Protocol Amlodipin 2019.04.08

STUDY PROTOCOL
StudyNo.: 49BE15
VersionNo.: 01
NATIONAL INSTITUTE OF DRUG
Date :09/04/2019
QUALITY CONTROL
Bioequivalence Center
STUDY TITLE:
In Vivo Single Dose, Randomized, Two-Period, Two-Sequence Crossover
BioequivalenceStudyOfCARDILOPIN(Amlodipine10 Mg Tablets) Versus
NORVASC® 10 Mg TabletsIn HealthyVolunteersUnderFastingConditions
SPONSOR:
EgisPharmaceuticals PLC.
Address: 1134 Budapest, Keresztúriút 30-38., Hungary
Tel: +3618032404
Proxy: Ms. Anna Cseh, MD. (Medical Director)
SPONSOR’S REPRESENTATIVE:
Côngty TNHH tưvấnnghiêncứu VIETSTAR
Address: No. 109 ToHieuStr., Nguyen Traiward, HaDongdistrict, Hanoi, Vietnam
Business headquarters: A2-A3, 3rd floor, Pullman Hanoi hotel, 40 Cat LinhStr, Dong
Da district, Hanoi, Vietnam
Tel: +84 4 32 000 867 Fax: +84 4 32 000 867
Proxy: Ms. Do ThiPhucThuy, General Director
CONTRACT RESEARCH ORGANIZATION:

BE Center, National Institute of Drug Quality Control
Address: Facility 1: 48 Hai Ba Trung street, Hanoi, Vietnam
Facility 2: Tam Hiep – Thanh Tri – Ha Noi
Tel: 024.3825.2791 Fax: 024.3825.6911
Proxy: PhD.Pharm. Ta ManhHung, Vice Director
PRINCIPAL INVESTIGATOR:
Pharm. Tran Hoang, MSc.
BE Center, NIDQC
Tel: 024 36 373 370. Fax: 024 36 373 377.
Email:tranhoangds@yahoo.com
BE/FM/GEN.06.01 Page 1/32 Issued date: 01/11/2018

BE CENTER - NIDQC Study No.:49BE 15
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INSTITUTIONAL REVIEW BOARD (IRB):

Institutional Review Board of National Institute of Drug Quality Control
Code: IRB-VN01061
Chairman: Assoc. Prof. Trinh Van Lau, PhD.,
Chairman of Vietnamese Pharmacopoeia Commission
Tel: 024.39 363 794
STUDY DURATION:
About 5months from study start-up to final report compilation.

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SIGNATURE PAGE
This study protocol has been developed in compliance with the guidelines for Good Clinical
Practice, Ethical Principles for Medical Research as published in the Declaration of Helsinki,
and theASEANGuidelines for Bioequivalence Studies.
We, the undersigned, have discussed with Sponsor and agreed with the contents of the study
protocol. We also informed to leader of NIDQC before submitting to IRB for approval.
Position Name Signature/ Date
Date:
Principal Investigator Pharm. Tran Hoang, MSc.
Signature:
Date:
Clinical Investigator Pharm. Nguyen ThiThuHoa, MSc.
Signature:
Date:
Analytical Investigator Pharm. Phan ThiNghia, MSc.
Signature:
Date:
Statistical Investigator Pharm. Ha ThiTuyen
Signature:
Date:
Quality assurance Pharm. Le Thi Thu Huyen, MSc.
Signature:
Name: Anna Cseh, MD. Name: …………………………………
Function: Medical Director Function: …………………………………
Date: ………………………………… Date: …………………………………
Signature: ………………………………… Signature: ……………………………………
SPONSOR CONTRACT RESEARCH ORGANIZATION
EgisPharmaceuticals PLC. National Institute of Drug Quality Control

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ABBREVIATIONS
Abbreviation Meaning
ADR Adverse Drug Reaction
AE Adverse Event
AUC Area Under the Curve
BE Bioequivalence
Cmax Maximum concentration
CRF Case Report Form
CRO Contract Research Organization
CV Coefficient of Variation
EC Ethics Committee
EDTA Ethylenediaminetetraacetic acid
Exp. Expiration date
GCP Good Clinical Practice
GLP Good Laboratory Practice
HQC High quality control
PK Pharmacokinetic
IRB Institutional review board
Kel Elimination rate
LLOQ Lower limit of quantification
LQC Low quality control
MQC Medium quality control
Mfg. Manufacturing date
NIDQC National Institute of Drug Quality Control
QC Quality control
Reg. No. Register number
SD Standard Deviation
Subj. Subject
tmax Time to maximum concentration
t1/2 Elimination half-life
RPM Revolutions per minute

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TABLE OF CONTENTS
STUDY PROTOCOL 1
SIGNATURE PAGE 3
ABBREVIATIONS 5
TABLE OF CONTENTS 6
STUDY ABSTRACT 8
1. INTRODUCTION ABOUT THE INVESTIGATIONAL DRUG 11
2. OBJECTIVE 13
3. INVESTIGATORS AND FACILITIES 13
3.1. Principal Investigator 13
3.2. Clinical Facilities 13
3.3. Clinical Laboratory Facilities 14
3.4. Analytical Facilities 14
3.5. Statistical Analysis 14
3.6. Quality Assurance 14
4. METHODOLOGY OF CLINICAL STUDY 15
4.1. Study design 15
4.2. Investigational products 15
4.3. Subjects 15
4.3.1. Number of subjects ......................................................................................15
4.3.2. Inclusion Criteria..........................................................................................16
4.3.3. Exclusion Criteria.........................................................................................16
4.4. Implementation procedures 17
4.4.1. Subject screening .........................................................................................17
4.4.2. Subject confinement .....................................................................................18
4.4.3. Drug administration .....................................................................................18
4.4.4. Sampling ......................................................................................................19
4.4.5. Sample processing and storage ....................................................................19
4.5. Life style and/or dietary restrictions 19
4.6. Concomitant medication 21
4.6.1. Permitted medications ..................................................................................21
4.7. Health monitoring 21
4.8. Adverse events and Serious adverse events 22
4.8.1. Definition .....................................................................................................22
4.8.2. Method of detecting AEs .............................................................................22
4.8.3. Recording and Evaluating of AEs ................................................................22
4.8.4. AEs reporting ...............................................................................................23
4.10. Withdrawal criteria 24
4.11. Replacement of withdrawal subjects 25
4.12. Early discontinuation of study 25
4.13. Summary of clinical procedures 25
5. Bioanalytical, Statistical methodology and Final Report 26
5.1. Bioanalysis 26
5.1.1. Method validation ........................................................................................26

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5.1.2. Analysis of subject samples .........................................................................26

5.2. Statistical analysis 27
5.2.1. Pharmacokinetic parameters ........................................................................27
5.2.2. Assessment of bioequivalence .....................................................................27
5.3. Report 27
5.4. Confidentiality of study results 28
6. QUALITY ASSURANCE 28
APPENDIX 1-TIMETABLE OF EVENTS 30
APPENDIX 2-LABORATORY PARAMETERS WITH REFERENCE RANGE 31

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STUDY ABSTRACT
1. Methodology for clinical study
Design:Randomized, open-label, single-dose,two-treatment, two-sequence, two-period,
crossover study. Take drug after an overnight fasting of at least 10 hours. Wash-out period isat
least 14 days. The study is conducted on 24 subjects.
Investigational Products:
Test Product:Cardilopin(Amlodipine10 mg tablet)
Manufacturer: EgisPharmaceuticalsPlc.
Reference Product:NORVASC®10 mg(Amlodipine10 mg tablet)
Manufacturer:Pfizer Ltd.
Selection of subjects:
Subjects are healthy men or nonpregnant women, 18-45 years old, have BMI between 18.5 –
25.0 kg/m2, inclusive,who volunteer to participate in study, havelaboratory test results within
normal limits or NCS as determined by the Investigator. The clinical laboratory tests include:
- Haematology: Complete blood count, ABO blood group.
- Biochemistry: sodium, potassium, chloride, total bilirubin, alkaline phosphatase,
albumin,AST(GOT), ALT(GPT), serum creatinine, glucose, urea.
- HIV Antibody, Hepatitis C and Hepatitis B Surface Antigen.
- General urinalysis
- Electrocardiogram
- Alcohol in breath: On the screening day and at the pre-dose evening of each period.
- Drug abuse test:on the screening day and in confinement evening of each period:
Morphin (MOP); Marijuana (THC); Amphetamin (AMP);
Methylenedioxymethamphetamin (MDMA).
- Pregnancy test (for women): serum hCG test on screening day and urine pregnancy test
in the morning before dosing in each period.
Methodology and procedures:

Volunteer screening: Screening will be conductedafter the protocol is approved by Ethics
Committee and within 4 weeks prior to period 1 dosing. Volunteers will register to participate
in study and sign the Informed Consent Form voluntarily after being fully informed of the study
contents. Then, they will be evaluated and selected according to inclusion/exclusion criteria
statedin the protocol.
Treatment: Single dose of 10mgof Amlodipin (one tablet ofthe Test or Reference product for
each period according to randomization table with 240 ml of room-temperature water.
Sampling: 5 ml of blood will be collected for each time-points indicated below (hours after
dosing):
0 1.5 3 4 5 6 7 8 9 10 12 15 24 48 72 96

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Total 32 blood samples of each subject will be collected for both periods.
Blood samplewill be collected in Eppendorfconical tubes containing EDTA as anticoagulant.
The total blood volume will be approximately 197 ml (including additional 1 ml in each
collection to flush out the remain of anticoagulant and 5 ml for screening). The samples will
becentrifuged within 30 minutes of sample collection.The plasma will be transferred into
storage tubes, and place in the freezer to store at -350C ± 50C within 1 hour of sample
collection.
AEs recording and monitoring: AEs happening from dosing throughout2weeks after dosingof
each period, or longer, if deemed necessary by the Sponsor or Investigatorwill be recorded.All
AEs will be monitored until the subject is fully recovered/in stable condition, or lost to follow-
up.
Food and drink: Subjects will be fasting at least 10 hours before dosing and at least 4 hours
after dosing. Standardized meal will be served at about 12 hours before dosing, then at 4 and 11
hours post dose. During 1 hour before and after dosing, no water is allowed except for drug
administration.
2. Sample Analysis and Statistical Analysis

- Samples from volunteers will be analyzed at CRO using a validated bioanalysis LC-MS/MS
method under positive electrospray ionization mode to quantify plasma amlodipine
concentration.
- Pharmacokinetic parameters determination and statistical assessment will be performed at
CRO, using Phoenix/WinNonlin computer package. For each treatment and each volunteer, the
following PK parameters must be calculated: Cmax, AUC0-t, AUC0-∞, tmax, t1/2,
Kel.Bioequivalence assessment will be performed following the guidelines of ASEAN:
comparison of Cmax, AUC0-t, AUC0-∞ by 90% confidence interval method and comparison of
tmaxusinga non–parametric method.
- Study report: Following the ASEAN format, the study report should contain the following
information:
 Clinical data
 Summary of analytical results
 Table of concentration versus time; individual and mean plasma concentration - time
curve, semi-logarithmic of plasma concentration - time curve.
 Details and descriptive statistic of pharmacokinetic parameters: Cmax, AUC, Tmax,
T1/2, Kel, % of extrapolated AUC of both the Test and the Reference product.
 Pharmacokinetic parameters (AUC and Cmax) statistical comparisons; assessments
of effects; intrasubject variation; power of the study.
 Results of bioequivalent assessment under fasting conditions (90 % CI of
test/comparator Geometric Means based on log-transformed data).
3. Ethical assurance in the study

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- Investigators and Contract Research Organization commit:

+ The study will be performed according to ethical principles in the Declaration of
Helsinki.
+ The study will be performed in compliance with the guidelines for Good Clinical
Practice of ICH and Ministry of Health, Good Laboratory Practice of WHO and Ministry of
Health.
- The protocol and Informed Consent Form will be submitted to the IRB for review. The study
and the beginning of the screening process will beconductedonly after the approval ofIRB and
in accordance with the approved protocol.
- The volunteers must be informed of the study contents according to Study information sheet
and sign the Informed Consent Form voluntarily before screening. When participating in the
study, the subjects will be paid adequate compensation as regulations.

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1. INTRODUCTION ABOUT THE INVESTIGATIONAL DRUG

Amlodipine is a dihydropyridine derivative belonging to the calcium channel blocker group,
active in blood vessels of heart and muscle.Amlodipine acts by relaxing the smooth muscle in
the peripheral arterial walls and has less effect in myocardial-calcium channel. The drug is
long-acting, which leads to little risk of acute hypotension or reflex tachycardia.Amlodipine has
anti-angina action since relaxing peripheral small arteries. Additionally, the drug also causesthe
dilatation of coronary arteries, which increases myocardial oxygen delivery in patients with
angina pectoris spasm.
Pharmacokinetics: Amlodipine is well absorbed after oral administration and not affected by
food, with bio-availability about 60% - 80%. The drug has Cmax about 6 ng/mL and tmaxabout 6-
10 hours after taking the dose of 10mg. Amlodipine is high protein-binding about 98%. The
drug is largely metabolized to inactive metabolites, excreted mainly through urine. T1/2 is about
30-40 hours.
Indications: Treatment of hypertension; Chronic stable angina pectoris; Vasospstic
(Prinzmetal’s) angina.
Contraindications:Amlodipine is contraindicated in patients with:
• hypersensitivity to dihydropyridine derivatives, amlodipine or to any of the inert excipients
• severe hypotension
• shock (including cardiogenic shock)
• obstruction of the outflow tract of the left ventricle (e.g., high grade aortic stenosis)
• haemodynamically unstable heart failure after acute myocardial infarction
Adverse drug reactions:
The most commonly reported adverse reactions during treatment are somnolence,
dizziness,headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and
fatigue.
Less commonly observed side effects in marketing experience include:
MedDRA System Organ Class Undesirable effects
Blood and lymphatic system Leukocytopenia, thrombocytopenia
disorders
Metabolism and nutrition Hyperglycaemia
disorders
Psychiatric disorders Mood altered, insomnia
Nervous system disorders Hypertonia,hypoaesthesia, paraesthesia, peripheral
neuropathy, tremor, dysgeusia, syncope, extrapyramidal
disorder
Eye disorders Visual impairement
Ear and labyrinth disorders Tinnitus
Vascular disorders Hypotension, Vasculitis

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Respiratory, thoracicand Cough, rhinitis,dyspnea

mediastinaldisorders
Gastrointestinal disorders Change in bowel habits,dyspepsia (including
gastritis),vomiting, dry mouth, pancreatitis, gingival
hyperplasia
Skin and subcutaneous tissue Alopecia, purpura, skin discolouration, hyperhidrosis,
disorders urticaria
Musculoskeletal andconnective Arthralgia, myalgia, back pain, muscle cramps
tissue disorders
Renal and urinary disorders Micturition disorder, nocturia, pollakiuria
Reproductive system and breast Erectile disfunction, gynaecomastia
disorders
General disorders and Asthenia, pain, malaise
administration site conditions
Investigations Weight increased, weight decreased
Rarely reported events were allergic reaction including pruritus, rash, angioedema, and
erythema multiforme.
Hepatitis, jaundice and hepatic enzyme elevations have also been reported very infrequently
(mostly consistent with cholestasis). Some cases severe enough to require hospitalization have
been reported and cannot be distinguished from the natural history of the underlying disease:
myocardial infraction, arrhythmia (including bradycardia, ventricular tachycardia and atrial
fibrillation) and chest pain.
Overdose:
Available data suggest that gross overdosage could result in excessive peripheral vasodilatation
and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to
and including shock with fatal outcome have been reported.
Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular
support including frequent monitoring of cardiac and respiratory function, elevation of
extremities and attention to circulating fluid volume and urine output. A vasoconstrictor may be
helpful in restoring vascular tone and blood pressure, provided that there is no contraindication
to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium
channel blockade. Gastric lavage may be worthwhile in some cases. In healthy volunteers the
use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to
reduce the absorption rate of amlodipine. Since amlodipine is highly protein-bound, dialysis is
not likely to be of benefit.
Interaction:
Effectsof other medicinal products on amlodipine:
CYP3A4 inhibitors

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Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease

inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or
diltiazem) may give rise to significant increase in amlodipine exposure resulting in an increased
risk of hypotension. The clinical translation of these PK variations may be more pronounced in
the elderly. Clinical monitoring and dose adjustment may thus be required.
CYP3A4 inducers
Upon co-administration of known inducers of the CYP3A4, the plasma concentration of
amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation
considered both during and after concomitant medication particularly with strong CYP3A4
inducers (e.g. rifampicin, hypericum perforatum).
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as
bioavailability may be increased in some patients resulting in increased blood pressure lowering
effects.
Dantrolene (infusion)
In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association
with hyperkalemia after administration of verapamil and intravenous dantrolene. Due to risk of
hyperkalemia, it is recommended that the co-administration of calcium channel blockers such as
amlodipine be avoided in patients susceptible to malignant hyperthermia and in the
management of malignant hyperthermia
Dosage and administration: For both hypertension and angina the usual initial dose is 5 mg
Amlodipine once daily which may be increased to a maximum dose of 10 mg depending on the
individual patient's response.
2. OBJECTIVE
This study will assess the bioequivalence ofCardilopin(Amlodipine10 mg tablet)manufactured
by EgisPharmaceuticals PLC.,versusNORVASC®10 mg(Amlodipine10 mg
tablet)manufactured byPfizer Ltd.in healthy adult volunteers after single-dose administration
(10mg)under fasting condition.
3. INVESTIGATORS AND FACILITIES
3.1. Principal Investigator

Pharm. Tran Hoang, MSc.
BE Center, NIDQC
Activities: Organize and manage the conduct of the study; check the final report.
3.2. Clinical Facilities

- BE Center, NIDQC
Head of group: Pharm. Nguyen Thi Thu Hoa, MSc.
Activities: Monitor dosing and sampling. Record all clinical data, assume responsibility
for ensuring the completeness and accuracy of all clinical records (including the data of
investigational products, subjects, dosing and sampling process and relative data).

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- Coordination Unit:
Intensive care unit, Dong Da Hospital, 192 Nguyen Luong Bang, Hanoi
(Medical Doctor: MD. DinhTrongHieu, MSc.)
Or Thang Long Hospital, 127 TuuLiet str., Thanh Tri district, Hanoi
(Medical Doctor: Dr. Nguyen Quoc Gia)
Activities: Conduct physical examination for subjects, on-site monitoring activities on
dosing and sampling day, responsible for the well-being of the subjects;
determine medical course of action for the subjects, and manage treatments and
investigations for AEs as needed.
3.3. Clinical Laboratory Facilities

Medical Laboratory Technology Company, 42 – Nghia Dung Street, Hanoi.
Head of group: MD. Nguyen Nghiem Luat, PhD.
Activities: Conduct clinical laboratory tests for screening and as required, certify the
results.
Or Medelab Clinic Viet Nam, 86 – 88 Nguyen Luong Bang street, Hanoi
Head of group: Nguyen Thi Thu Ha, Prof. PhD.
Activities: Conduct clinical laboratory tests for screening and as required, certify the
results.
(*): NIDQC will sign a contract with a qualified clinical laboratory facility as regulations
3.4. Analytical Facilities

- BE Center, NIDQC
Head of group: Pharm. Phan ThiNghia, MSc.
Activities: Organize, determine drug concentration in subjects’ plasma samples; assume
responsibility for ensuring the completeness and accuracy of all analytical records
(including the data during sample preparation, treatment and analytical results).
(*): NIDQC can sign a contract with other laboratories compliant with standards to
determine drug concentrations in plasma samples.
3.5. Statistical Analysis

Pharm. Ha Thi Tuyen,BE Center, NIDQC
Activities: Statistical analysis to determine pharmacokinetic parameters and assess
bioequivalence, assume responsibility for ensuring the completeness and accuracy of all
statistical records (including the tables and results of statistical calculation,
bioequivalence assessment). Collect the results and prepare final report.
3.6. Quality Assurance

Pharm. Le ThiThu Huyen, MSc., BE Center, NIDQC
Activities:Conduct monitoring activitieson the study of the research groups in
accordance with the statement; assure the lab’s activities compliant with the guidelines
for GLP and GCP. Audit the precision and reliability of study data. Maintain all study

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records, including clinical, analytical, statistical records and final report. Provide QA
statement at the end of the study for the Final Report.
4. METHODOLOGY OF CLINICAL STUDY
4.1. Study design

Randomized, single-dose,two-treatment, two-sequence, two-period, crossover study. Take drug
afteran overnight fasting of at least 10hours. Wash-out period isat least 14days. Sample size
is24subjects.
4.2. Investigational products

Test Product: Cardilopin(Amlodipine10 mg tablet)
Manufactured by: EgisPharmaceuticalsPlc.
Reference Product: NORVASC®10 mg(Amlodipine10 mg tablet)
Manufactured by: R-Pharm Germany GmbH,
Heinrich-Mack-Straße 3589257 IllertissenGermany,
European Union(Market Authorization Holder: Pfizer Kft.)
The investigational products must conform to in-house specification. BE Center – NIDQC will
control the quality of investigational products based on the provided results of the following
tests (dentification, assay, uniformity) according to appropriate qualified specification. The
difference of quantitative contents between two products would beless than 5%.
Before dosing day of each period, the study drugs will be separatedand repackaged into labeled
jars for each subject. The label wouldinclude study number, subject code and study period and
product information
The investigational products will be managed following SOPs issued by BE Center – NIDQC.
4.3. Subjects
4.3.1.Number of subjects
- Number of subjects participating in study (sample size) is estimated based on:
+ The intra-subject coefficient of variation of pharmacokinetic parameters.
+ The significance level desired (α = 0.05).
+ The expected ratio of the geometricmean ofpharmacokineticparametersbetween the
Test and the Reference product.
+ The expected dropout rate during the study (estimated as 10%).
+ The requiredstatistical power of study.
- Sample size will be agreedbetween BE Center and the sponsor but not less than 12 subjects
(according to ASEAN Guidelines).
- With α = 0.05; expectedpower ≥ 80%; intra-subject coefficient of variation of
pharmacokinetic parameters is about 15%; expected ratio of the geometricmean of
pharmacokineticparametersbetween the Test and the Reference productisabout 90% - 110%; the
calculated sample size is 24 – 26 subjects expecting a drop-out rate of 10%.
- BE Center and the Sponsorhas decidedafter due discussion to conductthe study on 24 subjects.

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4.3.2.Inclusion Criteria
Subject participating in the study must meet all of the following inclusion criteria:
- Healthy men or women, 18 – 45 yearsold with normal civil behavior.
- BMI will be in the range of 18.5 – 25.0kg/m2 for body frames as per Desirable Weights
for Adults –1983 Metropolitan Height and Weight Table.
- Negative screening test for HIV, HepC and HepB (by quick test or by Elisa test or ECLIA
test).
- A female subject is eligible to participate if she is not pregnant or lactating or intending to
become pregnant or donate ova within 1 month after participating in the study. Females
with child-bearing potential must agree to adhere to a medically acceptable method of
contraception(male condom combined with a female diaphragm, intrauterine device or
system, either with or without a vaginal spermicide, complete abstinence) per protocol.
- Subjects who have signed theInform consent form in a fit state and after due deliberation.
- Vital signs are in normal range: Systolic blood pressure ≥ 90 mmHg and ≤ 140 mmHg;
diastolic blood pressure ≥ 60 mmHg and ≤ 90 mmHg; pulse ≥ 60 bpm and ≤ 100 bpm;
respiratory rate ≥ 14 rpm and ≤ 20 rpm; body temperature ≥ 36.0oC rpm and ≤ 37.5 oC
- Laboratory parameters (haematology and clinical chemistry) are within normal range; or
out of normal range but not clinical significant as determined by the Investigator.
- Normal electrocardiogram.
- Agree to cooperate andadhere toall requirements of the protocol as stated in the Informed
Consent Form.
4.3.3.Exclusion Criteria
Subject participating in the study must not be one of the following:
- Volunteers with detected alcohol in breath.
- Volunteers with detected addictive substances in urine (by quick stick): Morphin (MOP);
Marijuana (THC); Amphetamin (AMP); Methylenedioxymethamphetamin (MDMA).
- Volunteers who are not non- or ex-smokers (not having smoked in the last 6 months).
- Volunteers with the presence of a clinically significant disorder involving the
cardiovascular, respiratory, renal, gastrointestinal, immunological, hematological,
endocrine, or neurological system(s) or psychiatric disease (as determined by the clinical
investigators).
- Volunteers with a positive hepatitis B surface antigen or positiveHepatitis C or HIV
antibody.
- Volunteers with history of allergic response(s) to Amlodipine or any related products as
well as severe hypersensitivity reactions (like angioedema) to any drugs.
- Volunteers with a clinically significant illness during the 4weeks prior to Period I dosing.
- Use of any enzyme-modifying drugs and/or other products, including strong inhibitors of
cytochrome P450 (CYP) enzymes (e.g., cimetidine, fluoxetine, quinidine, erythromycin,
ciprofloxacin, fluconazole, ketoconazole, diltiazem and HIV antivirals) and strong
inducers of CYP enzymes (e.g., barbiturates, carbamazepine, glucocorticoids, phenytoin,

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St. John´s Wort, and rifampicin) in the previous 30 days before first study drug
administration.
- Volunteers who have participated in blood donation within 90 days to Period 1 dosing or
any other clinical study within 45 days prior to Period 1 dosing.
- Volunteers who have received any investigational or prescription drug within 14 days
prior to Period 1 dosing.
- Volunteers who have received any non-prescription drug or supplements within 14days
prior to Period 1 dosing.
- Consumption of food or beverages containing grapefruit and/or pomelo within 10 days
prior to the first study drug administration.
- Consumption of food or beverages containing caffeine/methylxanthines, poppy seeds
and/or alcohol within 48 hours before dosing in each study period.
- Individuals having undergone any major surgery within 6 months prior to the start of the
study or have surgery planned during the study, unless deemed otherwise by the
Investigator.
- Pregnant females as determined by positive urine hCG test before study drug
administration of each period or serum hCG at all other timepoints while participating in
the study.
- Volunteers who have a history of difficulty in swallowing, or any gastrointestinal disease
which could affect the drug absorption
- Volunteers with history of orthostatic hypotension, fasting hypoglycemia or fear of blood.
- Volunteers are study site employees.
4.4. Implementation procedures

4.4.1.Subject screening
- After study protocol is approved by Ethics Committee and within 4 weeks prior to Period
1, 24 official and 2 stand-by subjects will be recruited.
- The volunteers will be informed of all study contents and sign the Informed Consent Form
voluntarily before screening.
- Determine body weight (kg), height (m), BMI (Kg/m2) and review medical history of
volunteers. Then, each volunteer will undergo a physical examination and laboratory tests
including:
 Haematology: Complete blood count, ABO blood group.
 Biochemistry: sodium, potassium, chloride, total bilirubin, alkaline phosphatase,
albumin, AST(GOT), ALT(GPT), serum creatinine, glucose, urea.
 HIV Antibody, Hepatitis C and Hepatitis B Surface Antigen.
 General urinalysis
 Electrocardiogram
 Alcohol in breath: On the screening day and at the pre-dose evening of each period.

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 Addictive substances in urine on the screening day and in confinement evening of

each period: Morphin (MOP); Marijuana (THC); Amphetamin (AMP);
Methylenedioxymethamphetamin (MDMA).
 Pregnancy test (for women): serum hCG for screening and urine pregnancy test in the
morning before dosing in each period.
Note: For volunteers who have already had a specific clinical laboratory test or tests
done within 4 weeks before Period 1, he/she will not have to redo the test in question as
part of the screening process.
- Physician, principal investigator will review and compare all information of each
volunteerwith inclusion and exclusion criteria to conclude that he or she is eligible or
ineligible to participate in the study.
4.4.2.Subject confinement
- In each period, subjects will be confined at clinical area from at least 12 hours before drug
administration to 24 hours post dose.Then, subjects come back to their residence and
return to clinical area for ambulatory samples (48, 72, 96 hours after dosing). Subjects
may be advised to stay at the clinical site for safety reasons, if judged necessary by the
physician in charge.
- During confinement, each subject will be worn an identified card containing the following
information: subject code, subject photo, and the study protocol number. This card will
identify subjects inevery study-related activities, such as blood sampling, health
monitoring or AE treatment.
4.4.3. Drug administration
- Using Excel software to randomize the dosing sequences of each subject. Divide into two
groups and take drugs as:
Period
1 2
Group
1 T R
2 R T
- Members of staff, who are involved in sample analysis will be blinded to the
randomization code.
- Dose: Single dose, 1tablet10mg of the Test orReference drug per period.
- Administration: Take intact tablets with 240 mL of room-temperature purified water.The
tablets must be swallowed whole and must not be chewed or broken.Following the
administration of the drug, hands and mouth will be checked in order to confirm
consumption of the medication.After dosing, subjects should remain awake andseated for
at least 4hours.

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4.4.4.Sampling
- Sampling points in each period (hour):
0 1.5 3 4 5 6 7 8 9 10 12 15 24 48 72 96
- Pre-dose sample (zero point) will be collected within 1.5 hours prior to dosing. For post
dose samples, the actual sampling time deviated from the scheduled sampling time as
below will not be considered as protocol deviations:
+ From 1.5 – 10 hours: ± 2 minutes.
+ From 12 – 15 hours: ± 4 minutes.
+ For 24 hour sample: ± 30 minutes
+ For 48 – 96 hour samples: ± 1 hour
- If there is any deviations greater than mention above,the actual sampling time will be
usedforpharmacokinetic analysis.
- Sample collection:
+ In dosing day: Samples will be collected through an indwelling cannula placed in
a forearm-vein.About 5.0 mL of blood will be collected for each point. For 1.5 – 15 hours
samples, the first 1.0 mL of heparinized blood will be discarded before sampling. In case
the cannula is blocked, samples will be collected directly from the forearm vein.
+ For 24-hour, 48-hour,72-hour, 96-hoursamples: Draw about 5 ml of blood directly
through forearm vein.
- Blood volume: For each subject completing the study, about 197 mL of blood will be
collected for both periods, including:
+ About 5 mL of blood for laboratory test on screening day.
+ 1 mL of heparinized blood discarding for each sampling-points(from 1.5 hour to
15 hours)
+ About 160 mL of blood for samples from 0 hour to 96 hours (16 samples x 2
periods x 5 mL = 140 mL)
4.4.5. Sample processing and storage

Blood sample will be collected in Eppendorf conical tubes containing EDTA as anticoagulant.
Within 30 minutes of sample collection, the samples will be centrifugedat approximately 4000
RPM for 10 minutes. The plasma will be transferred into two separate 1.5 ml storage tubes, and
placed in the freezer to store at -350C ± 50C within 1 hour of sample collection.Labels for all
biological sample collection and storage tubes wouldcontain information of the subject’s code,
period, sampling time-point and study number. At the end of the clinical stage, plasma samples
will be delivered to the analytical area and analyzed using a validated LC-MS/MS method as
described in section 5.1
4.5.Life style and/or dietary restrictions

- Drinks:

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+ On the dosing day, drinking water will not be allowed within 1 hour prior to and after
dosing, except that given with drug administration. At other time, the subjects can drink water
as their demand. Subjects would be encouraged to stay hydrated throughout the clinical phase.
+ Consuming of products containing alcohol/caffeine/methylxanthines is prohibited
from at least 48 hours prior to dosing until the last blood sample in each period.
+ Subjects will be instructed to avoid food or beverages containing grapefruit and/or
pomelo for 10 days prior to the first dosing and during the study.
- Food:
+ In confinement evening, subjects will have dinner at about 12 hours before dosing
+ On the dosing day, subjects will be fasting at least 10 hours before dosing and at least
4 hours after dosing. Standardized meals will be served to each subject approximately 4 hours
and 11 hours after dosing as scheduled. Standard meals are homogenous for both periods.
+ The meals will be standardized as:
Main meals
Total calories: About 1500 – 2000 Kcal, including:
Calories fromProtein ........................... 14%
Calories fromLipit ............................... 30%
Calories from Carbohydrate.................. 56%
Vegetable .................... ...........150 g
Fruit ....................................... 200 g
- Activity:
+ Subjects should remain in an upright position and awake for the first 4hours after
dosing.Subject may participate in light recreational activities during studies (e.g., watch
television, read). Should adverse events occur, subjects may be placed in an appropriate
position.
+ During confinement, subjects should avoid severe physical activities after dosing.
+ Severe physical activities should be limited during wash-out period.
- Smoking:
+ Only non- or ex-smokers (someone who completely stopped smoking for at least 6
months before day 1 of this study) will be allowed in this study.
- Contraception requirements: Male subject and female subjects of childbearing potential must
be sexually inactive by complete abstinence or use contraceptive methods.
+ Abstinence from penile-vaginal intercourse must be consistent with the preferred and
usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of
contraception.
+ Contraceptive methods allowed in the study are male condom combined with a female
diaphragm, intrauterine device or system, either with or without a vaginal spermicide.
These allowed methods are only effectivewhen used consistently, correctly and in

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accordance with the product label. The investigator is responsible for ensuring subjects
understand how to properly use these methods of contraception and are in compliance
with the approved methods by protocol and by local regulation.
4.6. Concomitant medication

4.6.1. Permitted medications
Paracetamol at doses of < 2 grams/day is permitted for use any time during the study. Other
concomitant medication may be considered on a case by case basis by the Medical Investigator
4.6.2. Prohibited medications
- Eligible volunteer must abstain from taking any prescription or non-prescription
drugs/supplements (including vitamins and dietary or herbal supplements)within two weeks
prior to the first dosing period until completion of the last visit, unless in the opinion of the
Investigator and sponsor the medication will not interfere with the study.
- If the subjects used any non-study medication in the duration described above, the principal
investigator will decide together with the Sponsor to remove the subject or not based on the
following:
 The pharmacology and pharmacokinetic of the non-study medication.
 The likelihood of drug-drug interactions.
 The time and duration of administration of the non-study medication.
4.7.Health monitoring
- During the study, vital signs (blood pressure, heart rate, breathing, body temperature) will be
measured at the following time- point:
+ In the confinement night
+ At the time prior to drug administration
+ 2, 4, 8, 12,24, 48, 72and 96hours post dose (± 30 minutes)
+ At any time when the subjects feel abnormal
- Subjects will undergo physical examination before drug administration and after 12-hour
sample.
- Health status/medical history of volunteers will be recorded from screening day until the end
of the study. During this time, any medical problems if occurred will be treated as follows:
+ In housing days at CRO: clinical doctor will be responsible for initial treatment and
monitoring until the subject is in stable status. For severe cases, subject will be admitted to the
nearesthospital if needed.
+ If medical problems occur outside of the CRO’s facility, clinical doctor will give
advice through telephone / email / follow-up for mild cases with clear symptoms. If is needed,
clinical doctorwill directly examine the subject or ask him or her to go to the nearest medical
facility for examination/extra test.
- Subject’s health status and medical/medication historywill be recorded in the CRFs

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4.8. Adverse events and Serious adverse events

4.8.1.Definition
- Any untoward medical occurrence in clinical investigation subject administered a
pharmaceutical product and which does not necessarily have to have a causal relationship with
this treatment.
Accordingly, an adverse event (AE) can therefore be any unfavorable and unintended sign
(including an abnormal laboratory finding, for example), symptom, or disease temporally
associated with the use of a medicinal product, whether or not considered related to the
medicinal product.
- A serious adverse event (SAE) is any AEs which results in one of the following cases:
a) Fatal
b) Life-threatening;
c) Hospitalization or prolong hospitalization (*);
d) Congenital Anomaly/Birth defect;
đ) Disability or Permanent damage
e) Required medical intervention to prevent above cases or other cases which is
clinical significant, according to the investigator judgment.
(*): Only official hospitalization (or prolong hospitalization) for more than 24 hours,
unplanned overnight stay will be considered as an SAE. Planned hospital stays or hospitalized
for social reasons (such as taking care of rest for the sake of home care) will not be counted as
SAEs. Similarly, cases admitted to the hospital for monitoring/observation (without any medical
intervention) will also not be considered SAEs
4.8.2.Method of detecting AEs
- Subjects will be instructed to inform clinic personnel of any untoward medical symptoms
and/or events that may arise during the course of the study.
- AEs will be documented based on one of the following criteria:
+ A new symptom, sign, disease/syndrome or abnormal laboratory test result was
not observed before using study drug.
+ A symptom, sign, disease/syndrome or abnormal laboratory test has worsened
after using study drug.
- AEs can be detected by following means:
 Health examination
 Vital sign measurement in housing day
 Questions in CRFs
 When reported by the subjects (report directly in the sampling day or by phone in
washout period or after finishing study).
4.8.3.Recording and Evaluating of AEs
- AEs happen from the first dosethroughout two weeks after the last visit will be recorded by
clinic staff andwill be reviewed by the Principal Investigator/Sub-Investigator prior to any
subsequent dosing. When appropriate, medical tests and examinations will be performed to
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document resolution of the event(s). All AEs will be followed until recovery or until the
condition stabilizes or until the subject is lost to follow-up.
- All AEs will be recorded in CRF with such details: name of AE, time occurred and ended,
treatments and medication used (if any), final outcome, classification
- AEs will be classified according to the Medical Dictionary for Regulatory Activities as below:
+ Intensity/severity: The incidence, severity and duration of all AEs will be recorded
according to the following scale:
Adverse event resulting in discomfort, but not sufficient to cause
Mild
interference in normal daily activities.
Adverse event resulting in discomfort that is sufficient to cause

Moderate
interference in daily activities.
Adverse event resulting in discomfort causing an inability to carry

Severe
out normal daily activities.
+ Relationship to studydrug: definite, probable, possible, remote, unrelated.

Shouldtherebeanyresonablepossibility for a causal relationship (ie. not unrelated), the
causalitywouldbetreated as related.
+ Seriousness: SAE and non-SAE
4.8.4. AEs reporting
Adverse events will be coded into the Preferred Term (PT), classified according to the Medical
Dictionary for Regulatory Activities (MedDRA v. 21.1 or higher) with System Organ
Classification (SOC) and reported with severity, duration, onset time, relationship to study drug
and action taken.
- For SAEs: All SAEs will be reported to ASTT-MOH (Administration of Science Technology
and Training– Ministry of Health) and National DI & ADR Centre(The National Centre of Drug
Information and Adverse Drug Reactions Monitoring) according to MOH regulation.
+ SAEs must be reported within 7 days(for fatal and life-threatening SAEs) and 15
days (for other SAEs) from the first receiving information.Any clinical significant additional
information or changes should be submitted within 15 days.
+ Responsibility: PI (along with CRO) must submit a written report (MOH template)
to IRB and NIDQC leader, then to ASTT-MOH and National DI & ADR Centre.
+ VIETSTAR will be notified of the SAE’s within 24 hours after becoming aware of
its occurrence and afollow-up report will be sent within 7 calendar days.The notificationwill
contain a description of the observed symptoms and an assessment of causality.
VIETSTAR is responsible for contacting the following Sponsor personnel on the occurrence of
a SAE:

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Anna Cseh, MD
Egis Pharmaceuticals PLC
Medical Director, QPPV
Keresztúri út 30-38,
1106 Budapest, Hungary
Tel: + 36 20 454 5413 (anytime)
Fax: +36 1 803 2480
Tel: + 36 1 803 2252 (working hours)
Email: cseh.anna@egis.huwith a copy to
pharmacovigilance@egis.hu and
kiss.marton@egis.hu
+ All SAEs would be listed in final report with details as for other AEs.
- For non-SAEs: Report to IRB and Sponsor after finishing the study in the final BE report.
4.9. Pregnancy
- All pregnancy information in female subjects will be collected from screening until
completion of the last study visit.
- Urine hCG test will be performed in all female subjects before dosing of each period.Females
with positive result will be withdrawn from the study by the investigator, clinic personnel will
report to the pregnancy immediately within 24 hours. All positive hCG results and pregnancy
information will be reported to IRB and Sponsor after finishing the studyin the final BE report.
- Althought positivehCG result and pregnancy will not be considered adverse events, the
samples collected from these subjects will not be analyzed.
4.10. Withdrawal criteria

Subjects can withdraw from the study at any time for any reason. In addition, Principal
Investigators mayconsider and decide to remove a subject from the study for any of the
following:
- The subject is found to be non-compliant to protocol requirements which can affect the
study results.
- The subject experiences adverse events.
- The subject suffers from significant illness or has to undergo surgery during the study.
- The subject vomits within the first 12 hours after drug administration.
- The subject with one episode of watery stool or at least 3 episodes of loose stools
within the first 16 hours after drug administration
- Subjects with four or more missing samples in any period.
- Subjects with three or more consecutive missing samples in any period.
Details of reasons for removal of subjects will be recorded, reported to the sponsor and
documented in the clinical study report.
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4.11.Replacement of withdrawal subjects

- In case there aresubjects withdrawing from the study before dosing of period 1, the withdrawal
subjects will be replaced by the stand-by ones (if any).
- In case the number of withdrawal subjects is higher than the back-up quantity, or in cases
subjects withdraw after dosing of period 1, CRO will discuss with the Sponsor to decide
conducting additional study and additional study must be approved by IRB before carrying out.
4.12. Early discontinuation of study

- Study will be discontinuedif :
+ Any fatal or life-threatening SADR occurs
+ ≥ 20% of subjects experience non-fatal/life-threatening SADRs
+ AEs occurs with high frequency and have impact on subjects health, significantly
related toTest drug rather than Reference drug.
+ Any risk related to subject safety or study result is detected.
+ Sponsor asks to discontinue study because safety problem of Test product with full
evidence or due to other reasons
+ More than 30% of subjects drop out/withdraw from study
- IRB and Sponsor will be announced when the study is discontinued early..
4.13. Summary of clinical procedures
Activities
Time Physical
Dosing Sampling Note
examination
Within 4
weeks before Recruitment and Screening Before period 1
dosing
Period 1
Subjects will be confined and
Day 0  - - have dinner about 12 hours
before dosing.
- Take drug after an overnight
Pre-dose and fasting of at least 10 hours.
Day 1
post dose - Taking standard meals about 4
(Dosing and  
samples as hours and 11 hours after dosing.
sampling)
schedule - Physical examination as
schedule
Day 2  -  24-hour sampling

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Washout period (at least 14days)
Period 2(repeat as period 1)

Note: “” = Done “-” = Not done
5. Bioanalytical, Statistical methodology and Final Report
5.1. Bioanalysis
5.1.1. Method validation
The analytical method (LCMS) was validated according to the current guidelines for
bioanalytical method validation with criteria: specificity/selectivity, linearity range, lower limit
of quantification, intra-day and inter-day accuracy and precision, stability of standard/IS
solution, stability of plasma samples, autosampler stability…The validation results are listed
below:
- Selective to Amlodipine and internal standard (IS) Felodipine.
- Linear correlation between Amlodipine concentration and the peak area ratio
Amlodipine/IS with linearity range of 0.1 ng/ml – 10 ng/ml, r  0.95.
- Lower limit of quantification (LLOQ): 0.1 ng/ml
- The intraday and interday accuracy and precision meet the requirements (± 15% of
nominal value for accuracy and CV ≤ 15% for precision)
- The recovery of Amlodipine at LQC, MQC and HQC also meet the requirements
(30% - 110%).
- The plasma sample is stable at - 350C  50C for about 60 days.
The validation results are presented in full validation report.
5.1.2.Analysis of subject samples
- Check the suitability of the analytical method prior to analysis of samples. The analytical
method can be modified but then must be validated partially following the guidelinesbefore
using, if necessary.
- Analysis will be performed as soon as possible after finishing the sampling of period II and
the analytical duration must be within the stability period of plasma sample.
- All the samples of one subject will be analyzed in one day and under the same analytical
conditions.
- Samples of subject will not be used for analysis if:
+ The subject not completing the study (Subjects will be considered as completing the
study when they take part in both periods and not more than two consecutive missing
samples or more than three missing samples in any period)
+ During the study or after finishing the study, the subject is found to be non-compliant to
protocol requirements which can affect thestudy results (such as subjects use non-study
medicine or drinks affecting pharmacokinetics of the study medicine…).
+ Subjects withfour or more missing samples in any period.
+ Subjects with three or more consecutive missing samples in any period.

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5.2. Statistical analysis

5.2.1. Pharmacokinetic parameters
Determine pharmacokinetic parameters of each subject based on drug concentration in plasma,
including:
- Maximum concentration (Cmax): Directly on measurement.
- Time to maximum concentration (tmax): Directly on measurement.
- Area under the curve: Using the trapezoidal method, bylinearity pharmacokinetic, non-
compartmental model.
+AUC0–t: From time 0 to last quantifiable concentration time-point.
+AUC0–: The sum of AUC0-t and extrapolated AUC from t to infinity.
5.2.2. Assessment of bioequivalence
All decisions regarding Subject inclusion in the analysis data set must be taken before the start
of bioanalysis.
Statistical analysis and bioequivalence assessment following the ASEAN’s guidelines (2015):
- Comparison of Cmax and AUC: Analyze the variance (ANOVA), determine the 90%
confidence interval (CI) for the ratio of the Test and Reference products,calculated on log-
transformed data using WinNonlin software.
- Comparison of tmax: using the non – parametric method (Wilcoxon signed – rank test), based
on determining sum of positive/negative rank or p-value according to Z value as below:
R  N ( N  1) / 4
Z
N ( N  1 / 2)( N  1) / 12
In which, R: Either larger or smaller rank sum
N: sample size (number of paired Tmax value that are different)
From Z value, check in table: Cumulative normal distribution to determine the value Area and
thep-value = 1- Area
- Power:Determine the power value of the study for Cmax, AUC0–t and AUC0–.
- Acceptance criteria for bioequivalence:
+ For Cmax; AUC0-t and AUC0-,90% confidence interval for the ratio of the Test and
Reference products under fasting condition must be in the range of 80.00% – 125.00%.
+ The difference of tmaxbetween the Test and Reference product under fasting condition
is not statistically significant (when sum of positive/negative rank is greater than the theoretical
value with size of n- n is number of paired tmaxvalue of the Test and Reference product that are
different or p-value > 0.05).
5.3. Report
- The final report following the ASEAN format, the study report should contain the following
information:
 Clinical data;

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 Table of concentration versus time; plasma concentration time – curve, semi-logarithmic

of plasma concentration - time curve.
 Pharmacokinetic parameters:Cmax, AUC, tmax, t1/2, Kel, % of extrapolated AUCof the Test
and the Reference product.
 The difference (T-R) of the above mentioned pharmacokinetic parameters.
 Ratio (T/R) of the above mentioned pharmacokinetic parameters
 Log of ratio T/R (log T/R) of the above mentioned pharmacokinetic parameters
 Result of bioequivalent assessment under fasting condition
- All the information and analysis resultswill be kept secure and stored at the research unit
according to the regulations.
5.4. Confidentiality of study results

The information and study results will be confidential and kept at CRO in accordance with
regulations.
All volunteers' personal information will not be disclosed in the resulting reports or in
specialized journals without the written consent of volunteers. Study reports and all study
records are only available to Sponsor or authorities upon request.
6. QUALITY ASSURANCE
- The study must beconducted according to the approved protocol. Any deviation must be
recorded in original documents and must be reported to IRB or the deviation must be approved
by IRB before conducting, depending on specific circumstances.
- The study must be performed in compliance with the guidelines for GCP, GLP and the current
SOPs. Data will be recorded and reported in accordance with the issued forms.
- The Principal Investigator is responsible for planning, informing study contents and plans,
assigning specific responsibilities to each other one before conducting study and monitoring the
entire study period.
- Quality assurance personnel, sponsor’s supervisor (if any) and IRB are responsible for
monitoring and auditing the compliance with the protocol and the principles of GCP, GLP
during the study period.

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REFERENCES
1.Ministry of Health (2015), Vietnamese National Drug Formulary, Scientific and technical
Publisher, p.187-188.
2. Ministry of Health (2008), Guideline for Good Clinical Practice, enclosed with Decision No.
799/2008/QĐ-BYT dated 7th March, 2008.
3. Ministry of Health (2012), Guidelinesfordocumenting, treatment and reportingserious
adverse events in clinicaltrials in Vietnam,enclosedwithDecision No. 62/QĐ-K2ĐTdated
2ndJune, 2017.
4. Ministry of Health, Guidelinesforclinicaldrugtrials,Circulars No. 03/2012/TT/BYT dated
2ndFebruary 2012.
5. Ministry of Health, Prescribingthedrugregistration,Circulars No. 44/2014/TT/BYT dated
25thNovember 2014.
6. Ministry of Health,
Guidelinesforreportofbioavailability/bioequivalencestudyondrugregistration,Circulars No.
08/2010/TT/BYT dated 26th April 2010.
7. ASEAN GuidelinefortheConductofBioavailability and BioequivalenceStudies, 2015.
8. Pfizer, Amlor SPC
9. ICH Harmonised Tripartite Guideline (1996), Guideline for Good Clinical Practice, current
step 4 version dated 10th June 1996.
10.ICH Harmonised Tripartite Guideline,Clinical Safety Data Management: Definitions and
Standards for Expedited Reporting E2A, current Step 4 version dated 27 October 1994
11. Shein-Chung Chow and Jen-Pei Liu, Design and Analysis of Bioavailability and
Bioequivalence Studies, Third Edition, CRC Press, p.154-160.

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APPENDIX 1-TIMETABLE OF EVENTS

The following timetable is a representative time schedule for one subject who will be
administered at 7h30. Timetable for other subjects will be adjusted according to their time of
drug administration.
Time relative to Approximate
Day Events
dosing time
Confinement, detection alcohol in breath and
18h30 – 19h30
addictive substances in urine
Prior to dosing 19h30 Have dinner
Day 0
day
20h00 – 21h00 Vital sign measurement.
22h – 23h Bed time
5h30 – 6h00 Wake up call
6h30 Starting water restriction
Prior to dosing
Physical examination, pregnancy test for
6h15 – 7h20 women, cannula insertion, pre-dose sample
collection
Dosing. Subjects should remain in an upright
0 hour 7h30
position for at least 2 hours after dosing
1 hour 8h30 Ending water restriction
1.5 hour 9h00 Blood sample collection
2 hour 9h30 Vital sign measurement
1 3 hour 10h30 Blood sample collection
Blood sample collection, vital sign
4 hour 11h30
measurement, lunch
5 hour; 6 hour; 12h30; 13h30
Blood sample collection
7 hour 14h30
Blood sample collection, vital sign
8 hour 15h30
measurement
9 hour; 10 hour 17h30 Blood sample collection
11 hour 18h30 Dinner
12 hour 19h30 Blood sample collection, Physical examination
15 hour 22h30 Blood sample collection
Physical examination, Blood sample
2 24 hour 7h30
collection, Going home
3 48 hour 7h30 Physical examination, Blood sample collection
Washout period (at least 14 days)
Period 2 (repeat as period 1)

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APPENDIX 2-LABORATORY PARAMETERS WITH REFERENCE RANGE

Normal range(*)
Parameters Acceptable range
Male Female
Haematology
White blood cell (WBC) 4-10 G/L
Neutrophils 1.8-7.0 G/L
% Neutrophils 40-75 %
Lymphocytes 1-4 G/L
% Lymphocytes 18-48 %
Monocytes 0-0.9 G/L
% Monocytes 0-12 %
Eosinophils 0 - 0.7 G/L
%Eosinophils 0-7 %
Basophils 0 - 0.2 G/L
%Basophils 0 - 2.5 %
Red blood cell ( RBC) 4.2-6.0 3,9-5,0 T/L ± 10% lower/upper
bound
Hemoglobin (Hb) 130-170 120-150 g/L
Hematocrit (HCT) 0.38-0.49 0,34-0,45 L/L
Mean corpuscular volume
79-97 75-96 fL
(MCV)
Mean corpuscular hemoglobin
26-33 24-33 pg
(MCH)
Mean corpuscular hemoglobin
31-37 g/dL
concentration (MCHC)
Red distribution width (RDW-
10.0-15.0 %
CV)
Platelet count (PLT) 150-400 G/L
Mean platelet volume (MPV) 6-12 fL
Platelet distribution width
10-24 %
(PDW)
Biochemical parameters
AST <37 <31 U/L ≤1.5 times upper
ALT <40 U/L bound
Blood Glucose 3.9-6.4 mmol/L
± 10% lower/upper
Blood Urea 1.7-8.3 mmol/L
bound
Blood Creatinine 62-106 44-88 μmol/L
Immunoassay
HBsAg Negative Negative

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HIV Negative Negative

General urinalysis
Density 1.015 – 1.025 ± 10% lower/upper
pH 4.8 – 7.4 bound
WBC Negative Leu/ul ≤ 25 Leu/μL
Nitrite Negative mg/dL ≤ 0.1 mg/dL
Protein Negative mg/dL ≤ 20 mg/dL
Glucose Negative mg/dL Negative
Ketone Negative mg/dL ≤ 10 mg/dL
Urobilirubin Negative mg/dL ≤ 1.0 mg/dL
Bilirubin Negative mg/dl ≤ 1.0 mg/dL
BLO Negative Ery/ul ≤ 10 ery/μL
Acid Ascorbic Negative mg/dL ≤ 20 mg/dL
hCG define (female) Negative Negative
(*): Normal range can be change according to laboratory equipment and method sensitivity.

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CONTRACT RESEARCH ORGANIZATION:

BE/FM/GEN.06.01 Page 1/32 Issued date: 01/11/2018

INSTITUTIONAL REVIEW BOARD (IRB):

BE/FM/GEN.06.01 Page 3/32 Issued date: 01/11/2018

Position Name Signature/ Date

Name: Anna Cseh, MD. Name: …………………………………

Function: Medical Director Function: …………………………………

Date: ………………………………… Date: …………………………………

Signature: ………………………………… Signature: ……………………………………

SPONSOR CONTRACT RESEARCH ORGANIZATION

EgisPharmaceuticals PLC. National Institute of Drug Quality Control

BE/FM/GEN.06.01 Page 4/32 Issued date: 01/11/2018

BE/FM/GEN.06.01 Page 5/32 Issued date: 01/11/2018

BE/FM/GEN.06.01 Page 6/32 Issued date: 01/11/2018

5.1.2. Analysis of subject samples .........................................................................26

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Methodology and procedures:

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2. Sample Analysis and Statistical Analysis

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- Investigators and Contract Research Organization commit:

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1. INTRODUCTION ABOUT THE INVESTIGATIONAL DRUG

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Respiratory, thoracicand Cough, rhinitis,dyspnea

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Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease

3. INVESTIGATORS AND FACILITIES

3.1. Principal Investigator

3.2. Clinical Facilities

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3.3. Clinical Laboratory Facilities

3.4. Analytical Facilities

3.5. Statistical Analysis

3.6. Quality Assurance

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4. METHODOLOGY OF CLINICAL STUDY

4.1. Study design

4.2. Investigational products

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4.4. Implementation procedures

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 Addictive substances in urine on the screening day and in confinement evening of

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4.4.5. Sample processing and storage

4.5.Life style and/or dietary restrictions

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4.6. Concomitant medication

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4.8. Adverse events and Serious adverse events

Adverse event resulting in discomfort that is sufficient to cause

Adverse event resulting in discomfort causing an inability to carry

+ Relationship to studydrug: definite, probable, possible, remote, unrelated.

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4.10. Withdrawal criteria

4.11.Replacement of withdrawal subjects

4.12. Early discontinuation of study

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Washout period (at least 14days)

Period 2(repeat as period 1)

5. Bioanalytical, Statistical methodology and Final Report