrinol. 1998; 23: 71-75.
General Health Act.
General Health Act's Regulation in the Field of Health Research.
Gold AE, Frier BM, MacLeod KM, Deary IJ: A structural equation model for predictors 
of severe hypoglycaemia in patients with insulin-dependent diabetes mellitus. Diabet Med 
14:309–315, 1997.
Goodarzi MO and Bryer-Ash M. Metformin revisited: reevaluation of its properties and 
role in the pharmacopoeia of modern antidiabetic agents. Diabetes Obes Metab. 2005; 7: 
654-665.


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
75/79
Green J and Feinglos M. New combination treatments in the management of diabetes: 
focus on sitagliptin-Metformin. Vasc Health Risk Manag. 2008; 4: 743-751.
Hoich RI, Ng FM. lnsulin-potentiating action of gliclazide (Diamicron) Pharmacol Res 
Commun 1986; 18(5):419-430
Hundal RS and Inzucchi SE. Metformin: new understandings, new uses. Drugs. 2003; 63: 
1879-1894.
Ings RMJ, Campbell B, Gordon BH, Beaufils M, Meyrier A, Jones R. The effect of renal 
disease on the pharmacokinetics of gliclazide in diabetic patients Br J Clin Pharmacol 
1986; 21(5):572-573.
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use - ICH Harmonized Tripartite Guideline - Guideline for 
Good Clinical Practice E6(R1) - June 10th, 1996.
Metformin, obtained at: 
http://www.ncbi.nlm.nih.gov/pccompound?term=%22Metformin%22
Mexican Official Standard for Drugs and Herbal Remedies Labelling (NOM-072-SSA1-
2012). 
Mexican Official Standard for Medical Charts (NOM-004-SSA3-2012).
Mexican Official Standard for the Prevention, Treatment and Control of Hypertension 
(NOM-030-SSA2-1999). 
Mexican Official Standard which states tests and procedures to prove that a drug is 
interchangeable. Requirements which authorized third parties should fulfill for 
interchangeability tests. Requirements for performing biocomparability studies. 
Requirements which authorized third parties, investigational sites and hospitals conducting 
biocomparability tests should fulfill (NOM-177-SSA1-2013).
Mexican Official Standard. Setting-up and Operations of Pharmacovigilance (NOM-220-
SSA1-2012). 
Ministry of Health, COFEPRIS. Requirements to request a meeting with the New 
Molecules Committee. Mexico, 2013.
Pentikainen PJ, Neuvonen PJ, Penttila A. Pharmacokinetics of Metformin after intravenous 
and oral administration to man. Eur J Clin Pharmacol. 1979; 16:195-202 [IDIS 105768] 
[PubMed 499320].


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
76/79
Ristic S, Collober-Maugeais C, Cressier F. Nateglinide or gliclazide in combination with
Metformin for treatment of patients with type 2 diabetes mellitus inadequately controlled 
on maximum doses of Metformin alone: 1-year trial results. Diabetes Obes Metab. 2007; 
9: 506-511.
Sarkar A, Tiwari A, Bhasin PS. Pharmacological and Pharmaceutical Profile of Gliclazide: 
A Review.  Journal of Applied Pharmaceutical Science 01 (09); 2011: 11-19.
Turner RC, Cull CA, Frighi V, et al. Glycemic control with diet, sulphonylurea, Metformin, 
or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple 
therapies (UKPDS 49) UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999; 
281: 2005-2012.
Type 
2 
Diabetes 
algorithm 
treatment, 
available 
at: 
http://www.nottsapc.nhs.uk/index.php/clinical-guidelines.
Zhong GP, Bi HC, Zhou S. Simultaneous determination of Metformin and gliclazide in 
human plasma by liquid chromatography-tandem mass spectrometry: application to a 
bioequivalence of two formulations in healthy volunteers. J Mass Spectrom. 2005; 40:
1462-1471.
14
Appendices


Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
77/79
1. Appendix 1: Schedule of collecting blood samples from subjects and 
meals of the study
Period 1 
TD̻1
TD 1
TD 3
TD 4
TD 5
TD 6
TD 7
TD 8
 EOT 13
wash-out
Period 2   
TD 21
TD 22
TD24
TD25
TD26
TD27
TD28 TD 29
 EOT 13
wash-out
Period 3 
TD42
TD 43
TD 45 TD 46 TD 47 TD 48 TD 49 TD 50
 EOT 13
wash-out
Period 4
TD 63
TD 64
TD66
TD67
TD68
TD69
TD70 TD 71
 EOT 13
Time Post-dose (h)
Pre-
dose
0
0.5
1
2
3
4
5
6
7
8
10
12
16
24
28
32
48
72
96
120
144
168
168
Informed Consent
X
Hospitalization 1
Ambulatory Visits
X
X
X
X
X
X
X
Incl./Excl. Criteria
X
X2
Medical History
X
Body weight height 3
X
X
Virus serology (HBsAg, 
HBc, HCV, HIV-1/-2)
X
Urine drugs-of-abuse & 
alcohol screens 
X
X
Serum Pregnancy Testing 
(WOCBP) 1
X
X
X
Physical examination 5
X
X
X
X
Vital Signs 6
X
X
X
X
X
X
X
X
X
ECG 12-lead 6
X
X
X
X
Safety Laboratory 1  
(Hematology, Coagulation, 
Clinical Chemistry 15,
Urinalysis)
X
X
X
Blood glucose 
determination 16
X
X
X
X
X
HGT 17
X
X
X
X
X
X
Randomization 9
X
IMP administration 10 
X
PK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X7
X7
X7
X7
X7
Safety
Adverse Events 11
X
X
X
Previous medication
X
X
X
Concomitant medication 12
Footnotes
1
2
3
5
6
7
9
10
11 Spontaneous AEs will be continously reported; subjects will be asked specifically at pre dose, 2,4,8,12,24,32,48,72,96,120,144,168 h after each administration
12
13
1
15
16
17
In general when multiple assessments are scheduled at same time points, the following sequence should be followed: (1) ECG recording; (2) vital sign assessment; (3) PK/Lab blood sampling and (4) meal
TD23
TD 8 - TD 20
Subjects will receive IMP after an overnight fast of at least 10 hours.  The IMP will be administered with 240 mL of water. No food will be allowed for the next 4 hours, until a standardized lunch will 
be served
Randomization will occur once all screening activities have been completed and the subject is deemed eligible 
Urine screen for drugs of abuse (cannabinoids, amphetamines, methamphetamines, opiates, methadone, cocaine, benzodiazepines, barbiturates, tricyclic anti-depressants and phencyclidine) 
and alcohol. The tests can be repeated at any time at the discretion of the investigator.
Complete physical examinations will be conducted at screening, TD–1, TD3,  and EOT of each period and abbreviated examinations at the other time points indicated. Abbreviated examinations 
will include: oral inspection, plus heart, lungs, abdomen, and further organs if required due to symptoms.
Vital signs include systolic and diastolic blood pressure, pulse rate and oral body temperature. For vital signs and ECG assessment, the subjects should be at rest and semi-supine for at least 10 
minutes before recording and should remain resting and supine during recordings.
Gliclazide only
PK
Trial Day SCR
TD 2
HGT = Hematoglucotest (bedside monitoring)
By using the clinical chemistry analyzer; for comparison purposes with HGT
Blood sample collection for safety laboratory assessments will be performed after a fast of at least 10 hours (including the collection at screening).
Hospitalization: From TD–1 until the 48 hours post-dose  for each period
Subject eligibility must be checked again on TD1 prior to randomization.
Height [cm] (screening) and weight [kg] (screening and EOT).
Subjects will be asked at pre dose, 2,4,8,12,24,32,48,72,96,120,144,168 h after each administration
In the event of trial discontinuation, subjects have to undergo the EOT assessments, regardless of the reason for discontinuation (at least 7 days after administration).
For female subjects who are post-menopausal for less than 2 years, post-menopausal status will be confirmed by FSH level determination (at screening only): results must be within the laboratory 
post-menopausal range.
TD 29- TD 41
TD44
TD 49 - TD 62
TD65




Drug's name: Metformin/Glicazide
Protocol number EMR200763-003/ BD1412-62CEC
79/79
Appendix 3:
Drugs classification according to risks during pregnancy and 
breastfeeding (FDA) 
A 
Without apparent 
risks 
Controlled studies in women do not show risk for the fetus during the first 
quarter; therefore, likelihood of fetal damage seems to be remote.  They can 
be used. 
B 
Without apparent 
risks 
Studies in animals do not show any risk for the fetus and there are no controlled 
studies in humans.Studies in animals do show adverse effects for the fetus; 
however, well controlled studies in pregnant women have not shown fetal risk. 
Probably safe 
C 
Undetectable risk 
Studies in animals have shown that the drug has teratogenic or embryonic 
effects. There are no controlled studies or there are no studies available in 
animals or women.    Avoid them if there is any other option. 
D 
Proven risk 
There is positive evidence about fetal risk in humans but, in some cases (for 
instance, life-threatening situations or severe illnesses where more secure 
drugs cannot be used or which they turn to be not effective), benefits can make 
the drug acceptable in spite of the risks. Avoid them if there is any other option. 
X 
Contraindicated 
drugs 
Studies in animals and humans have shown fetal abnormalities, or there is 
evidence of fetal risk based on the experience in human beings; or both 
situations apply and risk clearly overcomes possible benefit. Contraindicated 
drugs 

SAP_000.pdf: 
BD1412-62CEC
Bioequivalence and secondarily drug-drug interaction of fixed 
combination of Metformin/Gliclazide fixed compared with the co-administrarion of 
individual tablets 
EMR200763-003
Version 1.0
Statistical Analysis Plan 
Clinical Trial Protocol 
Identification No. 
BD1412-62CEC EMR200763-003
Title: 
Randomized, Open label, Single Dose, 4-treatments, 4-periods, 
Crossover design (4 x 4) Study to evaluate the Bioequivalence 
and Secondarily Drug - Drug Interaction of Fixed Combination 
of Metformin Tablets 1000 mg/Gliclazide 30 mg MR, 
Compared with the Co-administration of Individual Tablets and 
Individual Administration of Each single tablet (Metformin 
1000 mg XR and Gliclazide 30 mg MR) in Healthy Volunteers.
Trial Phase 
I
Investigational Medicinal 
Product(s) 
Metformin/ Gliclazide
Clinical Trial Protocol 
Version 
2 October 2017/Version 1.0
Statistical Analysis Plan 
Author 
Statistical Analysis Plan 
Date and Version 
Agust 2018/Version 1.0
Statistical Analysis Plan 
Reviewers 
, Biostatistics Responsible.
, Principal investigator.
, Quality Control Responsible
, Sanitary Officer.
, Quality Assurance Officer.
, Bioanalytics Investigator.
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its 
affiliated companies. 
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It is intended for restricted use only and may not - in full or part - be passed on, reproduced, 
published or used without express permission of Merck KGaA, Darmstadt, Germany or its 
affiliate.  
Copyright © 2017 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights 
reserved.
1. Signature Page
Statistical Analysis Plan:  BD1412-62CEC EMR200763-003
Randomized, Open label, Single Dose, 4-treatments, 4-periods, Crossover design (4 x 4) 
Study to evaluate the Bioequivalence and Secondarily Drug - Drug Interaction of Fixed 
Combination of Metformin Tablets 1000 mg/Gliclazide 30 mg MR, Compared with the Co-
administration of Individual Tablets and Individual Administration of Each single tablet 
(Metformin 1000 mg XR and Gliclazide 30 mg MR) in Healthy Volunteers.
Biostatistics Responsible,
Medical Responsible,
Merck KGaA Frankfurter Strasse 250
64293 Darmstadt, Germany
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2. Table of Contents 
 
 
 
1 
Singature page 
2 
2 
Table of contents 
3 
3 
List of abbreviation and definition of terms 
4 
4 
Modification history 
6 
5 
Purpose of the statistical analysis plan 
6 
6 
Summary of clinical trial features 
6 
6.1 Primary objectives and endpoint 
6 
6.2 Secondary objectives and endpoint 
7 
6.3 Overall trial design and plan 
7 
7 
 
Sample size 
8 
8 
 
Overview of planned analyses 
9 
 8.1 Interim analysis 
9 
9 
 
Changes to the planned analyses in the clinical trial protocol 
10 
10 
 
Protocol deviations and analysis sets 
10 
 10.1 Definition of protocol deviations and analysis sets 
10 
11 
 
General specifications of statistical analyses 
11 
12 
 
Protocol deviations   
11 
 12.1 Important protocol deviations 
11 
 12.2 Reasons leading to the exclusion from an analysis set 
11 
13 
 
Demographics and other baseline characteristics 
12 
 13.1 Demographics   
12 
14 
 
Treatment compliance and exposure 
13 
15 
 
Endpoint evaluation 
14 
 15.1 Primary endpoint analyses 
14 
 15.2 Bioavailability statistics 
14 
15.3 Box and whiskers plots 
17 
15.4 Secondary endpoint analyses 
20 
15.5 Other endpoint analyses 
22 
16 
Estimation of individual pharmacokinetic parameters 
32 
17 
Safety evaluation 
34 
17.1 Pharmacokinetic parameter's outliers 
34 
18 
Averse events 
38 
19 
References 
38 
20 
Appendices 
38 
 
 


BD1412-62CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-003
Version 1.0
3
List of Abbreviations and Definition of Terms 
AE 
Adverse Event 
AUC 
Area under the plasma concentration-time curve 
AUC0→∞
The AUC from time zero (dosing time) extrapolated to infinity 
AUC0→t
The AUC from time zero (= dosing time) to the last sampling time (tlast) at 
which the concentration is at or above the lower limit of quantification 
AUCextra%
The AUC from time tlast extrapolated to infinity given as percentage of 
AUC0→
BE 
Bioequivalence 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CL/f
The apparent total body clearance of drug following extravascular 
administration. 
Cmax
Maximum observed plasma concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Report 
CTMS 
Clinical Trial Management System 
CTP 
Clinical Trial Protocol 
CV 
Coefficient of Variation (%) 
CYP 
Cytochrome P 450 
ECG
Electrocardiogram 
ECOG
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
GCP 
Good Clinical Practice 
GeoCV% 
Geometric Coefficient of Variation 
GeoMean 
Geometric Mean 
GIR 
Glucophage Immediate Release  
HR
Hazard ratio 


BD1412-62CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-003
Version 1.0
HAV
Hepatitis A Virus 
HbA1C
Glycosylated Hemoglobin Type A1C
HBsAg 
Hepatitis B Surface Antigen 
HCV
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
LLOQ 
Lower Level of Quantification 
Max 
Maximum 
Mean 
Arithmetic mean 
Min
Minimum 
MedDRA 
Medical Dictionary For Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MSS 
Merck Santé s.a.s. in Semoy 
N
Number of non-missing observations 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Preferred team 
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
SASS 
Sino-American Shanghai Squibb Pharmaceuticals Ltd 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SEM 
Standard Error of the Mean 
SOC 
System Organ Class 
t1/2
Apparent terminal half-life 
T2DM 
Type 2 Diabetes Mellitus 
TEAE 
Treatment-Emergent Adverse Event 
TLF 
Tables, Listings, and Figures 


BD1412-62CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-003
Version 1.0
tlast
The last sampling time at which the concentration is at or above the lower 
limit of quantification 
tmax
The time to reach the maximum observed concentration  
TP 
Treponema Pallidum 
Vz/f 
Apparent volume of distribution during the terminal phase following 
extravascular administration 
λz
Terminal elimination rate constant 
WHO 
World Health Organisation 


BD1412-62CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-003
Version 1.0
4
Modification History 
5
Purpose of the Statistical Analysis Plan 
The purpose of this SAP is to document technical and detailed specifications for the final analysis 
of data collected for protocol BD1412-62CEC EMR200763-003. Results of the analyses described 
in this SAP will be included in the Clinical Study Report (CSR). Additionally, the planned analyses 
identified in this SAP will be included in regulatory submissions or future manuscripts. Any post-
hoc.  
The SAP is based upon section 9 (Statistical and Pharmacokinetical Analysis) of the trial protocol 
and is prepared in compliance with ICH E9.
6
Summary of Clinical Trial Features 
6.1
Primary Objectives and Endpoints 
x
To demonstrate bioequivalence of the fixed combination of Metformin tablets 1000 mg 
XR plus Gliclazide 30 mg MR compared to the co-administration of the individual tablets 
of Metformin 1000 mg XR and Gliclazide 30 mg MR, given as single dose to healthy 
volunteers in fasting state. Primary endpoints will be AUC0-t, AUC0-∞ and Cmax for 
Metformin and Gliclazide.
x
To demonstrate the lack of an effect of Gliclazide on the PK of Metformin by comparing 
the Metformin PK following administration of the fixed combination tablet 
Metformin/Gliclazide and Metformin alone (AUC0-t, AUC0-∞ and Cmax of Metformin).
x
To demonstrate the absence of an effect of Metformin on the PK of Gliclazide by comparing 
the Gliclazide PK following administration of the fixed combination tablet
Metformin/Gliclazide and Gliclazide alone (AUC0-t, AUC0-∞ and Cmax of Gliclazide).
6.2
Secondary Objectives and Endpoints 
•
The secondary endpoints variable are volume of distribution Ke, half-life elimination, 
clearance, and median residence time all these parameters will be presented only for 
informative reasons for both medications.
•
To compare the safety and tolerability of all the experimental treatments.
Unique 
Identifier for 
SAP Version
DATE OF SAP 
Version 
Author
CHANGE 
DESCRIPTION from the 
previous version
LEVEL
March 2019
New Document
1.0
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BD1412-62CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-003
Version 1.0
6.3
Overall Trial Design and Plan 
This randomized, open-label, single dose, four-treatment, four period crossover design (4x4) trial 
with a 14-day wash-out period along 4 study stages will investigate the bioequivalence (primary 
endpoints are AUC0-t, AUC0-∞ or Cmax for Metformin and Gliclazide) of a Metformin/Gliclazide 
fixed combination tablet (1000 mg /30 mg MR) compared with the co-administration of the 
individual tablets (Metformin 1000 mg and Gliclazide 30 mg MR) and the drug-drug interaction 
between the Metformin/Gliclazide fixed combination and the administration of each single tablet, 
administered in fasted condition in 40 healthy volunteers. Secondarily, safety and tolerability will 
be also investigated in every case. 
The subjects will be randomized to one of the 4 treatment sequences (see table below). Ten subjects 
will be randomized to each treatment sequence with a minimum proportion of 30% for each sex in 
each treatment sequence. 
Sequence
Period 1
Wash-out period
Period 2
Wash-out period
Period 3
Wash-out period
Period 4
1
Fixed 
combination
Metformin + 
Gliclazide
Metformin
Gliclazide
2
Metformin + 
Gliclazide
Gliclazide
Fixed 
combination
Metformin
3
Metformin
Fixed 
combination
Gliclazide
Metformin + 
Gliclazide
4
Gliclazide
Metformin
Metformin + 
Gliclazide
Fixed 
combination
7
Sample Size 
The sample size estimation is based on the CV intrasubject variability of both drugs. Because the 
pharmacokinetic and drug-drug interaction, evaluates changes in the bioavailability, the propose is 
the use the same determination for both aims. 
The sample size is determined by the primary endpoint with the greatest variability under fasting 
conditions, AUC0-t of Metformin (CV=23%). Assuming a mean treatment ratio of 0.95, and 
aiming at a power of 90% for the individual test, alpha=0.05 one-sided, 32 evaluable subjects are 
sufficient to demonstrate bioequivalence in the first step. The same arguments can be applied to the 
second step: Test absence of an effect of Gliclazide on the PK of Metformin, whereas the power 
for the third test is close to 100% with 32 subjects, due to the low variability of Gliclazide PK. 
Therefore, the overall power is still greater than 80% with 32 evaluable subjects. Considering a 
drop-out rate of approximately 20%, 40 subjects should be randomized. 


BD1412-62CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-003
Version 1.0
According to NOM-177-SSA1-2013, this sample determination was realized with Chow & Wang 
(2001) equation
Where:
t(alfa, 2n-2) and t(beta, 2n-2) considered the error alfa and beta respectively
CVintra: intra subject variability for crossover (or replicate crossover) study.
Tetha: 0.95: the target ratio in average BA between the two formulations expressed in percentage 
of the average reference
0.8: the least statistical power to detect (1-Power) differences between the Test and the Reference 
formulation (in this case the power expected is 90%)
8
Overview of Planned Analyses 
Statistical analysis and analysis of PK parameters will be performed using Phoenix WinNonlin 
software Version 6.3 (
).
Descriptive statistical methods will be used to summarize demographic characteristics, 
pharmacokinetics parameters and adverse events. After the data base closing
Individual plasma concentration-time will be tabulated and plotted. Primary pharmacokinetics 
parameters, AUC and Cmax, will be tabulated and plotted by subject. Likewise, differences and 
odd ratios for test/reference will be tabulated for each subject for those parameters. Plasma 
concentration - time graphs will be made using arithmetic and semi-logarithmic scale. All de 
calculations will be determinated in concordance with NOM-177-SSA1-2013
The following sequential testing of a priori ordered hypotheses will be applied, as shown below. 
Bioequivalence test methodology will be used in all 3 steps:
1. Test bioequivalence of fixed combination and separate tablets
2. Test absence of an effect of Gliclazide on the PK of Metformin
3. Test absence of an effect of Metformin on the PK of Gliclazide
8.1
Interim Analysis 
Bioequivalence in step1:
A mixed model will be applied to log-transformed Cmax, AUC0-t and AUC0-∞ (both analytes) 
with treatment, period and sequence as fixed effects, and subject (sequence) as a random effect. 
Based on the residual error term 90% confidence intervals will be computed for the estimated 
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BD1412-62CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-003
Version 1.0
differences Test – Reference, resulting in 90% confidence intervals for the Test/Reference ratios 
after back-transformation.
Drug-drug interaction in steps 2 and 3:
A mixed model will be applied to log-transformed Cmax, AUC0-t and AUC0-∞ (one analyte) with 
treatment as fixed effect, and subject as a random effect. Based on the residual error term 90% 
confidence intervals will be computed for the estimated differences Test – Reference, resulting in 
90% confidence intervals for the Test/Reference ratios after back-transformation.
1. Bioequivalence will be concluded, if all six 90% CIs for all six primary endpoints reside 
within the acceptance range [0.80 – 1.25]
2. Absence of an effect of Gliclazide on the PK of Metformin will be concluded, if all three 
90% CIs for Metformin endpoints reside within the range [0.80 – 1.25]
3. Absence of an effect of Metformin on the PK of Gliclazide will be concluded, if all three 
90% CIs for Gliclazide endpoints reside within the range [0.80 – 1.25]
Additionally, the primary endpoints will be descriptively analyzed and graphical displays (Box-
whiskers-plots) will be prepared.
Statistical model in the variance analysis of mixed effects should be applied for log-transformed 
parameters Cmax, AUC0-t and AUC0-∞ (one analyte) with TREATMENT as fixed effect and 
SUBJECT as randomized effect. Based on residual errors, confidence interval of 90 % will be built 
for estimated differences for test - reference, resulting in a confidence interval of 90 % for the 
test/reference ratio following transformation.
Using minimum mean squares for AUC and Cmax, two-side t test will be performed (Schuirmann's 
test) by constructing confidence intervals of 90 % for test/reference ratios. If and only if intervals 
are within interval (80, 125), bioequivalence will be proven for both drugs.
Bioequivalence is concluded if 6 confidence intervals for the analytes are included into the 
bioequivalence limits.
9
Changes to the Planned Analyses in the Clinical Trial Protocol 
The statistical methods as described in the protocol were adopted.  
There are no changes to the planned analyses. 
10
Protocol Deviations and Analysis Sets 
10.1
Definition of Protocol Deviations and Analysis Sets 
All deviations should be justified with statistical or scientific data and any change to the original 
statistical plan should be documented, in the study master file and in the pharmacokinetics
statistical report as well as in the final study report. Subjects' data will not be replaced. Any missing 


BD1412-62CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-003
Version 1.0
data will be considered as non-existent data. Likewise, data cannot be removed from the statistical 
analysis, except in the following events.

Research Subjects with Pre-dose Concentrations in the Biological Matrix
In the event pre-dose concentration is < 5 % of the Cmax value for a research subject, subject's data 
can be included without any adjustment to measurement and pharmacokinetic calculations. When 
pre-dose value is > 5 % of the Cmax, research subject should be removed from all study 
bioequivalence assessments.

Exclusion of data due to vomit or diarrhea.
Data from research subjects who experience vomiting and diarrhea throughout the bioequivalence 
study for immediate release products can be removed from the statistical analysis if vomiting and
diarrhea occur before 2 fold the median for tmax or 2 fold tmax value obtained from the research 
subject in a given period. 

Research subject with very low plasma concentrations for study drugs.
As established by NOM-177-SSA1-2013, research subjects in a cross designed who 
provide evaluable data for test drug and reference drug, or who do not have evaluable data in the 
single period of a parallel design, should not be either included in the statistical analysis.
It is considered that a research subject has very low concentrations, if the AUC is lower than 5 % 
of the geometric means for the reference drug's AUC (it should be calculated without including 
outliers). Exclusion of data due to this reason will only be accepted prior scientific rationale and 
review of the case by the COFEPRIS.
11
General Specifications for Statistical Analyses 
Pharmacokinetic parameters (non-compartmental analysis) and statistical analysis for determining 
bioequivalence will be calculated using Phoenix WinNonlin 8.0 software.
The results of this trial will be reported using summary tables, figures, and data listings, as 
appropriate. All data will be summarized by treatment and/or scheduled time point, as appropriate. 
12
Protocol Deviations 
12.1
Important Protocol Deviations
Not applicable. No deviation was observed in the study
12.2
Reasons Leading to the Exclusion from an Analysis Set 

Research Subjects with Pre-dose Concentrations in the Biological Matrix
In the event pre-dose concentration is less than 5 % of the Cmax value for a research subject, subject's 
data can be included. When pre-dose value is greater than 5 % of the Cmax, research subjects data
should be removed from all study of food effect on bioavailability.


BD1412-62CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-003
Version 1.0

Exclusion of data due to vomit or diarrhea.
Data from research subjects who experience vomiting and diarrhea throughout the study for 
immediate release products can be removed from the statistical analysis if vomiting and diarrhea 
occur before 2 fold the median for tmax or 2 fold tmax value obtained from the research subject in a 
given period.

Research subject with very low plasma concentrations for study drugs.
As established by NOM-177-SSA1-2013, research subjects in a cross designed who 
provide evaluable data for test drug and reference drug, or who do not have evaluable data in the 
single period of a parallel design, should not be either included in the statistical analysis.
It is considered that a research subject has very low concentrations, if the AUC is lower than 5 % 
of the geometric means for the reference drug's AUC (it should be calculated without including 
outliers). Exclusion of data due to this reason will only be accepted prior scientific rationale and 
review of the case by the COFEPRIS.
13
Demographics and Other Baseline Characteristics 
Demographic data from each volunteer is shown in table 13.1 and the descriptive statistics for the 
demographic variables from volunteers recruited in the study are shown in table 13.2. 
 
13.1
Demographics 
Table 13.1. Demographic Variables' Individual Data
Case
Sex
Age
Weight
Height
BMI
Sequence
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BD1412-62CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-003
Version 1.0
Table 13.2. Demographic Variables' Descriptive Statistics
Statistics 
Age (years)
Weight (kg)
Height (m)
BMI 
(Kg/m2)
Mean
SD
Median
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BD1412-62CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-003
Version 1.0
25th percentil
75th percentil
Minimum
Maximum
14
Treatment Compliance and Exposure 
All subjects receive the investigational treatment at the pre-specified fixed dosage. Information 
relating to the extent of exposure is thus contained in the treatment labelling. 
15
Endpoint Evaluation 
15.1
Primary Endpoint Analyses 
The determination of pharmacokinetics parameters were determined using WinNonlin software 
depending of their own characteristics as follows:
Cmax: is the peak or maximum concentration
AUC0-t: area under de curve computed from time zero to the time of the last positive Y value.
AUC0-∞: area under de curve computed from time zero to extrapolated from infinity.
Ke: First-order rate constant associated with the terminal (log-linear) elimination phase. This is 
estimated via linear regression of time vs. log concentration.
To demonstrate bioequivalence of the fixed combination of Metformin tablets 1000 mg XR plus 
Gliclazide 30 mg MR compared to the co-administration of the individual tablets of Metformin 
1000 mg XR and Gliclazide 30 mg MR, given as single dose to healthy volunteers in fasting state. 
Primary endpoints will be AUC0-t, AUC0-∞ and Cmax for Metformin and Gliclazide.
To demonstrate the lack of an effect of Gliclazide on the PK of Metformin by comparing the 
Metformin PK following administration of the fixed combination tablet Metformin/Gliclazide 
and Metformin alone (AUC0-t, AUC0-∞ and Cmax of Metformin).
To demonstrate the absence of an effect of Metformin on the PK of Gliclazide by comparing the 
Gliclazide PK following administration of the fixed combination tablet Metformin/Gliclazide and 
Gliclazide alone (AUC0-t, AUC0-∞ and Cmax of Gliclazide).
15.2 Bioavailability Statistics
In tables 15.2.1 and 15.2.2, pharmacokinetic equivalence statistical results are shown for the 
metformin’s logarithmically transformed pharmacokinetic data, taking Dabex® XR + Diamicron 
MR® (B formulation) as reference drug. In tables 15.2.3 and 15.2.4, pharmacokinetic equivalence 
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BD1412-62CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-003
Version 1.0
statistical results are shown for the metformin’s logarithmically transformed pharmacokinetic 
data, taking Dabex® XR (C formulation) as the reference drug.
Table 15.2.1. Statistics for the Metformin’s Pharmacokinetic Equivalence Determination. The 
Assessed Products are: Metformin-Gliclazide vs Dabex® XR + Diamicron MR®. (Dabex® XR as 
reference) 
Parameter 
Point 
Estimate
90% Confidence 
Interval
Two one-sided T-
test
Power
P < 
80%
P > 
125%
LnCmax
LnAUC0-t
LnAUC0-∞
Table 15.2.2. Statistics for the Metformin’s Pharmacokinetic Equivalence Determination. The 
Assessed Products are: Metformin-Gliclazide vs Dabex® XR.
Parameter 
Point 
Estimate
90% Confidence 
Interval
Two one-sided T-
test
Power
P < 
80%
P > 
125%
LnCmax
LnAUC0-t
LnAUC0-∞
Table 15.2.3. Statistics for the Metformin’s Pharmacokinetic Equivalence Determination. The 
Assessed Products are: Dabex® XR vs Dabex® XR + Diamicron MR®. (Dabex® XR alone as
reference) 
Parameter 
Point 
Estimate
90% Confidence 
Interval
Two one-sided T-
test
Power
P <
80%
P > 
125%
LnCmax
LnAUC0-t
LnAUC0-∞
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Table 15.2.4. Statistics for the Gliclazide’s Pharmacokinetic Equivalence Determination. The 
Assessed Products are: Metformin-Gliclazide vs Dabex® XR + Diamicron MR®. (Diamicron 
MR® as reference) 
Parameter 
Point 
Estimate
90% Confidence 
Interval
Two one-sided T-
test
Power
P < 
80%
P > 
125%
LnCmax
LnAUC0-t
LnAUC0-∞
Table 15.2.5. Statistics for the Gliclazide’s Pharmacokinetic Equivalence Determination. The 
Assessed Products are: Metformin-Gliclazide vs Diamicron MR®.
Parameter 
Point 
Estimate
90% Confidence 
Interval
Two one-sided T-
test
Power
P < 
80%
P > 
125%
LnCmax
LnAUC0-t
LnAUC0-∞
Table 15.2.6. Statistics for the Gliclazide’s Pharmacokinetic Equivalence Determination. The 
Assessed Products are: Diamicron MR® vs Dabex® XR + Diamicron MR®. (Diamicron MR®
alone as reference)
Parameter 
Point 
Estimate
90% Confidence 
Interval
Two one-sided T-
test
Power
P < 
80%
P > 
125%
LnCmax
LnAUC0-t
LnAUC0-∞
As set for in the Mexican Official Standard, NOM-177-SSA1-2013, the parameters to be assessed 
in this study to establish the conclusion about the potential bioequivalence of drugs are Cmax as 
indicative of the rate of absorption and the AUC as indicative of the absorbed amount. Results of 
bio-inequivalence are shown. 
 
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Table 15.2.1 shows the results of the evaluation of the metformin and gliclazide given 
concomitantly versus the test formulation containing both drugs. 
In table 15.2.3, when the metformin reference drug is administered versus the concomitant 
administration of the reference drugs (metformin + gliclazide), a
Tables 15.2.4, 15.2.5, and 15.2.6 show the gliclazide’s pharmacokinetic equivalence results in all 
assessments made; 
The estimated statistical power was greater than 80 % for all the parameters assessed, which 
implies a good certainty to determine a bioequivalence and that the sample size was appropriate. 
 
15.3 Box and Whiskers plots.
In tables 15.3.1 and 15.3.2, box and whiskers plots corresponding to the parameters used to assess 
the absorption and bioavailability for metformin and gliclazide, respectively, are shown. 
 
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Figure 15.3.1 Box and Whiskers Plot for the Metformin’s Pharmacokinetic Parameters
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Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-003
Version 1.0
Table 15.3.2. Box and Whiskers Plot for the Gliclazide’s Pharmacokinetic Parameters 
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15.4
Secondary Endpoint Analyses 
Average results of the metformin's pharmacokinetic parameters are shown in tables 15.4.1 for test 
formulation, 15.4.2 for metformin + gliclazide reference formulations and 15.4.3 for metformin 
reference. In these tables are shown the pharmacokinetics parameters determined for metformin. 
Table 15.4.1. Metformin's Pharmacokinetic Parameters Results for test formulation
Table 15.4.2. Metformin's Pharmacokinetic Parameters Results for concomitant reference 
administration
Table 15.4.3. Metformin's Pharmacokinetic Parameters Results for reference administration alone
N
Mean
SD
CV%
Min
Max
Median
Geometric 
Mean
CV% Geometric 
Mean
AUC_%Extrap_obs
AUCINF_obs
AUClast
Cl_F_pred
Cmax
HL_Lambda_z
MRTINF_obs
Tmax
Vz_F_pred
Metformin-Gliclazide
Variable
N
Mean
SD
CV%
Min
Max
Median
Geometric 
Mean
CV% Geometric 
Mean
AUC_%Extrap_obs
AUCINF_obs
AUClast
Cl_F_pred
Cmax
HL_Lambda_z
MRTINF_obs
Tmax
Vz_F_pred
Variable
Dabex® XR + Diamicron MR®
N
Mean
SD
CV%
Min
Max
Median
Geometric 
Mean
CV% Geometric 
Mean
AUC_%Extrap_obs
AUCINF_obs
AUClast
Cl_F_pred
Cmax
HL_Lambda_z
MRTINF_obs
Tmax
Vz_F_pred
Variable
Dabex® XR
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Version 1.0
Average results of the gliclazide's pharmacokinetic parameters are shown in tables 15.4.4 for test 
formulation, 15.4.5 for metformin + gliclazide reference formulations and 15.4.6 for gliclazide 
reference. In these tables are shown the pharmacokinetics parameters determined for metformin. 
Table 15.4.4. Gliclazide's Pharmacokinetic Parameters Results for test formulation
Table 15.4.5. Glicalzide's Pharmacokinetic Parameters Results for concomitant reference 
administration
Table 15.4.6. Gliclazide's Pharmacokinetic Parameters Results for reference administration alone
N
Mean
SD
CV%
Min
Median
Max
Geometric Mean CV% Geometric 
Mean
AUC_%Extrap_obs
AUCINF_obs
AUClast
Cl_F_pred
Cmax
HL_Lambda_z
MRTINF_obs
Tmax
Vz_F_pred
Metformin-Gliclazide
Variable
N
Mean
SD
CV%
Min
Median
Max
Geometric Mean CV% Geometric 
Mean
AUC_%Extrap_obs
AUCINF_obs
AUClast
Cl_F_pred
Cmax
HL_Lambda_z
MRTINF_obs
Tmax
Vz_F_pred
Variable
Dabex® XR + Diamicron MR®
N
Mean
SD
CV%
Min
Median
Max
Geometric Mean CV% Geometric 
Mean
AUC_%Extrap_obs
AUCINF_obs
AUClast
Cl_F_pred
Cmax
HL_Lambda_z
MRTINF_obs
Tmax
Vz_F_pred
Variable
Diamicron MR®
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15.5
Other Endpoint Analyses 
Data about plasma concentration versus time for each subject, as well as the descriptive statistics 
are shown in tables 15.5.1 for metformin test formulation, 15.5.2 for metformin + gliclazide 
reference formulations concomitant administration and 15.5.3 for metformin reference alone 
administration.
Table 15.5.1. Individual concentrations table corresponding to metformin-gliclazide test 
formulation. n = 
volunteers
0.0000
0.5000
1.0000
2.0000
3.0000
4.0000
5.0000
6.0000
7.0000
8.0000
10.0000
12.0000
16.0000
24.0000
28.0000
32.0000
48.0000
72.0000
96.0000
120.0000
144.0000
168.0000
Time
Volunteer
Form
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EMR200763-003
Version 1.0
Table 15.5.2 Individual concentrations table for metformin + gliclazide, reference formulation, 
concomitant administration. n = 
volunteers
0.0000
0.5000
1.0000
2.0000
3.0000
4.0000
5.0000
6.0000
7.0000
8.0000
10.0000
12.0000
16.0000
24.0000
28.0000
32.0000
48.0000
72.0000
96.0000
120.0000 144.0000 168.0000
Form
Volunteer
Time
P
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EMR200763-003
Version 1.0
Table 15.5.3 Individual concentrations table for metformin reference formulation, alone 
administration. n = 
volunteers
0.0000
0.5000
1.0000
2.0000
3.0000
4.0000
5.0000
6.0000
7.0000
8.0000
10.0000
12.0000
16.0000
24.0000
28.0000
32.0000
48.0000
72.0000
96.0000
120.0000
144.0000
168.0000
Form
Volunteer
Time
P
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EMR200763-003
Version 1.0
Data about plasma concentration versus time for each subject, as well as the descriptive statistics 
are shown in tables 15.5.4 for gliclazide test formulation, 15.5.5 for metformin + gliclazide 
reference formulations concomitant administration and 15.5.6 for gliclazide reference alone 
administration.
Table 15.5.4. Individual concentrations table corresponding to metformin-gliclazide test 
formulation. n = 
volunteers
Table 15.5.5 Individual concentrations table for metformin + gliclazide, reference formulation, 
concomitant administration. n = 
volunteers
0.0000
0.5000
1.0000
2.0000
3.0000
4.0000
5.0000
6.0000
7.0000
8.0000
10.0000
12.0000
16.0000
24.0000
28.0000
32.0000
48.0000
72.0000
96.0000
120.0000
144.0000
168.0000
Time
Volunteer
Form
P
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EMR200763-003
Version 1.0
-: Sample not delivered.
Table 15.5.6 Individual concentrations table for metformin reference formulation, alone 
administration. n = 
volunteers
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EMR200763-003
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Bioavailability of a Metformin/Gliclazide fixed combination tablet
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Version 1.0
Average values for the metformin and gliclazide's concentration obtained in the study as well as 
the descriptive statistics are shown in tables 15.5.7 and 15.5.8.
Table 15.5.7. Descriptive Statistics of the Values of the Metformin's Concentration in Biological 
Fluid
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Table 15.5.8 Descriptive Statistics of the Values of the Gliclazide's Concentration in Biological 
Fluid
Figures 15.5.1 and 15.5.2 show the average charts in arithmetic and logarithmic scales, 
respectively, for gliclazide are shown in figures 15.5.3 and 15.5.4 in arithmetic and logarithmic 
scales.
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Version 1.0
Figure 15.5.1. Metformin's average concentration versus time chart in an arithmetic scale 
following the test and reference administration (standard deviation bars) 
Figure 15.5.2. Metformin's average concentration versus time chart in logarithmic scale 
following the test and reference administration (standard deviation bars) 
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Version 1.0
Figure 15.5.1. Metformin's average concentration versus time chart in an arithmetic scale 
following the test and reference administration (standard deviation bars) 
Figure 15.5.2. Metformin's average concentration versus time chart in logarithmic scale following 
the test and reference administration (standard deviation bars)
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16.
Estimation of Individual Pharmacokinetic Parameters 
Non-compartmental computation of pharmacokinetic parameters was performed using the 
computer program Phoenix® WinNonlin® version 8.0 (
).  
The pharmacokinetic analysis was performed with a non-compartmental analysis, using real times 
following the dosing of the studied drugs. Pharmacokinetic parameters were determined as shown 
in tables 16.1. and 16.2, which include the individual values and descriptive statistics used for 
determining bioequivalence and drug-drug interaction, between the active ingredients, for 
metformin and gliclazide, respectively. 
Table 16.1. Individual Data and Descriptive Statistics for Metformin's Pharmacokinetic 
Parameters (Cmax in ng/mL, AUC0Æt in h*ng/mL and AUC0Æ∞in h*ng/mL).
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Version 1.0
Table 16.2. Individual Data and Descriptive Statistics for Gliclazide's Pharmacokinetic 
Parameters (Cmax in ng/mL, AUC0Æt in h*ng/mL and AUC0Æ∞in h*ng/mL).
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The Phoenix WinNonlin NCA Core Output is provided in a separate listing. 
17
Safety Evaluation 
According to the Mexican Official Standard, NOM-177-SSA1-2013, there are several statistical 
tests to identify extreme values. Most of them start by calculating the student residual absolute 
value. Likewise, it is stated that "since studies are generally crossed designed, the most important 
extreme values is the extreme value for the subject". 
An adequate method for estimating extreme values allows increasing reliability of the study 
conclusion. An analysis to identify outliers (extreme) values based on the student residual 
estimation among subjects will be performed using Bear software (current) for R environment.
Criterion: extreme values are those data which degree is higher than ± 2 standardized residuals 
intra-subject.
17.1 Pharmacokinetic Parameters' Outliers
Outliers determination is by means of the intra-subject student residuals calculation according to 
the Mexican Official Standard, NOM-177-SSA1-2013; therefore, the potential outliers are those 
which exceed the criterion of ± 2 student residuals. In this study, outliers were determined 
according to Rasheed A. et al 2011, who states the statistical methodology to determine the outliers 
for the designs of more than two formulations, by means of the Andrew’s curve. In figures 17.1.1, 
17.1.2 and 17.1.3 the assessed pharmacokinetic parameters plots to determine the metformin’s 
pharmacokinetic equivalence are shown, and in figures 17.1.4, 17.1.5 and 17.1.6 the assessed 
pharmacokinetic parameters plots to determine the gliclazide’s pharmacokinetic equivalence are 
shown.
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Figure 17.1.1. Intra-subject Student Residuals Plot for the Metformin’s Pharmacokinetic 
Parameter Ln Cmax
Figure 17.1.2. Intra-subject Student Residuals Plot for the Metformin’s Pharmacokinetic 
Parameter Ln AUC0-t
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Version 1.0
Figure 17.1.3. Intra-subject Student Residuals Plot for the Metformin’s Pharmacokinetic 
Parameter Ln AUC0-∞
Figure 17.1.4. Intra-subject Student Residuals Plot for the Gliclazide’s Pharmacokinetic 
Parameter Ln Cmax
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Figure 17.1.5. Intra-subject Student Residuals Plot for the Gliclazide’s Pharmacokinetic 
Parameter Ln AUC0-t
Figure 17.1.6. Intra-subject Student Residuals Plot for the Gliclazide’s Pharmacokinetic 
Parameter Ln AUC0-∞
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18.
Adverse Events 
All the information related with clinical results is included in clinical inform
19
References 
-
Chow S.S, Liu JP. (2009). Design and Analysis of Bioavailability and Bioequivalence 
Studies. 3rd edition. US: CRC Press.
-
Mexican Official Standard NOM-177-SSA1-2013 which sets out the tests and procedures 
to prove that a drug is interchangeable, requirements for the authorized third parties 
performing interchangeability tests; requirements for the conduct biocomparability studies, 
requirements for authorized third parties, research centers and hospitals conducting 
biocomparability tests.   
20
Appendices 
x
Quality Assurance Report.
x
Individual Concentrations
x
Winnonlin Core Outputs