Conditions: Healthy
Keywords: Metformin Bioavailability Food effect Pharmacokinetics
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 21
Healthy volunteers: yes

Brief summary:
This study will assess the food effect on bioavailability of Metformin/Gliclazide fixed dose combination tablet in fed and fasted state.

Detailed description:

Arms:
arm 1: Participants received single dose of Metformin 1000 milligram (mg) and Gliclazide 30 mg fixed combination tablet in fasting state in treatment period 1 followed by single dose of Metformin 1000 mg and Gliclazide 30 mg fixed combination tablet in fed state in treatment period 2. Each treatment period was separated by a 14-day wash-out period. arm 2: Participants received single dose of Metformin 1000 mg and Gliclazide 30 mg fixed combination tablet in fed state in treatment period 1 followed by single dose of Metformin 1000 mg and Gliclazide 30 mg fixed combination tablet in fasting state in treatment period 2. Each treatment period will be separated by a 14-day wash-out period.

Interventions: intervention 1: Metformin/Gliclazide Fixed Combination
Intervention descriptions: intervention 1: Participants will receive single oral dose of Metformin 1000 mg and Gliclazide 30 mg fixed combination tablet in fasting or fed state.

Protocol document:
Prot_000.pdf: 
Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
1/74
Clinical Trial Protocol
Clinical trial protocol number
BD1412-63CEC
EMR200763-004
Title
A randomized, open-label, single dose, 2x2 crossover 
trial to evaluate the food effect on the bioavailability 
of a Metformin/Gliclazide fixed combination tablet 
(1000 mg / 30 mg MR) given in fasting and fed state
to healthy volunteers. 
International non-proprietary 
name 
Metformin/Gliclazide.
Phase
Phase I (food interaction)
IND Number
not applicable
EudraCT Number
not applicable
Principal Investigator
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor
Merck KGaA Darmstadt.  
Name: 
Address Frankfurter Strasse 250 64293 Darmstadt, 
Germany
(phone)|
Study Monitor
Date of elaboration and version 
Nov/15/2017, version 2.0
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 © 
2015 by Merck KGaA, Darmstadt, Germany, or its affiliate. All rights reserved.
PPD
PPD
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
2/74
C l i n i c a l  U n i t
Name:
Signature:
Role:
Principal Investigator 
Date:
 
Name:
Signature:
Role:
Sanitary Officer
Date:
Name:
Signature:
Role:
Quality Assurance Officer
Date:
Address:
Telephone:
/Fax: 
A n a l y t i c a l  U n i t
Name:
Signature:
Role:
Bioanalytics Investigator
Date:
Name:
Signature:
Role:
Sanitary Officer 
Date:
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
3/74
Name:
Signature:
Role:
Responsible for Biostatistics  
Date:
Name:
Signature:
Role:
Quality Manager 
Date:
Address:
 
 
 
 
 
 
Telephone:
S p o n s o r
Name:
Signature:
Role:
Responsible for the Study
Date:
C o m m i t t e e s
Ethics 
on
Investigation 
Committee
 
 
Investigation Committee:
PPD
PPD
PPD
PPD
PPD
PP
D
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
4/74
C l i n i c a l  L a b o r a t o r y
Ph. 
Clinical Laboratory:
PPD
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
5/74
Table of contents
Table of contents
5 
Abbreviations list
9 
1 
Summary.............................................................................................11 
2 
Sponsor, Principal Investigator and Study Administrative Staff........17 
3 
Background.........................................................................................17 
3.1.1 
Metformin's Pharmacology.................................................................18 
3.1.2 
Absorption ..........................................................................................18 
3.1.3 
Distribution.........................................................................................18 
3.1.4 
Metabolism .........................................................................................18 
3.1.5 
Excretion.............................................................................................18 
3.1.6 
Mechanism of action...........................................................................19 
3.1.7 
Pharmacological Properties ................................................................19 
3.1.8 
Adverse reactions................................................................................19 
3.2 
Gliclazide's Pharmacology .................................................................20 
3.2.1 
Gliclazide's Chemical Structure..........................................................20 
3.2.2 
Absorption ..........................................................................................20 
3.2.3 
Distribution.........................................................................................20 
3.2.4 
Metabolism .........................................................................................21 
3.2.5 
Excretion.............................................................................................21 
3.2.6 
Mechanism of action...........................................................................21 
3.2.7 
Pharmacological Properties ................................................................21 
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 
Investigational Plan ............................................................................24 
6.1 
Experimental design and study plan...................................................24 
6.2 
Rationale for Study Design.................................................................25 
6.3 
Study population screening.................................................................26 


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
6/74
6.3.1 
Inclusion criteria:................................................................................26 
6.3.2 
Exclusion criteria:...............................................................................27 
6.3.3 
Study withdrawal criteria....................................................................28 
6.4 
Start-up criteria for the study treatment..............................................29 
6.5 
Study Subject Withdrawal ..................................................................29 
6.5.1 
Early study termination.......................................................................30 
6.5.2 
End of Study Definition......................................................................30 
7 
Investigational Drug ...........................................................................30 
7.1 
Investigational Drug Description........................................................30 
7.2 
Dosage and administration .................................................................31 
7.3 
Randomization to treatment groups....................................................32 
7.4 
Selection and Dosing Schedule for Each Subject...............................32 
7.5 
Concomitant therapies and drugs........................................................33 
7.5.1 
Allowed Drugs....................................................................................33 
7.5.2 
Forbidden Drugs .................................................................................34 
7.5.3 
Special Warnings................................................................................34 
7.5.4 
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................34 
7.6 
Investigational Drug Packaging and Labeling....................................34 
7.7 
Preparation, Management and Storage of Study Drug .......................34 
7.8 
Study Drug Accountability.................................................................35 
7.9 
Assessment of Study Drug Compliance .............................................36 
7.10 
Blinding ..............................................................................................36 
7.11 
Overdose treatment.............................................................................36 
7.12 
Medical Care for Subjects Following the End of the Study...............38 
8 
Study Assessments and Procedures....................................................38 
8.1.1 
Subjects screening ..............................................................................38 
8.1.2 
Study periods ......................................................................................38 
8.1.3 
Control of Meals and Liquid Intake....................................................39 
8.2 
Schedule of Assessments....................................................................40 
8.2.1 
First Administration Period ................................................................40 
8.2.2 
Washout Period...................................................................................44 


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
7/74
8.2.3 
Second Administration Period............................................................44 
8.2.4 
End of Trial (EoT) ..............................................................................44 
8.3 
Baseline demographic characteristics.................................................44 
8.4 
Efficacy assessments ..........................................................................45 
8.5 
Safety Assessments.............................................................................45 
8.5.1 
Adverse Event.....................................................................................46 
8.5.2 
Pregnancy and exposure to drugs in the Uterus..................................53 
8.5.3 
Clinical Laboratory Assessments .......................................................54 
8.5.4 
Vital signs, ECGs, Physical Examinations and other Assessments....57 
8.6 
Pharmacokinetics................................................................................58 
9 
Pharmacokinetic and statistical analysis.............................................61 
9.1 
Sample Size ........................................................................................61 
9.2 
Randomization....................................................................................62 
9.3 
Outcome variables ..............................................................................62 
9.3.1 
Main outcome variable .......................................................................62 
9.3.2 
Secondary outcome variables .............................................................62 
9.4 
Deviation and Exclusion to the Statistical Analysis...........................63 
9.5 
Statistical Analyses Description .........................................................63 
9.6 
Extreme Values...................................................................................65 
10 
Ethical and Regulatory Issues.............................................................65 
10.1 
Principal Investigator's Responsibilities.............................................65 
10.2 
Information for the Subject and Informed Consent............................65 
10.3 
Subject's Identification and Confidentiality .......................................66 
10.4 
Medical Insurance and Subjects' Compensation.................................67 
10.5 
Ethics and Investigation Committee and Investigational 
Committee...........................................................................................67 
10.6 
Health Authorities...............................................................................67 
11 
Study Management .............................................................................67 
11.1 
Case Report Form...............................................................................67 
11.2 
Source Document and Subject's Medical Chart..................................67 
11.3 
Site's File and Master File...................................................................68 
11.4 
Quality Management ..........................................................................68 


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
8/74
11.5 
Changes to the Protocol......................................................................69 
11.6 
Study Report and Publication Policy..................................................69 
11.6.1 
Clinical Study Report .........................................................................69 
11.6.2 
Publication..........................................................................................69 
12 
Deviations to the Protocol ..................................................................70 
13 
References...........................................................................................70 
14 
Appendices .........................................................................................72 
Appendix 2: 
Diet .....................................................................................................74 
 


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
9/74
Abbreviations list
μg
Microgram
A
Treatment in fasted state
A´
Treatment in fed state
AE
Adverse Event
AUC
Area under the plasma/serum - concentration time curve
AUC0of
Area under the plasma/serum concentration time curve from 0 to 
extrapolated to infinity
AUC0ot
Area under the plasma/serum concentration time curve from 0 to last 
time of sampling
BMI
Body Mass Index
CARPERMOR
CBC
Complete Blood Count
CL/f
Apparent total body clearance of drug from plasma
Cmax
Maximum Plasma Concentration
CNFV
Mexican National Center of Pharmacovigilance
COFEPRIS
Federal Commission for the Protection against Sanitary Risks
CRF
Case Report Form
DBP
Diastolic Blood Pressure
dL
Deciliter
E
Elimination
ECG
Electrocardiogram
FDA
Food and Drug Administration (U.S.)
g
grams 
GCP
Good Clinical Practice
h
Hour
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Conference of Harmonization
IUPAC
International Union of Pure and Applied Chemistry
IV
Intravenous
Ke
Elimination Rate Constant
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
10/74
min
Minute
mL
Milliliter
MoH
Ministry of Health
MRT
Mean Residence Time
PI
Principal Investigator (Study Coordinator, Clinical Unit)
PT
Prothrombin time 
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SD
Standard Deviation 
SOPs
Standard Operating Procedures
t
Time
t½
Elimination Half Time
tmax
Time of peak plasma concentration
TPT
Partial thromboplastin time 
Vz/f
Apparent volume of distribution


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
11/74
1
Summary 
Protocol number
BD1412-63CEC
EMR200743-004
Title
A randomized, open-label, single dose, 2x2 
crossover trial to evaluate the food effect on the 
bioavailability of a Metformin/Gliclazide fixed 
combination tablet (1000 mg /30 mg MR) given 
in fasting and fed conditions to healthy volunteers.
Phase
Phase I (food interaction) 
IND Number
Must match title page or indicate ‘not applicable’ 
FDA covered trial
Indicate ‘yes’ or ‘no’
EudraCT Number
Must match title page or indicate ‘not applicable’ 
Principal Investigator
Sponsor
Merck KGaA 
Sponsor's legal representative at the 
European Union
Merck KGaA 
Investigational sites/Countries
Not applicable
Scheduled study period (first subject 
and last subject)
Not applicable
Study approval
COFEPRIS
Objectives: 
Primary objectives
To assess the food effect on bioavailability (AUC0-∞, AUC 0-t and Cmax) for the fixed dose 
combination Metformin 1000 mg/Gliclazide 30 mg MR, given as single dose in fasted state 
and with food to healthy volunteers. 
Secondary objectives
To determine further pharmacokinetic parameters such as tmax, t1/2, Vz/f and Cl/f.
To assess the safety and tolerability of the fixed dose combination in fed and fasted state
Methodology: A randomized, open label, single dose, 2 period crossover design will be used 
with 22 subjects in fed and fasted state, with a 14-day washout period between 2 study stages.
Planned number of subjects: 22 (at least 40 % for each gender by study group).
Primary variable: the variables going to be AUC0-∞, AUC 0-t and Cmax for Metformin and 
Gliclazide, in fed and fasted state.
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
12/74
Secondary objectives: 
-
Pharmacokinetic parameters will be determined: tmax, Vz/f and CL/f.
-
To assess and compare the safety and tolerability of the fixed dose combination
Metformin /Gliclazide administered in fasted and fed state.
Pharmacokinetic parameters: Main parameters will be AUC0-t, AUC0-∞and Cmax for 
Metformin and Gliclazide.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
13/74
Key inclusion and exclusion criteria:
Inclusion criteria:
Subject grants informed consent prior any study related activity will be performed.
1. Ethnicity: Mexicans (e.g., Caucasian, native people and Mestizo [mixed race])
2. Gender: Female and male (at least 40 % for each gender by study group).
3. Age between 18 and 55 years old, both including.
4. Weight between 55 and 95 kg.
5. Body mass index between 18 and 27 kg/m2.
6. Nonsmokers or subjects who do not smoke more than 5 cigarettes or 1 pipe a day
7. Good physical and mental health based on the clinical history and physical examination.
8. 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.
10. Liver Function Test, including direct and indirect bilirubin, glutamic oxaloacetic 
transaminase (aspartate aminotransferase) and glutamic pyruvic transaminase (alanine 
aminotransferase), 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.
11. Electrocardiogram (12 leads) without clinically significant pathological signs, particular in 
QTc interval Bazett (normal value < 450 ms).
12. 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 8.5.3.
13. Vital signs (blood pressure and pulse) in supine position within normal ranges or with 
clinically significant abnormalities as per the Principal Investigator's judgment.
a.
Heart rate between 50 and 100 beats per minute.
b. Respiratory rate between 12 and 20 per minute.
c.
Systolic blood pressure between 80 and 129 mmHg.
d. Diastolic blood pressure between 50 and 89 mmHg.
e.
Forehead temperature between 36.0 and 37.0 °C.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
14/74
14. All women of childbearing 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.
15. Negative result for alcohol breath test and urine test for drugs of abuse (opioids, 
barbiturates, cocaine and its metabolites, amphetamines, metamphetamines, morphine, 
cannabinoids, benzodiazepines and tricyclic antidepressants), at screening and at each day 
-1 of the 2 treatment periods.
16. Negative serology tests for human immunodeficiency virus (HIV1 and HIV2 antibodies), 
hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV) and VDRL test screening.
Exclusion criteria:
1. Subjects who have received any investigational drug within 21 days prior to the 
study start.
2. Subjects who have donated or lost 450 mL or more of blood within 21 days prior to 
the study start.
3. Subjects with history of cardiovascular, renal, liver, metabolic, gastrointestinal, 
neurological, endocrine, or hematopoietic (any type of anemia) diseases; mental 
disease, surgery or other organic abnormalities which might affect the study of the 
investigational drug pharmacokinetics.
4. History of gastrointestinal tract surgery that might affect gastrointestinal absorption 
and/or motility as per the investigator's judgment.
5. Subjects with history of hypersensitivity to the study drug and/or any formulation's 
ingredient; history of drug induced anaphylaxis.
6. Subjects who take any other drug, prescribed or over the counter drugs 30 days
before the study drug dose and for which at least seven elimination half-lives had 
not elapsed, including multi-vitamins and herbal products (e.g., St. John's Wort) 
including ASA and oral contraceptives for women. Except for paracetamol 
(maximum 1000 mg per day for three consecutive days) that can be given if
required, as per the Principal Investigator's judgment. 
7. Renal failure or renal impairment (creatinine clearance < 80 mL/min), assessed by 
using the Cockcroft-Gault formula.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
15/74
8. Subject's disagreement or lack of capacity to communicate and cooperate with the 
Investigator, lack of legal capacity or limited legal capacity which prevent him/her 
from continuing in the study. 
9. Refusal of the high-fat diet which is necessary to assess the food effect.
Considerable deviations to the diet's normal nutritional patterns.
10. Subjects who have smoked tobacco, having drunk alcohol, or xanthines containing 
beverages or food (coffee, tea, cacao, chocolate, mate, coke drinks, etc.) above 600 
mg of caffeine a day (a 240-mL cup of coffee contains 100 mg of caffeine, one cup 
of tea contains 30 mg and a glass of coke contains 20 mg of caffeine); those who 
have had grilled food (charcoal) within 24 h prior to the drug dosing (Fuhr 1998).
11. Intake of grapefruit, orange, cranberries or their juices within 14 days prior to the 
drug's dosing and throughout the study.
12. Legal inability or limited legal capacity
13. Incarcerated subjects.
14. Subjects who have been exposed to agents known as liver enzyme systems' inducers 
or inhibitors, or who have taken potentially toxic drugs within 30 days prior to the 
study.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
16/74
Study drug: dosage/route/dosing schedule: 
Fixed dose of Metformin 1000 mg/Gliclazide 30 mg MR (one tablet), single dose, given in 
fasting or postprandial state.
Study duration: Approximately seven weeks
Statistical method:
According to the
goals for the study,
treatment
regarding
postprandial/fasting, pharmacokinetic parameters will be calculated AUC and Cmax for both
analytes, Metformin and Gliclazide. In order to have an accurate and reasonable precision for 
the estimated ratios, a sufficient amount of subjects will be randomized. Taking 90 % 
confidence interval for the postprandial/fasting ratio as a measure for accuracy and assuming
an average variation coefficient of 20 % for AUC (AUC0-∞, AUC0-t) and Cmax for Metformin or 
Gliclazide, then with 18 evaluable subjects the food effect on pharmacokinetics can be 
estimated with an accuracy of 12 %.
The following ratio will be carried out, being R the estimated ratio and LCL/UCL lower and 
upper confidence limit for the 90 % confidence interval for R:
0.89 * R ≤LCL < UCL ≤1,12 * R
An accuracy of 12 % or higher will result in an accurate description for the food effects.
Besides, 18 evaluable subjects are enough to detect a difference among treatments of 18 % or 
higher with a power of 80 % at least. Taking into account a drop-out rate around 20 %, 22 
subjects should be randomized.
This trial intends to estimate the food effects on the pharmacokinetics. It is not intended to 
prove or confirm statistically the lack of food effect.  
Therefore, no statistical hypothesis is shown. As primary analysis, a mix model for Cmax, AUC0-
tand AUC0-∞log-transformed will be applied. With TREATMENT, PERIOD and SEQUENCE 
as fixed effects, and the SUBJECT (SEQUENCE) as random effect. Based on residual errors 
term, confidence intervals of 90 % will be built for estimated differences for postprandial -
fasting, resulting in confidence intervals of 90 % for the postprandial/fasting ratios following 
transformation.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
17/74
2
Sponsor, Principal Investigator and Study Administrative 
Staff 
The study will be sponsored by: Merck KGaA. Frankfurter Strasse 250 64293 Darmstadt, Germany
The study will be conducted in one site, 
.
The 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. 
 is responsible for the review and approval of the clinical study report. 
This protocol meets requirements of current clinical research regulations, including: GCP's, 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.
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 a 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 trial protocol is justified.
Refer to the Investigator's Brochure (IB) to get more information about programs and non-clinical 
and clinical advice for the Investigator.
PPD
PPD
PPD
PP
PPD
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
18/74
3.1.1
Metformin's Pharmacology
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 (Vz/f) following oral single dose of Metformin HCl 850 
mg tablets averaged 654 ± 358 L. Metformin has a minimum bound to proteins. At usual clinical 
doses and dosage of Metformin hydrochloride, plasma concentration in steady state is achieved 
within 24-48 h and generally is < 1 mg/mL (Green and Feinglos, 2008, Cho et al., 2009). Following 
the oral dose of Metformin XR 500 mg, Tmax was of 7 hours and Cmax of 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 following IV administration is between 63 and 276 L.
It is quickly distributed to tissues and peripheral body fluids. It is slowly distributed in erythrocytes 
(Pentikainen et al., 1979).
3.1.4
Metabolism
Metformin does not undergo metabolism in humans; 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's renal clearance is > 400 mL/min, which shows that Metformin is cleared by 
glomerular filtration and tubular secretion. 


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
19/74
Maximum plasma concentration time is approximately 2 hours. The plasma half-life, ranges 
between 4 and 6 hours (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 closet al., 2005; Hundal and Inzuchi, 2003; Ristic et al., 2007).
3.1.7
Pharmacological Properties 
Throughout Metformin's chronic treatment, internal absorption of vitamin B12, folates and 
calcium supplements is reduced, reverting then 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 reactions may occur with Metformin treatment: taste impairment, nausea, 
vomiting, diarrhea, anorexia, abdominal pain and loss of appetite (CCSI V7 for metformin 
hydrochloride).
Gastrointestinal disorders
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
Skin reactions such as erythema, pruritus, or urticaria.
Metabolism and nutrition disorders
Lactic acidosis 


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
20/74
Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of 
metformin. Consideration of such etiology is recommended if a patient presents with megaloblastic 
anemia.
Hepatobiliary disorders
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) sulphonylurea.
Gliclazide's empiric formula is C15H21N3O3S. Gliclazide's molecular weight is 323.41 g/mol 
(Pubchem, 2015).
Figure 2. - Gliclazide
3.2.2
Absorption
It is quickly and well absorbed, following Gliclazide's oral dosing, plasma concentrations increase 
progressively until the 6th hour, and it will get steady until 6th and 12 hour. (PI Diamicron MR, 
2013). Gliclazide it is fully absorbed. Intra-individual variability is low.季It has a bioavailability of 
80 % (Sarkar et al., 2011; Campbell et al., 1991).
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 placental 
barrier and travels in the fetal blood stream. A low apparent distribution volume is likely seen in 
the high binding degree to proteins for Gliclazide (approximately 94 % of a plasma concentration 
of 8 μg/mL) (Sarkar et al., 2011).


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
21/74
3.2.4
Metabolism
It 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. 
Involved enzymes 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 120 h following dosing (Ings et 
al., 1986).
Fecal clearance is approximately 11 % of the administered dose (Ings et al., 1986). Gliclazide's 
elimination half-life ranges between 12 and 20 hours (IP 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 second generation sulphonylurea commonly used for the treatment of Type 2 
Diabetes, used in poorly controlled patients with Metformin as monotherapy, and provides a 
complementary mechanism of action for Metformin (Ristic et al., 2007).
3.2.8
Adverse reactions
Overall, 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.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
22/74
Usually, symptoms disappear after intake of carbohydrates (sugar). However, artificial sweeteners 
have no effect. Experience with other sulphonylureas shows that hypoglycemia can recur even 
when measures prove effective initially.
Gastrointestinal disturbances, including abdominal pain, nausea, vomiting dyspepsia, diarrhea, and 
constipation have been reported: if these should occur they can be avoided or minimized if 
Gliclazide is taken with breakfast. The following undesirable effects have been more rarely 
reported:
• Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, angioedema, erythema, 
maculopapular rashes, bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis).
• Blood and lymphatic system disorders: Changes in hematology are rare. They may include 
anemia, leucopenia, thrombocytopenia, granulocytopenia. These are in general reversible upon 
discontinuation of medication.
• Hepato-biliary disorders: raised hepatic enzyme levels (AST, ALT, alkaline phosphatase), 
hepatitis (isolated reports). Discontinue treatment if cholestatic jaundice appears. These symptoms 
usually disappear after discontinuation of treatment.
• Eye disorders
Transient visual disturbances may occur especially on initiation of treatment, due to changes in 
blood glucose
• Class attribution effects:
As for other sulphonylureas, the following adverse events have been observed: cases of 
erythrocytopenia, agranulocytosis, hemolytic anemia, pancytopenia, allergic vasculitis, 
hyponatremia, elevated liver enzyme levels and even impairment of liver function (e.g. with 
cholestasis and jaundice) and hepatitis which regressed after withdrawal of the sulphonylurea or 
led to life-threatening liver failure in isolated cases (EMC SmPC Diamicron).
Gliclazide is classified as category "C" for its use during pregnancy and breastfeeding as per the 
FDA (FDA, 2015).
4
Adverse 
Reactions 
of 
the 
combination 
product 
(Metformin/Gliclazide)
Hypoglycemia
As for other sulphonylureas, treatment with Gliclazide can cause hypoglycemia, if mealtimes are 
irregular and, in particular, if meals are skipped. Possible symptoms of hypoglycemia 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.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
23/74
Usually, symptoms disappear after intake of carbohydrates (sugar). However, artificial sweeteners 
have no effect. Experience with other sulphonylureas shows that hypoglycemia can recur even 
when measures prove effective initially. If a hypoglycemic episode is severe or prolonged, and
even if it is temporarily controlled by intake of sugar, immediate medical treatment or even 
hospitalization is required.
Blood and lymphatic system disorders
Rare: Hematologic disturbances which may include anemia, 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 Gliclazide. Consideration of such etiology is recommended if a patient 
presents with megaloblastic anemia.
Frequency not known: Hypoglycemia.
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, diarrhea, 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 Gliclazide 
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 urticarial.
Frequency not known: Angioedema, maculopapular rashes, and bullous reactions (such as 
Stevens-Johnson syndrome and toxic epidermal necrolysis).
Related to sulphonylureas


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
24/74
Class attribution effects:
As one of the active ingredients in Gliclazide belongs to sulphonylureas, the following adverse 
events have been observed: cases of erythrocytopenia, agranulocytosis, hemolytic anemia, 
pancytopenia, allergic vasculitis, hyponatremia.
5
Study Objectives
5.1
Primary Objective 
To assess the food effect on bioavailability (AUC0-∞, AUC 0-t and Cmax) for the fixed dose 
combination Metformin 1000 mg/Gliclazide 30 mg MR, given as single dose in fed and fasted 
state to healthy volunteers.
5.2
Secondary objectives: 
Additional Pharmacokinetic parameters will be determined: t ½, tmax, Vz/f and Cl/f.
To assess and compare safety and tolerability of the fixed dose combination Metformin 
/Gliclazide administered in fast and fed state.
6
Investigational Plan 
6.1
Experimental design and study plan 
The IMP will be given in fast and fed state. A randomized, open label, single dose, 2 x 2 cross 
design will be used with a 14-day washout period between 2 study stages. Treatment groups will 
be balanced, with the same number of subjects, who will be randomized to the dosing sequences
(see table below).
Food's effect study
Sequence
Period 1
Washout
period
Period 2
1
Fast
Fed
2
Fed
Fast
All data from participant subjects should be analyzed and included in the statistical analysis, as 
long as they meet the established criteria.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
25/74
6.2
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 
A1c target for more than 3 months, then it will be necessary to add a second oral agent from another 
pharmacological family, such 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 and Gliclazide 
association and it is particularly recommended by some clinical guidelines (Theobald, 2014) when 
Metformin monotherapy is not enough to achieve treatment objectives. 
Therefore, a fixed dose combination has been developed as second line therapy, in cases when 
Metformin's monotherapy has not shown a satisfactory benefit/risk ratio. Therefore, this 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.)
Prior to this proposed study, a study to assess bioequivalence between fixed dose and concomitant 
administration was performed, in addition to the lack of drug - drug interaction.
According to the international guidelines, studies to compare relative bioavailability in fasting and 
food conditions are necessary for combined modified release drugs, such as the combination 
proposed herein. Therefore, as part of the full clinical development for the fixed dose combination, 
food interaction should be studied. Study design adheres to the Mexican regulations as well as to 
the international guidelines for food assessment (Diabetes Care, 2014).
The purpose of this clinical study is to assess the food effect on bioavailability for the new fixed 
dose combination for Metformin 1000 mg/Gliclazide 30 mg MR.
In addition to the inclusion and exclusion criteria, potentially confounding factors to be controlled 
are: fast state and dosing immediately after food intake, as well as the type breakfast; morning 
schedule for treatment's dosing; volume and type of liquids to drug's intake; schedule, type and 
amount of food; physical activity restricted to minimum which does not modify heart rate; supine 
or seated positions up to reaching the stated time for tmax; exclusion of caffeine and/or theophylline 
products; controlled access to the health services until reaching stated time for tmax. In addition, 
concomitant use of drugs is not allowed, unless prescribed drugs for adverse events, with the 
exception for paracetamol that can be given if required, as per the Principal Investigator's judgment
This study will be carried out in male and female healthy volunteers.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
26/74
6.3
Study population screening 
Only those people who meet all inclusion criteria and no 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 9.2, Subject's information 
and informed consent form.
Recruitment by invitation by means of an open announcement.
Inclusion of 22 subjects in study as per protocol's criteria.
Female and male (at least 40 % for each gender by group).
6.3.1
Inclusion criteria:
Subject grants informed consent prior any study related activity will be performed.
1. Ethnicity: Mexicans (e.g., Caucasian, native people and Mestizo [mixed race])
2. Gender: Female and male (at least 40 % for each gender by study group).
3. Age between 18 and 55 years old, both including.
4. Weight between 55 and 95 kg.
5. Body mass index between 18 and 27 kg/m2.
6. Non smokers or subjects who do not smoke more than 5 cigarettes or 1 pipe a day
7. Good physical and mental health based on the clinical history and physical examination.
8. 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.
10. Liver Function Test, including direct and indirect bilirubin, glutamic oxaloacetic transaminase 
(aspartate aminotransferase) and glutamic pyruvic transaminase (alanine aminotransferase), 
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.
11. Electrocardiogram (12 leads) without clinically significant pathological signs, particular in 
QTc interval Bazett (normal value < 450 ms).


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
27/74
12. All women of childbearing potential should test negative for pregnancy qualitative and 
quantitative test during screening period and at the start of each visit (day -1 for each treatment 
period.)
13. Vital signs (blood pressure and pulse) in supine position within normal ranges or with 
clinically significant abnormalities as per the Principal Investigator's judgment.
f.
Heart rate between 50 and 100 beats per minute.
g. Respiratory rate between 12 and 20 per minute.
h. Systolic blood pressure between 80 and 129 mmHg.
i.
Diastolic blood pressure between 50 and 89 mmHg.
j.
Forehead temperature between 36.0 and 37.0 °C.
14. All women of childbearing 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.
15. Negative result for alcohol breath test and urine test for drugs of abuse (opioids, barbiturates,
cocaine and its metabolites, amphetamines, metamphetamines, morphine, cannabinoids, 
benzodiazepines and tricyclic antidepressants), at screening and at each day -1 of the 2 treatment 
periods.
16. Negative serology tests for human immunodeficiency virus (HIV1 and HIV2 antibodies), hepatitis 
A (HAV), hepatitis B (HBV), hepatitis C (HCV) and VDRL test screening.
6.3.2
Exclusion criteria:
1
Subjects who have received any investigational drug within 90 days prior to the study start.
2
Subjects who have donated or lost 450 mL or more of blood within 90 days prior to the study 
start.
3
Subjects with history of cardiovascular, renal, liver, metabolic, gastrointestinal, neurological, 
endocrine, or hematopoietic (any type of anemia) diseases; mental disease, surgery or other 
organic abnormalities which might affect the study of the investigational drug pharmacokinetics.
4
History of gastrointestinal tract surgery that might affect gastrointestinal absorption and/or 
motility as per the investigator's judgment.
5
Subjects with history of hypersensitivity to the study drug and/or any formulation's ingredient; 
history of drug induced anaphylaxis.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
28/74
6
Subjects who take any other drug, prescribed or over the counter drugs 30 days before the study 
drug dose and for which at least seven elimination half-lives had not elapsed, including multi-
vitamins and herbal products (e.g., St. John's Wort) including ASA and oral contraceptives for 
women. Except for paracetamol that can be given if required, as per the Principal Investigator's 
judgment. 
7
Renal failure or renal impairment (creatinine clearance < 80 mL/min), assessed by using the 
Cockcroft-Gault formula.
8
Subject's disagreement or lack of capacity to communicate and cooperate with the Investigator, 
lack of legal capacity or limited legal capacity which prevent him/her from continuing in the study. 
9
Refusal of high-fat diet which is necessary to assess the food effect. Considerable deviations to 
the diet's normal nutritional patterns.
10 Subjects who have smoked tobacco, having drunk alcohol, or xanthines containing beverages or 
food (coffee, tea, cacao, chocolate, mate, coke drinks, etc.) above 600 mg of caffeine a day (a 240-
mL cup of coffee contains 100 mg of caffeine, one cup of tea contains 30 mg and a glass of coke 
contains 20 mg of caffeine); those who have had grilled food (charcoal) within 24 h prior to the 
drug dosing (Fuhr 1998).
11 Intake of grapefruit, orange, cranberries or their juices within 14 days prior to the drug's dosing 
and throughout the study.
12 Legal inability or limited legal capacity
13 Incarcerated subjects.
14 Subjects who have been exposed to agents known as liver enzyme systems' inducers or inhibitors, 
or who have taken potentially toxic drugs within 30 days prior to the study.
6.3.3
Study withdrawal criteria 
Subjects can be withdrawn from the study, as per the Principal Investigator's judgment, for the 
following reasons:
1.
In case continuous participation in the trial is detrimental for subject's health, as per 
Investigator's judgment.
2.
Hypertension signs and symptoms which require pharmacological treatment.
3.
Syncope or shock.
4.
Severe adverse reaction.
5.
Serious Adverse Event.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
29/74
6.
Concurrent diseases or concomitant treatments not allowed by the protocol.
7.
Lack of discipline.
8.
Lack of compliance with the diet.
9.
Loss of two samples within absorption period or near to the Cmax.
10.
Should emesis occur within the established time for tmax.
11.
Data from subjects who experience emesis during the course of the bioavailability study 
should be removed from the statistical analysis if vomiting occurs in or after twice the 
median value for tmax.
12.
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.
13.
Positive test for drugs of abuse (drug screening) such as: amphetamines, benzodiazepines, 
cocaine, metamphetamines, morphine and tetrahydrocannabinoids.
14.
Positive pregnancy test, qualitative and quantitative test during screening period and at 
the start of each visit (day -1 for each treatment period) following the study drug dosing.
15.
All cases where the Principal Investigator judges as lack of compliance to the protocol or 
which may risk final results.
16.
Lost to follow-up.
17.
Participation in another investigational study.
18.
Any event which in the opinion of the Investigator might risk subject's safety unacceptably.
6.4
Start-up criteria for the 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 should have negative results for alcohol screening (breath test) at day -1 for each 
treatment period and drugs of abuse (opioids, barbiturates, cocaine and its metabolites, 
amphetamines, metamphetamines, morphine, cannabinoids, benzodiazepines and tricyclic 
antidepressants) on each admission (day -1 for each treatment period).
6.5
Study Subject Withdrawal 
Participant subjects in the study are free to drop the study at any moment and they will only be 
asked to give the reason of their drop out.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
30/74
Drop out reason should be documented in the medical chart and in the case report form. Study 
drug assigned to the dropped subject cannot be assigned to another subject. Subjects who drop out 
will not be replaced.
6.5.1
Early study termination 
The clinical study can be finished or stopped 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 scheduled 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.
6.5.2
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). 季
7
Investigational Drug
7.1
Investigational Drug Description 
Study Sponsor will provide drugs to be given to the subjects in each of the study visits.
International non-proprietary name: Metformin/Gliclazide.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
31/74
Test drug: Metformin 1000 mg/Gliclazide 30 mg MR.
Dosage form: tablets
Quali-Quantitative Formula: Each tablet contains Metformin 1000 mg/Gliclazide 30 mg 
MR.
Manufacturer: Merck, SA, Brazil.
Distributor: Merck, SA, Brazil. 
Marketing Holder: Merck, SA, Brazil.
Dosage: Metformin 1000 mg/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.
Batch number:
Laboratory's Approval Number
Quantity required for each stage of the research: 12 tablets.
44 tablets for the study.
44 tablets as retention sample.
Manufacturer: 
Merck, SA, Brazil.
Product's importer:
Ph. 
Tax ID number: 
:
7.2
Dosage and administration 
The IMP (investigational medicinal product) will be given fast or fed state orally at a dose of 
Metformin 1000 mg/Gliclazide 30 mg (one tablet) with 250 mL of water. Only a single dose will 
be administered.
PPD
PPD
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
32/74
Fast treatment: subjects should fast for at least 10 hours before dosing. IMP will be dosed orally 
with 250 mL of water. No food intake is allowed for 4 hours following drug's dosing. Subjects be 
allowed water ad libidum except for 1 hour before and after drug administration.
Fed treatment: following night fasting for at least 10 hours, subjects should be provided the 
recommended food 30 minutes prior to the IMP dosing. They will be given 30 minutes as 
maximum for finalizing the food intake. IMP will be given 30 minutes following the start of food
intake. Drug should be given with 250 mL of water. No food intake is allowed for 4 hours 
following drug's dosing. Subjects be allowed water as desired except for 1 hour before and after 
drug administration.
7.3
Randomization to treatment groups 
Once it is confirmed that all inclusion criteria and none exclusion criteria have been met, a 
consecutive number in ascendant order will be assigned to subjects, starting by 1 up to the last case 
(22). For each one of these numbers, it will correspond one of the sequences R (fasted conditions)
- T' (fed conditions) or T' (fed conditions) - R (fasted conditions) from a randomization list, 
previously generated by the site www.randomization.com and in accordance with the standard 
operating 
procedure 
code: 
, 
RANDOMIZATION 
IN 
AN 
INTERCHANGEABILITY AND BIOCOMPARABILITY CLINICAL STUDY
7.4
Selection and Dosing Schedule for Each Subject
Twenty two male and female subjects will be included in the study. Both genders will be included 
in a minimum ratio of 40 % at least for each gender by study group, it is intended to include an 
equal number of females and males.
The IMP dosing will occur in the morning (around 8 a.m.) following fasting (at least 10 hours) and 
according to the randomization list. Drug's dosing will be documented in the case report form.
The IMP will be dosed for all subjects from 08:00 till 8:10 h, in 5 groups of 4 subjects and 1 of 2, 
with a 2-minute gap among each group for dosing and each one of the activities. Groups' 
distribution can be changed due to operational reasons, as long as there is no impact in the study 
results.
Groups' distribution, subjects and dose schedules are shown in the following table.
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
33/74
Dosing scheme
Group
No. of subjects
Dosing schedule
A
01, 02, 03 and 04
08:00 h
B
05, 06, 07 and 08
08:02 h
C
09, 10, 11 and 12
08:04 h
D
13, 14, 15 and 16
08:06 h
E
17, 18, 19 and 20
08:08 h
F
21 and 22
08:10 h
7.5
Concomitant therapies and drugs
Subjects who take any other drug, (prescribed or over the counter drugs) within 30 days before the 
first IMP administration and for which at least seven elimination half-lives had not elapsed, are 
not eligible. This includes e.g. multi-vitamins and herbal products (e.g., St. John's Wort) as well 
as ASA and oral contraceptives for women. The only exception is given for paracetamol which 
may be given if required, as per the Principal Investigator's judgment (see section 7.5.1)
All concomitant drugs taken by the subjects during the study, starting as per informed consent 
signature have to be appropriately recorded in the Case Report Form (CRF), stating the name, dose 
and indication for each drug. Non-pharmacological interventions or any other intervention should 
be recorded in the CRF.
7.5.1
Allowed Drugs 
Concomitant use of drugs is not allowed, unless those prescribed for adverse events (except for 
paracetamol [acetaminophen], which can be given if necessary) and to protect subjects' well-being 
who will be allowed to continue in the study as per the Principal Investigator's judgment. This 
should be justified in the medical chart. As long as the drug does not interfere with the study 
medication. 
Occasional use of paracetamol will be permitted within the screening period. The investigator may 
allow the subject to take paracetamol in case of pain during the trial, but the dose should not exceed 
1000 mg/day. The administration of paracetamol is limited to 3 consecutive days per period. The 
amount of paracetamol administered must be recorded in the CRF.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
34/74
7.5.2
Forbidden Drugs
Subjects who take any other drug, prescribed or over the counter drugs 30 days before the first 
IMP administration and for which at least seven elimination half-lives had not elapsed, including
multi-vitamins and herbal products (e.g., St. John's Wort) in addition to acetylsalicylic acid and 
oral contraceptives for women (with paracetamol being the only exemption). 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 in the study or to continue 
in the study as per the Principal Investigator's judgment.
7.5.3
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.
7.5.4
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 Study Principal Investigator will decide care following to the 
event.
7.6
Investigational Drug Packaging and Labeling
The IMP (combination of fixed dose of Metformin 1000 mg/Gliclazide 30 mg MR) will be 
provided by the Sponsor, in its primary and secondary original packages 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 products’ needs.
All study drugs will be packaged and labeled according to the applicable standards and directives 
from Good Manufacturing Practices.
7.7
Preparation, Management and Storage of Study Drug
The IMP will be received at the 
by the Samples Processing and Pharmacy Coordinator or by the designated staff, 
as per the standard operating procedures, code: 
: RECEIPT, USE, BALANCE AND
PPD
PPD
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
35/74
FINAL DISPOSITION OF THE STUDY DRUG. Once drugs have been identified, they will be 
kept by the clinical unit they are administered to the subjects.
Acceptance criteria for drugs.
Complete documentation:
9 Copy of the certificate of analysis which contains quality control tests, including:
o
Assessment.
o
Uniformity of expressed dose as content uniformity, if applicable.
o
Dissolution.
9 Copy of the letter issued by the Sponsor, specifying that the drug meets with Good
Manufacturing Practices for drug.
Test drug with label compliant with the minimum requirements from NOM-072-SSA1-
2012, Labeling of Drugs and Herbal Remedies.
Enough quantities of the study drug to conduct the study and keep some as "retention 
samples".  
Expiry date not due at the moment of use in the clinical study.
Test and reference drug in good physical conditions.
Rejection criteria for IMP.
Blisters 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 or 
30 °C according to the label information.
7.8
Study Drug Accountability 
The Sponsor will provide enough quantities of the IMP (investigational medicinal product) to 
conduct the study to the 
and keep "retention samples" as requested by the authority. The Principal Investigator, Sample 
Processing and Pharmacy Coordinator 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.
PPD
PPD
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
36/74
7.9
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 INTERCHANGEABILITY AND 
BIOCOMPARABILITY CLINICAL STUDIES.
A subject is compliant with the treatment only if he/she completes both study periods.
7.10
Blinding 
Randomization codes for dosing sequence will be kept by the Principal Investigator. The analytical 
unit, in charge of the biological samples processing will be blinded throughout the samples 
analysis, according to the standard operating procedures.
7.11
Overdose treatment
Overdose is defined as any dose higher than the highest daily dose included in the clinical trial 
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 7.5.1. 
In this trial, the IMP will be administered under medical supervision as 2 oral single doses of one 
tablet of the fixed dose combination of 1000 mg Metformin and 30 mg Gliclazide separated by a
14-day washout period. 
Overdosage is accordingly unlikely, however in case of overdose, close monitoring will be 
performed and adequate medical care will be provided based on the clinical judgment of the 
Investigator (for further details see text below).
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.
PPD
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
37/74
During the study all subjects will have their finger stick blood glucose measured (see section 8.5)
and will be will be applied intravenously 10 mL of concentrated glucose solution 10 % within 1 
or 2 hours following the dose. Glucose solution charges are not limited to these two occasions. 
Should hypoglycemia symptoms occur, additional glucose solution can be given. The concentrated 
glucose solution 10 % 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:
Hypoglycemia 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 hemodialysis.
Symptoms and Management of overdose of the combination drug product (metformin &
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 hypoglycemia.
Management
Management of a metformin overdose
The most effective method to remove lactate and metformin is hemodialysis.
Management of a Gliclazide overdose
Moderate symptoms of hypoglycemia, without any loss of consciousness or neurological signs, 
must be corrected by carbohydrate intake, dose adjustment and/or change of diet.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
38/74
If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid i.v. injection 
of 50 mL of concentrated glucose solution 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.
7.12
Medical Care for Subjects Following the End of 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.
8
Study Assessments and Procedures 
8.1.1
Subjects screening
Once the Informed Consent Form has been signed, subject's eligibility will be checked according 
to the inclusion and exclusion criteria, including the result of all investigations. Preparation and 
update of clinical chart will be made according to the Standard Operating Procedure, code: 
, 
PREPARATION 
AND 
HANDLING 
OF 
MEDICAL 
CHART 
IN 
INTERCHANGEABILITY AND BIOCOMPARABILITY STUDIES, at the 
 In the event 
the subject already has a medical chart, clinical history will only be updated.
Subjects should have:
Laboratory tests within 21 days prior to the start of the study.
Electrocardiogram within 21 days prior to the start of the study, unless any pathology has 
been reported during that period of time.
8.1.2
Study periods 
At the beginning of each period, a clinical assessment consisting of an examination by apparatus 
and systems by means of a physical examination will be made in order to check if the subject 
remains eligible for the study. Blood sample will be taken for pregnancy tests for women of 
childbearing potential and urine sample for drug screening. Alcohol breath 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 assistance and notes will be made in the appropriate 
documents.
PPD
PP
D


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
39/74
During admission, subjects will be continuously monitored and an electrocardiogram will be 
performed pre-dose, during 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 to subjects for safety laboratory 
tests such as hematology, blood chemistry - 6 elements (glucose, urea, creatinine, uric acid, 
cholesterol and triglycerides), prothrombin time (PT) and partial thromboplastin time (PTT) and 
urinalysis. Samples will be taken pre-dose (following a 10-h fasting period) and at discharge (48 
h post-dose). 
Glucose measurements will be performed: pre-dose and 2, 4, 12, 24, and 32 h post-dose. Finger 
stick glucose measurement (Hematoglucotest) will be made pre-dose and 2, 4, 8, 12 and 24 h post-
dose.
At the end of each period, a clinical assessment consisting of an interview, physical examination 
(including general appearance, skin, head, neck (including thyroid), ears, nose, throat, 
cardiovascular and pulmonary system, abdomen, neurological, peripheral vascular, and 
musculoskeletal system oral cavity examination), vital signs measurement and follow-up of 
adverse events will be made. Blood and urine samples will be taken for safety laboratory tests such 
as hematology; blood chemistry - 6 elements (glucose, urea, creatinine, uric acid, cholesterol and 
triglycerides), 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 consisting of an 
interview, physical examination (see above) will be performed. Weight and height, and vital signs 
will be measured; and electrocardiogram and adverse events follow-up will carried out. Blood 
sample will be taken for pregnancy tests for women of childbearing potential. For post-menopausal 
women (amenorrhoeic for at least 12 months), post-menopausal condition will be confirmed by 
means of follicle-stimulating hormone level measurement 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.
8.1.3
Control of Meals and Liquid Intake
Subjects from R treatment should fast for at least 10.5 hours before the dosing and at least for 4 
hours following the dosing. The study drug will be administered (08:00 h). Water is allowed ad
libitum, except for the period between one hour prior to dosing and the first meal.
Subjects from the T' treatment will have a standardized breakfast after a fast of at least 10.5 hours.
Study subjects have to eat this meal in 30 minutes. 30 minutes after start of the breakfast the study 
drug will be administered (08:00 h). Water is allowed ad libitum 1 hours following the dose. 
During the rest of 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.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
40/74
R' treatment's meals schedule
MEALS
DAYS 0 and 14, 
DAYS 1 and 15
DAYS 2 and 16
Breakfast
-----
As from 07:30 h
As from 09:00 h
Lunch
-----
As from 16:00 h
As from 15:00 h
Dinner
21:00 h 
As from 21:00 h
As from 20:00 h
T treatment's meals schedule
MEALS
DAYS 0 and 14, 
DAYS 1 and 15
DAYS 2 and 16,
Breakfast
-----
As from 12:00 h
As from 09:00 h
Lunch
-----
As from 16:00 h
As from 15:00 h
Dinner
21:00 h
As from 21:00 h
As from 20:00 h
Groups will be unsynchronized for 2 minutes among them for food delivery which is appropriate 
for the dosing order and interval.
Study breakfast consist of two fried eggs with butter, two bacon strips, two toasts with butter, 113 
g of potato croquettes and 240 mL of whole milk (approximately 800 to 1000 calories) (150, 250, 
and 500-600 calories from protein, carbohydrate, and fat, respectively), substitutions in this test 
meal can be made as long as the meal provides a similar amount of calories from protein, 
carbohydrate, and fat and has comparable meal volume and viscosity. (FDA, 2002, EMA 2013). 
8.2
Schedule of Assessments 
Prior any study assessment, the Principal Investigator or designated person will obtain written 
informed consent from the study subjects.
8.2.1
First Administration Period 
Admission the day prior to the visit for assuring 10.5-h fasting period.
Dinner at least 10.5 h before the dosing in fasted condition or breakfast in fed condition.
Subject's eligibility will be checked again before catheter insertion and drug's dosing.
Catheter insertion at the moment of blood sampling for gonadotropins determination 
(elective, only for women).


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
41/74
First day (treatment R):
At 5:00 h, grooming and intake of 250 mL of water.
Between 05:20 and 06:30 h electrocardiogram.
Following electrocardiogram the following activities will be performed:
9
Vital signs measurement.
9
Catheter insertion (control blood sampling).
9
Blood sampling for safety laboratory tests.
9
Finger stick for blood glucose determination.
9
Adverse events and prior medication.
9
Urine sampling for safety laboratory tests.
At 08:00 h, oral administration of IMP 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 schedule of assessments.
At 09:00 h, intravenous administration of 10 mL of 10% glucose solution.
At 10:00 h Measurement of blood glucose and capillary glucose on a test strip 
(hemoglucotest), 2 hours post dose and intravenous administration of 10 mL of 10% 
glucose solution.
Finger stick and IV blood glucose, vital signs measurement 4 hours following dose.
As from 12:00 h, breakfast.
Finger stick for blood glucose determination and vital signs 8 hours following dose.
As from 16:00 h, lunch.
Finger stick and IV blood glucose, vital signs measurement 12 hours following dose.
As from 21:00 h, dinner.
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
42/74
First day (treatment T': food + drug):
At 5:00 h, grooming and intake of 250 mL of water.
Between 05:20 and 06:30 h electrocardiogram.
Following electrocardiogram the following activities will be performed:
9 Vital signs measurement.
9 Catheter insertion (control blood sampling).
9 Blood sampling for safety laboratory tests.
9 Finger stick for blood glucose determination.
9 Adverse events and prior medication.
9 Urine sampling for safety laboratory tests.
At 7:30 h, breakfast. They will be given 30 minutes as maximum for food intake (FDA, 
2002).
At 08:00 h, oral administration of IMP 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 schedule of assessments.
At 09:00 h, intravenous administration of 10 mL of 10% glucose solution.
At 10:00 h Measurement of blood glucose and capillary glucose on a test strip 
(hemoglucotest), 2 hours post dose and intravenous administration of 10 mL of 10% 
glucose solution.
Finger stick and IV blood glucose measurement 2 hours following dose.
Finger stick and IV blood glucose, vital signs measurement 4 hours following dose.
Finger stick for blood glucose determination and vital signs 8 hours following dose.
As from 16:00 h, lunch.
Finger stick and IV blood glucose, vital signs measurement 12 hours following dose.
As from 21:00 h, dinner.
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
43/74
Second day:
At 8:00 h, 24.0-h sampling.
Finger stick for blood glucose determination, blood glucose and vital signs measurement
24 hours following dose.
As from 9:00 h, breakfast.
At 12:00 h, 28.0-h sampling.
As from 15:00 h, lunch.
Finger stick, IV blood glucose and vital signs measurement 32 hours following dose.
At 16:00 h, 32.0-h sampling.
As from 20:00 h, dinner.
Third day:
At 8:00 h, 48.0-h sampling and safety laboratory tests.
Physical examination.
Vital signs measurement.
Electrocardiogram.
Approximately at 10:30 h, temporary discharge from the clinical unit.
Fourth day (ambulatory visit):
At 8:00 h, 72.0-h sampling.
Fifth day (ambulatory visit):
At 8:00 h, 96.0-h sampling.
Sixth day (ambulatory visit):
At 8:00 h, 120.0-h sampling.
Seventh day (ambulatory visit):
At 8:00 h, 144.0-h sampling.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
44/74
Eight day (ambulatory visit):
At 8:00 h, 168.0-h sampling.
Approximately at 10:00 h, temporary discharge and free appointment.
8.2.2
Washout Period
Washout period lasts for 14 days after first dosing. 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.
8.2.3
Second Administration Period 
Analogous to the First period of treatment after a 14 days wash-out period
8.2.4
End of Trial (EoT)
At 08:00 h, 168.0-h sampling. 
Weight measurement for each subject.
Blood for qualitative and quantitative pregnancy test in childbearing potential women.
Blood sampling for safety laboratory tests.
Urine sampling for safety laboratory tests.
Physical examination.
Vital signs measurement.
Electrocardiogram.
Approximately at 11:00 h, temporary discharge and free appointment.
8.3
Baseline demographic characteristics 
At screening (within 21 days before first administration), the following demographic data will be 
collected: date of birth, sex (gender), race, and ethnicity
Specify any additional critical variables to be assessed such as:
x Information about previous and concomitant medications 
x Medical history data including medication history


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
45/74
x Weight, height and BMI
x Special diets
x For women, menstrual status and date of last menstrual period.
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 
8.4
Efficacy assessments 
Not applicable.
8.5
Safety Assessments 
Clinical safety will be assessed by means of a complete physical examination (at SCR, before each
IMP administration and 48 and 168 h after each dose). On the other hand, throughout the study, 
subjects will be continuously monitored, including vital signs measurements (baseline and 4, 8, 
12, 24, 32, 48 and 168 h post-dose) and electrocardiograms will be performed (baseline, 48 and 
168 h post-dose). All examinations 168 h after second administration correspond to the EOT
examination.
Safety will be assessed by means of full laboratory tests (at screening, at each baseline and 48 h
after each administration) (hematology, clinical chemistry, coagulation, and urinalysis). In blood 
analyses besides glucose (baseline, 2, 4, 12, 24, and 32 post-dose), finger-stick glucose 
(Hematoglucotest) will be monitored (baseline, 2, 4, 8, 12 and 24 h post-dose), see flow chart.
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 including hematology, clinical chemistry, coagulation,
urinalysis).


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
46/74
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 8.5.1.2). Reporting period for adverse events is described in section 8.5.1.3.
8.5.1
Adverse Event
8.5.1.1
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 
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.
8.5.1.2
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 (NOM-220-SSA1-2012):
A causality assessment would include.-


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
47/74
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.
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.
Investigators
must
also
systematically assess
the
causal
relationship
of
AEs
to
metformin/Gliclazide using the following definitions. Decisive factors for the assessment of
causal relationship of an AE to the metformin/Gliclazide include, but may not be limited to,
temporal relationship between the AE and the metformin/Gliclazide treatment, known side
effects of metformin/Gliclazide, medical history, concomitant medication, course of the 
underlying disease, trial procedures.
Unrelated:
Not reasonably related to the metformin/Gliclazide treatment. AE could 
not medically (pharmacologically/clinically) be attributed to the IMP/study treatment
under study in this clinical trial protocol. A reasonable alternative explanation must be 
available.
Related: Reasonably related to
the IMP/study
treatment. AE could medically 
(pharmacologically/clinically) be attributed to the IMP/study treatment under study in 
this clinical trial protocol.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
48/74
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.
8.5.1.3
Adverse Event Severity 
Adverse events intensity or severity should be classified as follows (NOM-220-SSA1-2012):
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.
8.5.1.4
Laboratory Abnormal Findings 
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, the 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/Gliclazide
Protocol number EMR200763-004
49/74
8.5.1.5
Unexpected Adverse Event
An unexpected adverse event is any adverse event which specificity or severity is not mentioned
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 which is more specific or more severe than those described in the Investigator's Brochure 
should be considered "unexpected".
8.5.1.6
Adverse Events of Special Interest
Hypoglycemia is a condition characterized by abnormally low blood glucose 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 in the event of a nonserious 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.
8.5.1.7
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 bronchospasm 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.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
50/74
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.
Disability means an important disorder in the capacity of a person to perform usual functions or 
activities.
For reporting purposes, any suspect of transmission of an infective agent by any of the study drugs 
is considered a serious adverse event, as described in section 8.5.1.4.
8.5.1.8
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. This information will be obtained from the subject 
of the study, which will be asked directly about the adverse event.
Documentation should be supported by a record in 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, causing 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 detail, 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, this information must 
be consistent with the CRF, the SAE and AESI Report Forms (as applicable).
8.5.1.9
Definition of Reporting Period for Adverse Events
Report of adverse events will start as per the informed consent form signature and until EOT.
8.5.1.10
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 standard operating 
procedure, code: 
, REPORT OF CLINICAL AND BIOAVAILABILITY STUDIES 
ADVERSE EVENTS
Report of adverse events will be made according to 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 which include all information collected, should be sent within 15 days. Report to the 
PPD
PPD
PP
D


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
51/74
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.
Means to notify the Sponsor are the following:
Fax:
Telephone:
Mobile:
E-mail:
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.
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, and 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.
The reports to Merck shall be sent in English using the Merck SAE form via fax or email within 
24 hours.
Fax No.: 
, email address: 
.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
52/74
The Investigator should answer any request of follow-up information (for instance, additional 
information, outcome, final assessment, and other records, whenever it is necessary) for any other 
question the Sponsor or designated person might have regarding the adverse event, within the same 
time periods aforementioned. This is necessary to ensure an expedited assessment of the event by 
the Sponsor or designated person and (as appropriate) to allow that the Sponsor meets stringent 
official deadlines with regard to the duty of reporting safety information in an expedited way.
8.5.1.11
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 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.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB of 
any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
For  trials  covered  by  the  European  Directive  2001/20/EC,  the  Sponsor’s  responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with that 
Directive and with the related Detailed Guidance documents.
8.5.1.12
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. 
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
53/74
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.
8.5.2
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 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 9.5.1.4.
The Principal Investigator or designated person should follow-up, document and report all 
pregnancies outcomes, even if subjects were withdrawn from the study.
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 9.5.1.4. All
outcomes should be reported 45 following the delivery.
In case of pregnancy during the study, the subject should be withdrawn and study drug should be 
immediately withdrawn. 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 of 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, but insulin should be used to maintain blood glucose levels as close to normal 
as possible.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
54/74
8.5.3
Clinical Laboratory Assessments
Blood and urine samples for safety lab (biochemistry, glucose, hematology; coagulation times,
urinalysis), and for pregnancy tests will be collected at Screening and EOT as well as described in 
the following and according to the schedule of assessments (Appendix 1).

Blood samples for hematology:
Two (2) blood samples will be collected per period (pre-dose and 48.0 h post-dose) in test tubes 
with EDTAK2, specifically designed for venipuncture (hemoglobin, hematocrit, erythrocytes, mean 
cell volume, mean corpuscular hemoglobin, white blood cells, platelets, neutrophils, lymphocytes, 
monocytes, eosinophils and basophils). Dosing and blood sampling sequence among subjects 
should be kept the same for all subjects according to the times for these activities. Exact time when 
samples have been taken should be recorded in the appropriate forms. Once the sample from the 
last group is taken, it will be taken to the sample processing area and kept at room temperature 
until their shipment to the analytical unit. Blood from these subjects will be collected as described 
in the following:
Two (2) blood samples will be collected for hematology per period at times established in 
the schedule. Test tubes with EDTAK2, specifically designed for venipuncture, will be used.
Each sample will be 6 mL. Blood withdrawn to clean catheter should be disposed prior to 
the blood sample collection (purge).
A ± 1 minute window is allowed for sampling.
Samples should be maintained at room temperature (between 20 and 25 °C [68 °F to 77 °C).
Blood tubes will be perfectly labeled with Study No. (##), Case No. (C##), Sample No. 
(S##) and Visit No. (V#) according to the SOP, code, 
, TUBES LABELING
AND DISTRIBUTION IN RACKS; 
 COLLECTION OF MULTIPLE 
BLOOD SAMPLES FOR INTERCHANGEABILITY AND BIOCOMPARABILITY 
STUDIES. They will be kept at room temperature until their delivery to the clinical 
laboratory.

Blood samples for blood chemistry and glucose determination:
Two samples will be collected per period for blood chemistry (albumin, alanine aminotransferase, 
aspartate aminotransferase, protein total, total bilirubin, conjugated bilirubin, unconjugated 
bilirubin, globulin, albumin/ globulin ratio, blood urea nitrogen, glucose, urea, creatinine, uric 
acid, cholesterol and triglycerides) (pre-dose and 48 h post-dose) and 5 samples for glucose 
determination (2, 4, 12, 24 and 32 h post-dose) in test tubes specifically designed for venipuncture 
without anticoagulant. Finger stick glucose measurement (Hematoglucotest) will be made pre-
dose and 2, 4, 8, 12 and 24 h post-dose per period. Dosing and blood sampling sequence among 
subjects should be kept in such a way that times are the same for these activities for all subjects.
Exact time when samples have been taken should be recorded in the appropriate forms. Once the 
sample from the last group is taken, it will be taken to the sample processing area and kept at - 20 
PPD
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
55/74
°C (- 4 °F) until their shipment to the analytical unit. Blood from these subjects will be collected 
as described in the following:
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).
A ± 1 minute window is allowed for sampling.
Each sample will be centrifuged at 2500x g for 15 minutes at 4 °C (39.2 °F) (± 2 °C 
[35.6 °F]), to obtain at least 1 mL of serum for blood chemistry and 1 mL of serum only 
for glucose determination.   
Blood tubes will be labeled with Study No. (##), Case No. (C##), Sample No. (S##) and 
Visit No. (V#) according to the SOP, code, 
, TUBES LABELING AND 
DISTRIBUTION IN RACKS; 
 COLLECTION OF MULTIPLE BLOOD 
SAMPLES FOR INTERCHANGEABILITY AND BIOCOMPARABILITY STUDIES. 
They will be kept at - 20 °C (- 4 °F) until their delivery to the clinical laboratory.

Blood samples for coagulation:
Two (2) blood samples per period will be collected for coagulation times (pre-dose and 48 h post-
dose) in test tubes with sodium citrate specifically designed for venipuncture (prothrombin time 
and partial thromboplastin time). Dosing and blood sampling sequence among subjects should be 
kept in such a way that times are the same for these activities for all subjects. Exact time when 
samples have been taken should be recorded in the appropriate forms.
Once the sample from the last group is taken, it will be taken to the sample processing area and 
kept at - 20 °C (- 4 °F) until their shipment to the analytical unit. Blood from these subjects will 
be collected as described in the following:
Each sample should have 3 mL to determine coagulation times. Blood withdrawn to clean 
catheter should be disposed prior to the blood sample collection (purge).
A ± 1 minute window is allowed for sampling.
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.
Blood tubes will be labeled with Study No. (##), Case No. (C##), Sample No. (S##) and 
Visit No. (V#) according to the SOP, code, 
, TUBES LABELING AND 
DISTRIBUTION IN RACKS; 
 COLLECTION OF MULTIPLE BLOOD 
SAMPLES FOR INTERCHANGEABILITY AND BIOCOMPARABILITY STUDIES. 
They will be kept at - 20 °C (- 4 °F) until their delivery to the clinical laboratory.

Urine samples for urinalysis / microscopic analysis / sediment:
PPD
PPD
PPD
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
56/74
Two (2) urine samples per period will be collected (pre-dose and 48 h post-dose) in containers 
specifically designed.  Time when samples have been taken should be recorded in the appropriate 
forms. Once the sample from the last subject is taken, it will be taken to the sample processing 
area and kept in the fridge until their shipment 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.
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.

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; 
 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.
PPD
PPD
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
57/74
8.5.4
Vital signs, ECGs, Physical Examinations and other 
Assessments 
At Screening, EOT and prior to each dosing, blood pressure, pulse, respiratory rate and forehead 
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.
These values should be within the normal range (SBP between 80 and 129 mmHg and DBP 
between 50 and 89 mmHg) 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 during the 2 cross over periods as shown in the following:

Record of Vital Signs
First Visit
Second Visit
Admission
Admission
Pre-dose
Pre-dose
Morning (4 hours
post-dose 
approximately)
Morning (4 hours post-dose 
approximately)
Evening (8 hours
post-dose 
approximately)
Evening (8 hours post-dose 
approximately)
Night (12 hours
post-dose 
approximately)
Night (12 hours post-dose 
approximately)
24 and 32 hours
post-dose 
approximately
24 and 32 hours post-dose 
approximately
Discharge (48 hours
post-dose 
approximately)
Discharge (48 hours post-dose 
approximately)
Ambulatory samples 
(72, 96, 120, 144 and 
168 hours post-dose 
approximately)
Ambulatory samples (72, 96,
120, 144 and 168 hours (EOT)
post-dose approximately)


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
58/74
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 closely 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.
At Screening, EOT and prior to each dosing and 48 hours after each IMP administration,
electrocardiograms will be measured.
8.6
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: -1.5 (Pre-treatment, 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 treatment.

Pharmacokinetics Blood Samples
Two (2) blood samples 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 elimination phase. 
Each sample will be centrifuged at 2500 x g for 5 minutes at 4 °C [39.2 °F] (± 2 °C [35.6 °F
– 42.8°F]).
Resulting plasma volume will be transferred into four 1.5 or 2 mL cryotubes. For each 
analyte one tube serves as back-up sample.
Plasma tubes will be identified with Study No. (##), Case No. (C##), Sample No. (S##) 
and Visit No. (V#). They will be kept 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 
PACKAGING 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.
PPD
PPD
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
59/74

Blood Sampling Schedule 
Clinical Phase 
NUMBER OF SUBJECTS: 
22 
 
GENDER: 
Female and male 
BIOLOGICAL MATRIX: 
Plasma 
 
DOSAGE FORM: 
Tablet 
FORMULATION: 
MR Tablet of fixed dose 
combination of Metformin 
1000 mg and Gliclazide 30 
mg  
 
DOSE AND DOSAGE UNITS: 
Metformin 
1000 mg/Gliclazide 30 mg 
(one MR tablet) 
WASH-OUT TIME: 
14 days 
 
ANTI-COAGULANT: 
Sodium heparin  
BLOOD VOLUME 
WITHDRAWN BY SAMPLE: 
10 mL 
 
TOTAL OF SAMPLES BY SUBJECT 
IN EACH PERIOD: 
22 
Sampling Interval 
Phase 
Sample 
Time 
Unit 
 
Total Number of Samples 
-- 
0 
-1.500 
h 
 
No. of 
Cases 
Samples 
Periods 
Total 
A 
1 
0.5 
h 
 
22 
22 
2 
968 
A 
2 
1.00 
h 
 
 
A 
3 
2.00 
h 
 
Diet 
~ Cmax  
4 
3.00 
h 
 
Standardized by the clinic 
~ Cmax 
5 
4.00 
h 
 
 
~ Cmax 
6 
5.00 
h 
 
 
~ Cmax 
7 
6.00 
h 
 
 
E  
8 
7.00 
h 
 
 
E  
9 
8.00 
h 
 
 
E 
10 
10.00 
h 
 
 
E 
11 
12.00 
h 
 
 
E 
12 
16.00 
h 
 
 
E 
13 
24.00 
h 
 
 
E 
14 
28.00 
h 
 
 
E 
15 
32.00 
h 
 
 
E 
16 
48.00 
h 
 
 
E 
17 
72.00 
h 
 
 
E 
18 
96.00 
h 
 
 
E 
19 
120.00 
h 
 
 
E 
20 
144.00 
h 
 
 
E 
21 
168.00 
h 
 
 


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
60/74
Each subject will participate for around 180 h (48 h confined and with outpatient follow-up for 
samples from 72.00, 96.00, 120.00, 144.00 and 168.00 h) for each of the periods and an approx. 
154 h period within the 14-day wash-out period. The wash-out period starts per the time of drug's 
intake in the first period and thus includes the 168 h period for sampling and the approx. 14 h 
period on day -1 to day 1 of the second period (until second administration).

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.
The Samples Processing and Pharmacy Coordinator or a 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 freezer. A reading will be 
made at least every 15 minutes with its appropriate record.
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.
All samples should arrive deep frozen (- 20 °C [- 4.0 °F] as maximum).

Samples Receipt, Check and Storage by the Analytical Unit 
The 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, according with the Manual of 
Operations Reception, storage, handling matrix and biological samples.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
61/74
(see Manual of Operations). 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 until the analytical unit and the 
clinical unit make an agreement about their disposition.
Further details e.g. on the collection, processing, labeling, and shipping of the samples will be 
detailed in the trial Manual of Operations (MOP).

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 Labeling
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. Label and printing type will ensure 
that that printing and adhesion resist several freezing and thaw cycles.
9
Pharmacokinetic and statistical analysis 
Pharmacokinetics and statistical analysis of Metformin and Gliclazide's plasma concentrations will 
be conducted by the analytical unit from the 
, according to their standard operating procedures and in accordance with the 
NOM-177-SSA1-2013.
Pharmacokinetic parameters (non-compartmental analysis) and statistical analysis for determining 
the food effect on bioavailability will be calculated using Phoenix WinNonlin 6.3 software.
9.1
Sample Size
According to the goals for the study treatment regarding postprandial/fasting, pharmacokinetic 
parameters will be calculated AUC and Cmax for both analytes, Metformin and Gliclazide. In order 
to have an accurate and reasonable precision for the estimated ratios, 22 subjects will be 
randomized. 
PPD
PP
D


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
62/74
Taking 90 % confidence interval for the postprandial/fasting ratio as a measure for accuracy and 
assuming an average variation coefficient of 20 % for AUC (AUC0-∞, AUC0-t) and Cmax for 
Metformin or Gliclazide, then with 18 evaluable subjects the food effect on pharmacokinetics can 
be estimated with an accuracy of 12 %. The following ratio will be carried out, being R the 
estimated ratio and LCL / UCL lower and higher confidence levels for the 90% confidence interval 
for R:
0.89 * R ≤ LCL < UCL ≤ 1,12 * R
An accuracy of 12% will result in an accurate description for the food effects. Besides, 18 
evaluable subjects are enough to detect a difference among treatments of 18 % or higher with a 
power of 80 % at least. Taking into account a drop-out rate around 20 %, 22 subjects should be 
randomized.
9.2
Randomization 
Valid statistical inferences are generally derived by assuming that errors in the observations are 
distributed independently, in random variables. Randomization generally ensures validity of this 
hypothesis. Full randomization of subjects to the treatment's sequence will be made according to 
the design sequences based on the internal procedures from the 
compliant with the Mexican Official Standard NOM-177-
SSA1-2013 using the randomization.com software.
A total of 22 subjects are to be enrolled in the trial and randomized to one of 2 treatment sequences, 
such that 11 subjects are assigned to each treatment sequence. Male and female subjects will be 
included. Every effort will be made to reach gender balance (at least 40 % for each gender).
Once it is confirmed that all inclusion criteria and none exclusion criteria have been met, a 
consecutive number in ascendant order will be assigned to subjects, starting by 1 up to the last case 
(22), as described in sections 7.3 and 7.4, and according with the SOP code: 
,
RANDOMIZATION IN AN INTERCHANGEABILITY AND BIOCOMPARABILITY 
CLINICAL STUDY.
9.3
Outcome variables
9.3.1
Main outcome variable 
To assess the food effect on bioavailability the pharmacokinetics metrics going to be AUC0-∞,
AUC 0-t and Cmax for Metformin and Gliclazide, given as single dose in fasting state and 
postprandial conditions.
9.3.2
Secondary outcome variables 
-
Additional pharmacokinetic parameters will be determined: t1/2, tmax, Vz/f and CL/f.
-
To assess and compare safety and tolerability of the fixed dose combination metformin 
/Gliclazide administered in fasting and fed state.
PPD
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
63/74
9.4
Deviation and Exclusion to the Statistical Analysis 
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 
data will not be replaced. 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 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.

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.
9.5
Statistical Analyses Description 
Descriptive statistical methods will be used to summarize demographic characteristics, 
pharmacokinetics parameters and adverse events.
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.
Statistical Analysis
This trial intends to estimate the effect of food on pharmacokinetics. It is not intended to prove or 
confirm statistically the lack of any food effect.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
64/74
Therefore, no statistical hypothesis is presented. As primary analysis, a mixed model will be 
applied for all Cmax, AUC0-t and AUC0-∞for Metformin and Cmax, AUC0-t and AUC0-∞for 
Gliclazide, of the fixed dose combination metformin /Gliclazide log transformed. With 
TREATMENT, PERIOD and SEQUENCE as fixed effects, and the SUBJECT (SEQUENCE) as 
random effect.
Based on the residual error term 90 % confidence intervals will be built for the estimated 
differences postprandial - fasting, resulting in 90 % confidence intervals for postprandial/fasting 
ratios following the repeated transformation.
Statistical comparisons between treatments A and B, with respect to Cmax, AUC0-t, and AUCf of
Metformin/Gliclazide, will in each case separate based on a mixed linear model for log 
transformed (natural log) pharmacokinetic parameter data. For each parameter evaluation and each 
pairwise comparison, the statistical model will include covariate adjustments for period and 
sequence as fixed effects, and subject, nested within sequence as random effect. Carry-over effects 
will be assumed ignorable.
General linear model for the analysis of variance, representing the experimental design, will be 
used for the analysis of data for pharmacokinetic variables by considering the additive form for 
the following variation sources:
Dosing sequence.
Subjects nested in the dosing sequence called variability or residual value between subjects.
Dosing period.
Treatment or formulation.
Experimental error, called variability or residual value between subjects.
That general linear model, applied to the crossed designs to determine the food effect on 
bioavailability is as follows: 
Yijk = μ + Gk + Sjk + Pj + F(j,k) + eijk    (Chow & Liu, 2009) 
Where: 
μ = overall mean 
Gk = fixed effect of kth sequence 
Sjk = randomized effect of the ith subject in the kth sequence, where i = 1,2,..., nk  y k = 1,2,...K 
Pj = fixed effect of the jth period, where j = 1,2,…, J y Σj Pj = 0 
F(j,k) = fixed direct effect of the formulation in the kth sequence, which is administered in the jth period and 
Σ F(j,k) = 0 
eijk = is the randomized error (intra-subject) in the Yijk observation     


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
65/74
The sequence effect should be assessed using the subject's square means nested in the sequence as 
error term. All other major effects should be assessed against the residual error (error square 
means) and report the F values respectively.  Besides, it should be stated if the variation source is 
significant, whenever p is less than 0.05 (p < 0.05).
Should significant effect is observed in the variability factors for sequence or periods, NOM-177-
SSA1-2013 will be followed.
9.6
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 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 the model used in the design.
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 trial protocol, ethical principles established in 
the Declaration of Helsinki, ICH, GCP and established regulation NOM-177-SSA1-2013, 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 unconditional 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 the 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.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
66/74
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/her 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.
10.3
Subject's Identification and Confidentiality 
A unique number is assigned to each subject that corresponds to their clinical file number, this 
number will be used as subject's identification in the study, as well as in the clinical study database. 
Once it is confirmed that all inclusion criteria and none exclusion criteria have been met, a 
consecutive number in ascendant order will be assigned to subjects. For each one of these numbers, 
it will correspond one of the three sequences as described in section 7.3.
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 
which 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.
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
67/74
10.4
Medical Insurance and Subjects' Compensation 
Subjects will sign a consent which states that they will receive a 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 has to 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 trial protocol, case report form or informed consent form, a new 
approval should be got from both Committees.
10.6
Health Authorities 
The clinical study as well as the appropriate documents will be submitted to the health authorities, 
according to the local and national applicable regulations.
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. CRFs 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.
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
68/74
Subject's complete name, date of birth, sex, height and weight.
Clinical history. 
Previous and concomitant medications / therapies (including changes during the 
study).
Study identification; that is, subject's number provided by the clinical study 
Sponsor, and subject's number. 
Study recruitment dates (informed consent) and visits to the site.
Any medical exam and pre-defined clinical findings in this clinical trial protocol.
All adverse events.
Date when the subject abandoned the study, including any reason for study 
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.
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, the 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 from 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. 
PPD
PPD
PPD
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
69/74
Quality Management follows up the conduct of the study by means of quality control monitoring 
for the review of compliance with the clinical trial 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, AND 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
Trial protocol amendments can be issued by the Principal Investigator and agreed with the Sponsor 
or vice-versa. Substantial changes should be approved by the Ethics and Investigation Committee 
and by the Investigational Committee.
Administrative 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.
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 
stage report according to the Mexican Official Standard 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)
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, 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, should 
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 outcomes 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.
PPD


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
70/74
12
Deviations to the Protocol 
Deviations to the trial protocol which occur during study conduct have to be documented. The 
Principal Investigator should informed immediately to the Study Sponsor.
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.
13
References 
American Diabetes Association. Standards of Medical Care in Diabetes - 2014. Diabetes 
Care 2014;37(Supp.1).
Campbell DB, Lavielle R, and Nathan C. The mode of action and clinical pharmacology 
of gliclazide: A review. Diabetes Res Clin Pract. 1991; 14: S21-S36.
CCSI for metformin&gliclazide
Cho HY, Yoon H, Lim YC et al. Pharmacokinetics and bioequivalence evaluation of 
gliclazide/metformin combination tablet and equivalent doses of gliclazide and metformin 
in healthy Korean subjects. International Journal of Clinical Pharmacology and 
Therapeutics, Vol. 47 – No. 12/2009 (770-779).
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.
European Medicines Agency. Science Medicines Health. Guideline on the Investigation 
of Drug Interactions. 21 June 2012. Date for coming into effect 1 January 2013.
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.


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
71/74
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.
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.
Guidance for Industry, Food-Effect Bioavailability and Fed Bioequivalence Studies. U.S. 
Department of Health and Human Services. Food and Drug Administration. Center for 
Drug Evaluation and Research (CDER). December 2002.
Hoich RI, and 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, et al: 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, 
Pubchem, 
Checked 
on 
Jan 
23rd, 
2015: 
http://pubchem.ncbi.nlm.nih.gov/compound/4091#section=Top.
Metformin, Review date: Jan 23rd, 2015, (http://www.drugs.com/pro/glucophage.html).
Mexican Official Standard for Drugs and Herbal Remedies Labeling (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).


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
72/74
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].
Ristic S, Collober-Maugeais C, Cressier F, et al. 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.
Ristic S, Collober-Maugeais C, Cressier F, et al. 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 P, et al. Pharmacological and Pharmaceutical Profile of 
Gliclazide: A Review.  Journal of Applied Pharmaceutical Science 01 (09); 2011: 11-19.
Theobald J. Diabetes - type 2 treatment algorithm. Nottinghamshire Health Community 
Treatment Guideline for the Management of Type 2 Diabetes. APC approved February 
2014.
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.
Zhong GP, Bi HC, Zhou S, et al. 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

Appendix 1: Schedule of Assessments


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
73/74
Period 1 
TD̻1
TD 1
TD 3
TD 4
TD 5
TD 6
TD 7
TD 8
 EOT 13
wash-out
Period 2      
TD 14
TD 15
TD17
TD18
TD19
TD20
TD21
TD22
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
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 4
X
X
Serum Pregnancy 
Testing (WOCBP) 14
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 14
(Hematology, 
Coagulation, Clinical 
Chemistry 15,
Urinalysis)
X
X
X
X
Blood glucose 
determination 16
X
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
X
X
X
X
X
Safety
Adverse Events 11
X
X
X
Previous medication
X
X
X
Concomitant 
medication 12
Footnotes
1
2
3
4
5
6
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
14
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
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 End of Trial (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.
Randomized, open-label trial with two parallel two-way crossover designs investigating the bioequivalence between the fixed dose combination of a metformin hydrochloride 1000 mg XR 
and gliclazide 30 mg MR and concomitantly administered metformin hydrochloride 1000 mg XR and gliclazide 30 mg tablets in healthy male and female subjects in fed and fasted states
 Group 1 fasted; Group 2 fed conditions
TD16
TD 8 - TD 13
For fasting conditions: Subjects will receive IMP (investigational medicinal product) after an overnight fast of at least 10 hours. For fed conditions:  the subjects will have to start the high-fat breakfast 30 
minutes prior to administration of the IMP. Subjects should eat this meal within 25 minutes or less. The IMP  should be administered 30 minutes after the start of the meal. For both groups 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, TD 21, TD 24 and EOT 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 electrocardiogram (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.
PK
Trial Day SCR
TD 2


Drug's name: Metformin/Gliclazide
Protocol number EMR200763-004
74/74
Appendix 2:
Diet
Diet to be given to subjects following dose in each of the periods will be the same in quantity and 
content to that provided during the previous period.
Study breakfast: two fried eggs with butter, two bacon strips, two toasts with butter, 113 g of potato 
croquettes and 240 mL of whole milk (approximately 800 to 1000 calories) (150, 250, and 500-
600 calories from protein, carbohydrate, and fat, respectively) (FDA, 2002, EMA 2013). 
The rest of the diet (Breakfast day 2 and 16, Lunch and dinner) will be as shown in the following
Energetic Distribution
Group
%
g
Kcal
Carbohydrates
55
275
1100
Proteins
15
75
300
Lipids
30
67
600
Total Kcal
----
----
2000

SAP_001.pdf: 
BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
Statistical Analysis Plan 
Clinical Trial Protocol 
Identification No. 
BD1412-63CEC EMR200763-004
Title: 
A randomized, open-label, single dose, 2x2 crossover trial to 
evaluate the food effect on the bioavailability of a 
Metformin/Gliclazide fixed combination tablet (1000 mg /30 
mg MR) given in fasting and fed conditions to healthy 
volunteers.
Trial Phase 
I
Investigational Medicinal 
Product(s) 
Metformin/ Gliclazide
Clinical Trial Protocol 
Version 
15 November 2017/Version 2.0
Statistical Analysis Plan 
Author 
Statistical Analysis Plan 
Date and Version 
12 march 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. 
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.
PPD
PPD
PPD
PPD
PPD
PPD
PPD


1. Signature Page
Statistical Analysis Plan:  BD1412-63CEC EMR200763-004
A randomized, open-label, single dose, 2x2 crossover trial to evaluate the food effect on the 
bioavailability of a Metformin/Gliclazide fixed combination tablet (1000 mg /30 mg MR) 
given in fasting and fed conditions to healthy volunteers.
Biostatistics Responsible,
Medical Responsible,
Merck KGaA Frankfurter Strasse 250
64293 Darmstadt, Germany
PPD
PPD
PPD
PPD
PPD


 
 
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 
6 
6.3 Overall trial design and plan 
7 
7 
 
Sample size 
7 
8 
 
Overview of planned analyses 
7 
 8.1 Interim analysis 
8 
9 
 
Changes to the planned analyses in the clinical trial protocol 
9 
10 
 
Protocol deviations and analysis sets 
9 
 10.1 Definition of protocol deviations and analysis sets 
9 
11 
 
General specifications of statistical analyses 
10 
12 
 
Protocol deviations   
10 
 12.1 Important protocol deviations 
10 
 12.2 Reasons leading to the exclusion from an analysis set 
11 
13 
 
Demographics and other baseline characteristics 
11 
 13.1 Demographics   
12 
14 
 
Treatment compliance and exposure 
12 
15 
 
Endpoint evaluation 
12 
 15.1 Primary endpoint analyses 
12 
 15.2 Bioavailability statistics 
13 
15.3 Box and whiskers plots 
14 
15.4 Secondary endpoint analyses 
16 
15.5 Other endpoint analyses 
18 
16 
Estimation of individual pharmacokinetic parameters 
26 
17 
Safety evaluation 
28 
17.1 Pharmacokinetic parameter's outliers 
28 
18 
Averse events 
32 
19 
References 
32 
20 
Appendices 
32 


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
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 
HAV
Hepatitis A Virus 


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
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 


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
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 
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 BD1412-63CEC EMR200763-004. 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 
•
To assess the food effect on bioavailability (AUC0-∞, AUC 0-t and Cmax) for Metformin 
1000 mg/Gliclazide 30 mg MR, fixed dose combination, tablets, given as single dose in 
fasting state and with food to healthy volunteers.
6.2
Secondary Objectives and Endpoints 
•
To estimate pharmacokinetic parameters such as tmax, t1/2, Vd and CL.
•
To compare all experimental treatments' safety.
Unique 
Identifier for 
SAP Version
DATE OF SAP 
Version 
Author
CHANGE 
DESCRIPTION from the 
previous version
LEVEL
March 2019
New Document
1.0
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
6.3
Overall Trial Design and Plan 
The IMP will be given in fast and fed state. A randomized, open label, single dose, 2 x 2 cross 
design will be used with a 14-day washout period between 2 study stages. Treatment groups will 
be balanced, with the same number of subjects, who will be randomized to the dosing sequences
(see table below).
Food's effect study
Sequence
Period 1
Washout
period
Period 2
1
Fast
Fed
2
Fed
Fast
All data from participant subjects should be analyzed and included in the statistical analysis, as 
long as they meet the established criteria.
7
Sample Size 
According to the goals for the study treatment regarding postprandial/fasting, pharmacokinetic 
parameters will be calculated AUC and Cmax for both analytes, Metformin and Gliclazide. In order 
to have an accurate and reasonable precision for the estimated ratios, a sufficient amount of subjects 
will be randomized. 
Taking  90 % confidence interval for the postprandial/fasting ratio as a measure for accuracy and 
assuming an average variation coefficient of 20 % or higher for AUC (AUC0-∞, AUC0-t) and Cmax
for Metformin y Gliclazide, then with 18 evaluable subjects the food effect on pharmacokinetics 
can be estimated  with an accuracy of 12 % or higher. The following ratio will be carried out, being 
R the estimated ratio and LCL / UCL lower and higher confidence levels for the 90% confidence 
interval for R:
0.89 * R ≤ LCL < UCL ≤ 1,12 * R
An accuracy of 12% or higher will result in an accurate enough description for the food effects. 
Besides, 18 evaluable subjects are enough to detect a difference among treatments of 18 % or 
higher with a power of 80 % at least. Taking into account a drop-out rate around 20 %, 22 subjects 
should be randomized.
8
Overview of Planned Analyses 
To determine and compare if the rate and extend of metformin and gliclazide's absorption is 
affected by food, metformin hydrochloride extended release (XR) 1000 mg/gliclazide 30 mg 
modified release (MR) in one tablet was assessed in fasting and post-prandial state, depending on 
the group it was assigned to. Twenty-two (22) subjects were randomized, they were randomly 
assigned to each of the treatment sequences and given the test formulation in two different periods 
(fasting and post-prandial state), with a 14-day wash-out period. According to the sampling 
schedule, plasma was obtained from blood samples collected and using a previously validated 


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
analytical method, the metformin and gliclazide concentrations were determined for each subject 
and then they were used to determine if bioavailability of the quantified analytes is changed by 
food. Only twenty-one (21) subject finished the study.
This trial intends to estimate the effect of food on pharmacokinetics. It is not intended to prove or 
confirm statistically the lack of any food effect.
Therefore, no statistical hypothesis is presented. As primary analysis, a mixed model will be applied
for all Cmax, AUC0-t and AUC0-∞for Metformin and Cmax, AUC0-t and AUC0-∞for Gliclazide, of the 
fixed dose combination metformin /Gliclazide log transformed. With TREATMENT, PERIOD and 
SEQUENCE as fixed effects, and the SUBJECT (SEQUENCE) as random effect.
Based on the residual error term 90 % confidence intervals will be built for the estimated 
differences postprandial - fasting, resulting in 90 % confidence intervals for postprandial/fasting 
ratios following the repeated transformation.
8.1
Interim Analysis 
To assess food influence on the study drug assessed, a crossed 2-period and 2-sequence design was 
used, with a sampling time of 168 hours which allowed to estimate the 90% of the average AUC 
for the analytes. 
The pharmacokinetic analysis for the plasma concentrations was performed using the WinNonlin®
software with a non-compartmental model and the use of real times. 
The tmax and Cmax values were obtained from the measures taken. The area under the curve of plasma 
concentration from t0 (dosing) to the tn (AUC0Æt), was estimated with the trapezoidal method with 
lineal interpolation. To determine the area under the curve from the last sampling time to the infinite 
time (AUCtÆ∞), the last plasma concentration quotient in the clearance rate was determined by
lineal regression, using the sampling points from the terminal lineal logarithm which fitted the best 
to the straight line. The AUC0-f was determined adding up the AUC0-t and the AUCt-f.
The statistical analysis was performed with the WinNonlin® using the least squares with the 
generalized lineal model (GLM).
The intra-subject Student residual analysis for the pharmacokinetic parameters was performed with 
Microsoft Excel®.
The following model was used for the analysis:
…… (Chow & Liu, 2009)
Where:
ijkl
l
j
k
i
k
ijkl
e
F
P
S
V
S
Y





 
)
()
(
P


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
Yijkl
is the response (pharmacokinetic parameter) in the ith volunteer, where j is the -th
period, and kth sequence with lth treatment. 
μ
is the overall mean.
Sk
is the effect of the kth dosing sequence.
V(S)i(k)
is the of the ith volunteer in the kth sequence, which is considered a randomized effect. 
Pj
is the effect of the jth period (or dosing phase).
Fl
is the effect of the lth treatment or formulation.
eijkl
is the experimental error, intra-volunteer variability and a randomized effect assumed 
with normal distribution, zero media, constant variance and independent of the 
volunteer's effect sequentially nested. 
Based on the determination of the average square error and the determination of the geometric 
means, the classic 90% confidence intervals estimation was made for the test-reference ratio in the 
previously logarithmic transformed data. Where the test corresponds to the post-prandial conditions 
and the reference to fasting conditions.
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 
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. 


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0

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.

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 


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
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
PPD
PPD
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
Table 13.2. Demographic Variables' Descriptive Statistics
Statistics 
Age 
(years)
Weight 
(kg)
Height 
(m)
BMI 
(Kg/m2)
Mean
SD
Median
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.
Primary pharmacokinetics parameters, AUC and Cmax, were used to estimate the effect of food on
pharmacokinetics. It is not intended to prove or confirm statistically the lack of any food effect.
As primary analysis, a mixed model will be applied for all Cmax, AUC0-t and AUC0-∞for Metformin 
and Cmax, AUC0-t and AUC0-∞for Gliclazide, of the fixed dose combination metformin /Gliclazide
log transformed. With TREATMENT, PERIOD and SEQUENCE as fixed effects, and the 
SUBJECT (SEQUENCE) as random effect.
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
Based on the residual error term 90 % confidence intervals will be built for the estimated 
differences postprandial - fasting, resulting in 90 % confidence intervals for postprandial/fasting 
ratios following the repeated transformation.
Statistical comparisons between treatments A and B, with respect to Cmax, AUC0-t, and AUCf of 
Metformin/Gliclazide, will in each case separate based on a mixed linear model for log 
transformed (natural log) pharmacokinetic parameter data.
15.2 Bioavailability Statistics
Table 15.2.1 shows the results of the statistic to determine food influence on the metformin's 
bioavailability. Table 16.1.4 shows the results for gliclazide.
Table 15.2.1. Statistics for the Metformin's Bioequivalence Determination
Parameter 
Point 
Estimate
90% Confidence 
Interval
Two one-sided T-
test
Power
Acceptance 
Criterion 
Meets 
the
Criterion 
P < 
80%
P > 
125%
LnCmax
LnAUC0-t
LnAUC0-∞
Table 15.2.2. Statistics for the Gliclazide's Bioequivalence Determination 
Parameter 
Point 
Estimate
90% Confidence 
Interval
Two one-sided T-
test
Power
Acceptance 
Criterion 
Meets 
the
Criterion 
P < 
80%
P > 
125%
LnCmax
LnAUC0-t
LnAUC0-∞
As set out in the Mexican Official Standard NOM-177-SSA1-2013, the parameters to establish 
the conclusion about the bioavailability for the metformin and gliclazide are the Cmax as 
absorption rate indicator and the AUC as the absorbed rate amount in this study. The 90% 
confidence interval results for the mean of the post-prandial/fasting quotients are shown; 
 
.
PPD
PPD
PPD
PPD
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
15.3 Box and Whiskers plots.
Box and whiskers plots for the parameters used to evaluate the absorption rate and the metformin 
and gliclazide's bioavailability, respectively, are shown in tables 15.3.1 and 15.3.2.
Table 15.3.1. Box and Whiskers Charts for the Metformin's Pharmacokinetic Parameters
PPD
PPD
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
Table 15.3.2. Box and Whiskers Charts for the Gliclazide's Pharmacokinetic Parameters
PPD
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
15.4
Secondary Endpoint Analyses 
Average results of the metformin's pharmacokinetic parameters are shown in tables 15.4.1 and 
15.4.2,
 
 
 
 
 
 
 
 
Table 15.4.1. Metformin's Pharmacokinetic Parameters Results for Fasting Conditions
Table 15.4.2. Metformin's Pharmacokinetic Parameters Results for Fed Conditions
Variable
N
Mean
SD
CV%
Min
Median
Max
Geo Mean
Geo CV%
Cmax
Tmax
Lambda_z
HL_Lambda_z
AUClast
AUCINF_obs
AUC_%Extrap_obs
Cl_F_obs
Vz_F_obs
MRTINF_obs
Metformin Fasting Conditions
Variable
N
Mean
SD
CV%
Min
Median
Max
Geo Mean
Geo CV%
Cmax
Tmax
Lambda_z
HL_Lambda_z
AUClast
AUCINF_obs
AUC_%Extrap_obs
Cl_F_obs
Vz_F_obs
MRTINF_obs
Metformin Fed Conditions
PPD
PPD
PPD
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
 
 
 
 
 
 
 
 
Table 15.4.3. Gliclazide's Pharmacokinetic Parameters Results for Fasting Conditions.
Variable
N
Mean
SD
CV%
Min
Median
Max
Geo Mean
Geo CV%
Cmax
Tmax
Lambda_z
HL_Lambda_z
AUClast
AUCINF_obs
AUC_%Extrap_obs
Cl_F_obs
Vz_F_obs
MRTINF_obs
Gliclazide Fasting Conditions
PPD
PPD
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
Table 15.4.4. Gliclazide's Pharmacokinetic Parameters Results for Fed Conditions.
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 and 15.5.2 for metformin, with a dosing schedule of the test drug, R for 
fasting state and T for post-prandial state. Gliclazide's concentrations for both conditions are shown 
in tables 15.5.1 and 15.5.2.
Table 15.5.1. Individual concentrations table corresponding to metformin in fasting state. n = 
 
volunteers
Variable
N
Mean
SD
CV%
Min
Median
Max
Geo Mean
Geo CV%
Cmax
Tmax
Lambda_z
HL_Lambda_z
AUClast
AUCINF_obs
AUC_%Extrap_obs
Cl_F_obs
Vz_F_obs
MRTINF_obs
Gliclazide Fed Conditions
PPD
PPD
P


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
Table 15.5.2 Individual concentrations table for metformin in post-prandial state. n = 
 volunteers
0.0
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
168.0
Time
Volunteer
Form
P
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
0.0
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
168.0
Form
Volunteer
Time
PPD
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
Table 15.5.3. Individual concentrations table for gliclazide in fasting state. n = 
 volunteers
0.0
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
168.0
Time
Form
Volunteer
P
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
Table 15.5.4 Individual concentrations table for gliclazide in post-prandial state. n = 21 volunteers
0.0
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
168.0
Form
Volunteer
Time
PPD
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
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 15.5.5 and 15.5.6.
Table 15.5.5. Descriptive Statistics of the Values of the Metformin's Concentration in Biological 
Fluid
Mean
Median
Minimum 
value
Maximum 
value
Standard 
deviation
CV%
Mean
Median
Minimum 
value
Maximum 
value
Standard 
deviation
CV%
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
Metformin/Gliclazide fed conditions 
Metformin/Gliclazide fasting contidions
Time
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
Table 15.5.6 Descriptive Statistics of the Values of the Gliclazide's Concentration in Biological 
Fluid
The pharmacokinetic profiles were satisfactorily characterized for metformin and gliclazide. 
Figures 15.5.1 and 15.5.2 show the average charts in arithmetic and logarithmic scales, 
respectively, for gliclazide. 
Mean
Median
Minimun 
value
Maximum 
value
Standard 
deviation
CV%
Mean
Median
Minimun 
value
Maximum 
value
Standard 
deviation
CV%
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
Metformin/Gliclazide fed conditions
Metformin/Gliclazide fasting conditions
Time
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
Figure 15.5.1. Gliclazide's average concentration versus time chart in an arithmetic scale 
following the test drugs dosing in fasting and post-prandial state (standard deviation bars) 
Figure 15.5.2. Gliclazide's average concentration versus time chart in logarithmic scale 
following the test drugs dosing in fasting and post-prandial state (standard deviation bars) 
Time (h)
PPD
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
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 food's influence 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).
R
T
R
T
R
T
R
T
Period
Form
Volunteer
Sequence
Cmáx
Form
Ln(T/R)
T/R
ABC0-t
Form
T/R
Ln(T/R)
ABC0-∞
Form
T/R
Ln(T/R)
PPD
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
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).
The Phoenix WinNonlin NCA Core Output is provided in a separate listing. 
R
T
R
T
R
T
R
T
ABC0-t
Form
T/R
Ln(T/R)
ABC0-∞
Form
T/R
Ln(T/R)
Period
Form
Volunteer
Secuencia
Cmáx
Form
Ln(T/R)
T/R
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
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 analysis' results by means of the intra-subject Student residual values calculation was 
performed according to the Mexican Official Standard NOM-177-SSA1-2013, which states that 
the possible outliers will be those which exceed the criterion of ± 2 Student residual values. Values 
exceeding that limit for metformin and gliclazide are shown in tables 17.1. and 17.2. Student 
residual values vs. the assessed pharmacokinetic parameter for metformin are shown in figures 
17.0.1 to 17.0.3. Student residual values for gliclazide are shown in charts 17.0.4 to 17.0.6.
Table 17.1. Volunteers Exceeding the Criterion of ± 2 Student Residual Values for Metformin
Pharmacokinetic 
Parameter
Volunteer
Student Residual Value
LnCmax
LnAUC0-t
LnAUC0-f
Table 17.2. Volunteers Exceeding the Criterion of ± 2 Student Residual Values for Gliclazide 
Pharmacokinetic 
Parameter
Volunteer
Student Residual Value
LnCmax
LnAUC0-t
LnAUC0-f
PPD
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
Figure 17.0.1. Intra-subject Student Residual Values Chart for the Metformin's Pharmacokinetic 
Parameter Ln Cmax
Figure 17.0.2. Intra-subject Student Residual Values Chart for the Metformin's Pharmacokinetic 
Parameter Ln AUC0-t
PPD
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
Figure 17.0.3. Intra-subject Student Residual Values Chart for the Metformin's Pharmacokinetic 
Parameter Ln AUC0-∞
Figure 17.0.4. Intra-subject Student Residual Values Chart for the Gliclazide's Pharmacokinetic 
Parameter Ln Cmax
PPD
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
Figure 17.0.5. Intra-subject Student Residual Values Chart for the Gliclazide's Pharmacokinetic 
Parameter Ln AUC0-t
Figure 17.0.6. Intra-subject Student Residual Values Chart for the Gliclazide's Pharmacokinetic 
Parameter Ln AUC0-∞
PPD
PPD


BD1412-63CEC
Bioavailability of a Metformin/Gliclazide fixed combination tablet
EMR200763-004
Version 1.0
To establish if the determined outliers influenced the result, a statistical exercise was performed to 
remove volunteer 1 from the gliclazide's analysis. It was seen that the statistic's results on food 
influence do not change; therefore, they are not influential outliers.   
Volunteer 1, identified as outlier did not show any incident in the clinical study process or in the 
analytical stage. Each area conducted the investigation of the previously mentioned cases and did 
not find any responsible cause for the results abnormality. Thus, there is no evidence supporting 
their removal from the statistical analysis.   
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