Conditions: Healthy
Keywords: Concor AM® Concor® Norvasc® Bisoprolol Amlodipine Bisoprolol-Amlodipine fixed dose combination Chinese Participants
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 32
Healthy volunteers: yes

Brief summary:
This is a Phase I, open-label, randomized, 2-period, 2-sequence, crossover study to demonstrate bioequivalence (BE) between the bisoprolol-amlodipine fixed-dose-combination (FDC) tablet (investigational product) and bisoprolol and amlodipine tablets administered concomitantly (comparators) given as a single oral dose in fasting and fed state.

Detailed description:

Arms:
arm 1: Participants received a single oral dose of 5 milligram(mg)/5 mg bisoprolol-amlodipine FDC tablet (Concor AM®) on Day 1 in treatment period 1 followed by a single oral dose of 5 mg bisoprolol and a single oral dose of 5 mg amlodipine given concomitantly on Day 15 in treatment period 2 under fasting conditions. The two periods were separated by a washout period of 14 days. arm 2: Participants received a single oral dose of 5 mg bisoprolol and a single oral dose of 5 mg amlodipine given concomitantly on Day 1 in treatment period 1 followed by a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet (Concor AM®) on Day 15 in treatment period 2 under fasting conditions. The two periods were separated by a washout period of 14 days. arm 3: Participants received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet (Concor AM®) on Day 1 in treatment period 1 followed by a single oral dose of 5 mg bisoprolol and a single oral dose of 5 mg amlodipine given concomitantly on Day 15 in treatment period 2 under fed conditions. The two periods were separated by a washout period of 14 days. arm 4: Participants received a single oral dose of 5 mg bisoprolol and a single oral dose of 5 mg amlodipine given concomitantly on Day 1 in treatment period 1 followed by a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet (Concor AM®) on Day 15 in treatment period 2 under fed conditions. The two periods were separated by a washout period of 14 days.

Interventions: intervention 1: Bisoprolol-Amlodipine FDC intervention 2: Bisoprolol intervention 3: Amlodipine
Intervention descriptions: intervention 1: Participants received a single oral dose of 5 milligram(mg)/5 mg bisoprolol-amlodipine FDC tablet (Concor AM®) either on Day 1 or Day 15 under fasting or fed conditions. intervention 2: Participants received 5 mg bisoprolol tablet as a single oral dose either on Day 1 or Day 15 under fasting or fed conditions. intervention 3: Participants received 5 mg amlodipine tablet as a single oral dose either on Day 1 or Day 15 under fasting or fed conditions.

Protocol document:
Prot_000.pdf: 
Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
C O N F I D E N T I A L
I N F O R M A T I O N
1/96
Clinical Trial Protocol 
Clinical Trial Protocol Number
EMR200006-001
Title
A Randomized, Two-period Crossover Trial
Examining 
Bioequivalence 
of 
Bisoprolol-Amlodipine 5 mg/5 mg Combination 
Tablets versus Bisoprolol 5 mg Tablets and 
Amlodipine 5 mg Tablets Given Concomitantly in 
Healthy Subjects in Fasting and Fed State
Phase
I
IND Number
Not applicable
EudraCT Number
Not applicable
Principal Investigator
Sponsor
Merck KGaA (Darmstadt, Germany)
Frankfurter Strasse 250
64293 Darmstadt
Germany
Protocol Lead:
Merck Serono Co., Ltd.
PPD
PPD
PPD


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
C O N F I D E N T I A L
I N F O R M A T I O N
2/96
Medical Responsible:
Merck Serono Co., Ltd.
Clinical Trial Protocol Version
Replaces Version
03 May 2017 / Version 3.0 including amendment 
2.0
16 February 2017 / Version 2.0
- Confidential - 
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is 
intended for restricted use only and may not – in full or part – be passed on, reproduced, published or used 
without express permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright© 2017 by 
Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights reserved. 
PPD
PPD


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
3/96 
 
 
Protocol Table of Contents 
Protocol Table of Contents .............................................................................................. 3 
Table of In-Text Tables ................................................................................................... 7 
Table of In-Text Figures.................................................................................................. 7 
List of Abbreviations....................................................................................................... 8 
1 
Synopsis.......................................................................................... 10 
2 
Sponsor, Investigators and Trial Administrative Structure ............... 18 
2.1 
Trial Structure ................................................................................. 18 
2.2 
Trial Center/Country ....................................................................... 18 
3 
Background Information ................................................................. 19 
3.1 
Amlodipine ..................................................................................... 19 
3.2 
Bisoprolol ....................................................................................... 20 
3.3 
Trial Rationale ................................................................................ 21 
4 
Trial Objectives ............................................................................... 22 
4.1 
Primary Objectives .......................................................................... 22 
4.2 
Secondary Objectives ...................................................................... 22 
5 
Investigational Plan ......................................................................... 23 
5.1 
Overall Trial Design and Plan ......................................................... 23 
5.2 
Discussion of Trial Design .............................................................. 26 
5.2.1 
Scientific Rationale for Trial Design ............................................... 26 
5.2.2 
Justification for Dose ...................................................................... 27 
5.2.3 
Rationale for Endpoints ................................................................... 27 
5.3 
Selection of Trial Population ........................................................... 27 
5.3.1 
Inclusion Criteria ............................................................................ 27 
5.3.2 
Exclusion Criteria ........................................................................... 28 
5.4 
Criteria for Initiation of Trial Treatment .......................................... 29 
5.5 
Criteria for Subject Withdrawal ....................................................... 29 
5.5.1 
Withdrawal from Trial Therapy ....................................................... 29 
5.5.2 
Withdrawal from the Trial ............................................................... 30 
5.5.3 
Withdrawal from the Investigational Medicinal Product .................. 30 
5.6 
Premature Termination of the Trial ................................................. 31 
5.7 
Definition of End of Trial ................................................................ 31 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
4/96 
 
 
6 
Investigational Medicinal Products and Other Drugs Used in the 
Trial ................................................................................................ 32 
6.1 
Description of the Investigational Medicinal Products ..................... 32 
6.2 
Dosage and Administration ............................................................. 33 
6.3 
Assignment to Treatment Sequences ............................................... 34 
6.4 
Non Investigational Medicinal Products to be Used ......................... 35 
6.5 
Concomitant Medications and Therapies ......................................... 35 
6.5.1 
Permitted Medicines........................................................................ 35 
6.5.2 
Prohibited Medicines ...................................................................... 35 
6.6 
Food Restriction and Standardization Diet....................................... 36 
6.7 
Special Precautions ......................................................................... 36 
6.7.1 
Alcohol Prohibition ......................................................................... 36 
6.7.2 
Smoking Prohibition ....................................................................... 37 
6.7.3 
Clinical Research Unit Inpatient Procedures .................................... 37 
6.7.4 
Safety Considerations ...................................................................... 37 
6.7.5 
Contraception .................................................................................. 38 
6.8 
Packaging and Labeling of the Investigational Medicinal Product ... 38 
6.9 
Preparation, Handling and Storage of the Investigational 
Medicinal Product ........................................................................... 38 
6.10 
Investigational Medicinal Product Accountability ........................... 39 
6.11 
Assessment of Investigational Medicinal Product Compliance ........ 40 
6.12 
Blinding .......................................................................................... 40 
6.13 
Emergency Unblinding ................................................................... 40 
6.14 
Treatment of Overdose .................................................................... 40 
6.15 
Medical Care of Subjects after End of Trial ..................................... 41 
7 
Trial Procedures and Assessments ................................................... 42 
7.1 
Schedule of Assessments ................................................................. 42 
7.1.1 
Screening (Day -7 to Day -1)........................................................... 42 
7.1.2 
Admission to Clinical Research Unit (Day -1) ................................. 46 
7.1.3 
Period 1 (Day 1 to Day 8)................................................................ 47 
7.1.4 
Washout Period 1 ............................................................................ 50 
7.1.5 
Admission to Clinical Research Unit (Day 14) ................................ 50 
7.1.6 
Period 2 (Day 15 to Day 22) ............................................................ 51 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
5/96 
 
 
7.1.7 
Washout Period 2 ............................................................................ 52 
7.1.8 
End of Trial (Day 29)/Premature Withdrawal .................................. 52 
7.1.9 
Estimated Blood Sample Volumes per Subject ................................ 53 
7.2 
Demographic and Other Baseline Characteristics ............................ 54 
7.3 
Assessment of Safety ...................................................................... 55 
7.3.1 
Adverse Events ............................................................................... 55 
7.3.2 
Pregnancy and In Utero Drug Exposure .......................................... 59 
7.3.3 
Clinical Laboratory Assessments ..................................................... 60 
7.3.4 
Electrocardiogram ........................................................................... 60 
7.3.5 
Vital Signs, Physical Examinations, and Other Assessments ........... 61 
7.3.6 
Pharmacokinetics ............................................................................ 61 
7.4 
Information to be Collected on Clinical Screening Failures ............. 62 
8 
Pharmacokinetic and Statistical Analyses ........................................ 63 
8.1 
Pharmacokinetic Analysis ............................................................... 63 
8.2 
Statistical Analysis .......................................................................... 63 
8.2.1 
Sample Size .................................................................................... 63 
8.2.2 
Endpoints ........................................................................................ 66 
8.2.3 
Analysis Sets ................................................................................... 67 
8.2.4 
Description of Statistical Analyses .................................................. 68 
8.2.5 
Interim and Additional Planned Analyses ........................................ 71 
9 
Ethical and Regulatory Aspects ....................................................... 72 
9.1 
Responsibilities of the Investigator .................................................. 72 
9.2 
Subject Information and Informed Consent ..................................... 72 
9.3 
Subject Identification and Privacy ................................................... 73 
9.4 
Emergency Medical Support and Subject Card ................................ 73 
9.5 
Clinical Trial Insurance and Compensation to Subjects ................... 73 
9.6 
Independent Ethics Committee or Institutional Review Board ......... 74 
9.7 
Health Authorities ........................................................................... 74 
10 
Trial Management ........................................................................... 75 
10.1 
Case Report Form Handling ............................................................ 75 
10.2 
Source Data and Subject Files ......................................................... 75 
10.3 
Investigator Site File and Archiving ................................................ 76 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
6/96 
 
 
10.4 
Monitoring, Quality Assurance and Inspection by Health 
Authorities ...................................................................................... 76 
10.5 
Changes to the Clinical Trial Protocol ............................................. 76 
10.6 
Clinical Trial Report and Publication Policy .................................... 77 
10.6.1 
Clinical Trial Report ....................................................................... 77 
10.6.2 
Publication ...................................................................................... 77 
11 
References Cited in the Text ........................................................... 78 
12 
Appendices ..................................................................................... 79 
Appendix I 
Contraceptive Guidance and Woman of Childbearing Potential ....... 79 
Appendix II 
Signature Pages and Responsible Persons for the Trial .................... 81 
Signature Page – Protocol Lead ..................................................................................... 82 
Signature Page – Principal Investigator ......................................................................... 83 
Sponsor Responsible Persons not Named on the Cover Page ......................................... 84 
Appendix III 
Protocol Amendments and List of Changes ..................................... 85 
Amendment 2.0 
 ....................................................................................................... 85 
Rationale 
 ....................................................................................................... 85 
Major Scientific Changes .............................................................................................. 85 
Administrative and Editorial Changes ........................................................................... 85 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
7/96 
 
 
Table of In-Text Tables 
Table 1 
Schedule of Assessments ................................................................. 16 
Table 2 
Assignment to Administration Sequences ........................................ 34 
Table 3 
Sampling Collection Schedule ......................................................... 49 
Table 4 
Estimated Blood Sample Volumes per Subject ................................ 54 
Table 5 
Randomization Allocation ............................................................... 66 
 
Table of In-Text Figures 
Figure 1 
Schematic of Trial Design ............................................................... 25 
Figure 2 
Trial Design Diagram with Subject Numbers .................................. 26 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
8/96 
 
 
List of Abbreviations 
ADR 
Adverse Drug Reaction 
AE 
adverse event 
AUC0-t 
area under the (plasma) concentration-time curve from time 0 to time t 
AUC0-∞ 
area under the plasma concentration-time curve from time 0 to infinity 
AUCextra 
extrapolated part of AUC0-f calculated by Clast/λz , expressed in percent 
BE 
bioequivalence 
BMI 
body mass index 
bpm 
beats per minute 
Cmax 
the maximum plasma concentration observed 
CI 
confidence interval 
CL/f 
total clearance following extravascular administration 
CRU 
Clinical Research Unit 
CYP 
cytochrome P450 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EGIS 
EGIS Pharmaceuticals Public Limited Company 
GCP 
good clinical practice 
HBsAg 
hepatitis B surface antigen  
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
9/96 
 
 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
PK 
pharmacokinetic(s) 
SAE 
serious adverse event 
SD 
standard deviation 
SEM 
standard error of the mean 
SOP 
standard operating procedure 
tmax 
time of maximum plasma concentration observed 
TP 
treponema pallidum 
t1/2 
half-life 
Vss/f 
apparent volume of distribution at steady-state after extravascular 
administration 
WOCBP 
woman of childbearing potential 
λz 
terminal elimination rate constant 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
C O N F I D E N T I A L
I N F O R M A T I O N
10/96
1
Synopsis 
Clinical Trial Protocol Number
EMR200006-001
Title
A Randomized, Two-period Crossover Trial Examining 
Bioequivalence of Bisoprolol-Amlodipine 5 mg/5 mg 
Combination Tablets versus Bisoprolol 5 mg Tablets and 
Amlodipine 5 mg Tablets Given Concomitantly in 
Healthy Subjects in Fasting and Fed State
Trial Phase
I
IND Number
Not applicable
FDA covered trial
No
EudraCT Number
Not applicable
Principal Investigator
Sponsor
Merck KGaA (Darmstadt, Germany)
Sponsor Legal Representative in 
the European Union
Merck KGaA (Darmstadt, Germany)
Trial center/country
Planned trial period
(first subject in-last subject out)
July 20th 2017-Sep 24th 2017
Trial Registry
Chinadrugtrials.org.cn
2016L04630
Objectives:
Primary Objective:
x
To 
demonstrate 
bioequivalence 
(BE) 
between 
the 
bisoprolol-amlodipine 
fixed-dose-combination tablet (investigational product) and bisoprolol and amlodipine 
tablets administered concomitantly (comparators) given as a single oral dose in fasting and 
fed state.
Secondary Objectives:
x
To compare the pharmacokinetic (PK) profiles of bisoprolol and amlodipine between the 
investigational product and comparators
x
To examine the safety and tolerability of bisoprolol and amlodipine for the 
fixed-dose-combination tablet compared with the bisoprolol and amlodipine tablets 
administered concomitantly
x
To explore the effect of food intake on the PK of the 2 active ingredients.
PPD
PPD


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
11/96 
 
 
Methodology: 
This trial is designed as a phase I, open-label, randomized, 2-period, 2-sequence, crossover trial 
where subjects will be randomized to receive, in each period, either 
x One fixed-dose-combination tablet of 5 mg/5 mg bisoprolol-amlodipine (Concor AM®), or 
x One tablet of bisoprolol 5 mg (Concor®) co-administrated with amlodipine 5 mg tablet 
(Norvasc®). 
x Drug administration will be done with or without food depending on cohort allocation to 
either fasting or fed state. The subjects will remain in the same cohort (fasting or fed) in 
both treatment periods. 
The trial has a duration of approximately 5 weeks for the fasting or fed cohort respectively for 
each subject, including: 
x Screening (assessments to determine eligibility for entry into the trial; occurring from 
Day -7 to Day -1) 
x Admission to the Clinical Research Unit (CRU) on Day -1 
x Period 1 (duration of 8 days; Day 1- Day 8) 
x Washout (duration of 14 days; Day 1- Day 14) 
x Admission to the CRU on Day 14 
x Period 2 (duration of 8 days; Day 15- Day 22) 
x Washout (duration of 14 days; Day 15- Day 28) 
x End of Trial (visit occurring after the second 14-day washout on Day 29) or premature 
withdrawal from the trial. 
Planned number of subjects: 
A total of 32 healthy male and female Chinese subjects will be enrolled in the trial, with each 
gender representing no less than 1/3 of the total number (also evenly allocated to fasting vs. 
fed cohort). Sixteen subjects each will be enrolled into the fasting cohort and fed cohort, 
respectively, and statistically powered to provide adequate sample size for BE testing. 
Primary endpoint: 
Primary endpoints will be the PK parameters area under the (plasma) concentration-time curves 
from time 0 to time t (AUC0-t) and maximum plasma concentration observed (Cmax) of 
bisoprolol and amlodipine. 
Secondary endpoints: 
Secondary endpoints include time of maximum plasma concentration observed (tmax), half-life 
(t1/2), area under the plasma concentration curve from time 0 to infinity (AUC0-∞), the 
extrapolated part of area under the plasma concentration curve (AUCextra), terminal elimination 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
12/96 
 
 
rate constant (λz), total clearance following extravascular administration (CL/f), and apparent 
volume of distribution (Vss/f) for bisoprolol and amlodipine, as well as safety and tolerability. 
Pharmacokinetics: 
The plasma concentrations of bisoprolol and amlodipine will be determined by a validated 
analytical method using HPLC with MS/MS detection. Pharmacokinetic parameters (primary 
and secondary endpoints) will be calculated according to non-compartmental analysis methods. 
The mixed trapezoidal rule will be used to calculate the area under the plasma concentration 
curve. 
Other assessments: 
The safety assessments comprise adverse events, laboratory tests, vital signs, 
electrocardiogram (ECG) and concomitant medications. 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
13/96 
 
 
Diagnosis and key inclusion and exclusion criteria: 
Subjects meeting all of the following criteria will be considered for enrollment in the trial: 
x Availability for the entire trial period and willingness to adhere to the protocol 
requirements as evidenced by the informed consent form (ICF) duly read, signed and 
dated by the volunteer 
x Chinese male and female volunteer 
x Volunteer aged ≥ 18 years, but ≤ 55 years 
x Volunteer with a body mass index greater than or equal to 18 and below 28 kg/m2 
x Systolic blood pressure (in supine position) within 100 to 139 mmHg (inclusive) and 
diastolic blood pressure (in supine position) within 65 to 90 mmHg (inclusive) at 
Screening, during Admission to the Clinical Research Unit (CRU) (12 hour predose) 
and before each dosing 
x Clinical laboratory values (within 1 month before screening) within the laboratory's 
stated normal range; if not within this range, they must lack clinical significance 
(laboratory tests are listed in Section 7.1) 
x Healthy according to assessment of the medical history, ECG, vital signs, physical 
examination, laboratory results, negative drug screening, and negative serology tests 
(except results after vaccination) 
x Non-smoker or ex-smoker, not using any nicotine product; an ex-smoker being defined 
as someone who completely stopped smoking for at least 12 months before Day 1 of 
the trial 
x Each subject has to be capable of understanding the trial procedures and sign the ICF 
prior to their participation in the trial 
x Subjects must consent to adhere to the recommended contraceptive methods as detailed 
in Section 6.7.5 and Appendix I. 
Subjects presenting with any of the following will not be included in the trial: 
x Significant 
history 
of 
hypersensitivity 
to 
bisoprolol, 
amlodipine, 
other 
dihydropyridines, or any related products (including excipients of the formulations) 
x Significant history of severe hypersensitivity reactions (eg, angioedema) to any drugs 
x Pulse rate (in supine position) less than 60 beats per minute (bpm) or more than 100 bpm 
at screening 
x Presence of significant arrhythmia: QTc interval prolongation (QTc greater than 
430 msec), severe sinus node dysfunction, or second or third atrioventricular block 
x History of low blood pressure (< 100/65 mmHg) or vegetative dystonia 
x History or presence of peripheral arterial occlusion or Raynaud's syndrome 
x Presence of diabetes mellitus 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
14/96 
 
 
x History or presence of asthma 
x Presence of significant gastrointestinal, liver, kidney disease, surgery, or any other 
conditions known to interfere with the absorption, distribution, metabolism, or 
excretion of drugs or known to potentiate or predispose to undesired effects 
x Use of any enzyme-modifying drugs, including strong inhibitors of cytochrome P450 
(CYP) enzymes (such as cimetidine, fluoxetine, quinidine, erythromycin, 
ciprofloxacin, fluconazole, ketoconazole, diltiazem, and human immunodeficiency 
virus [HIV] antivirals) and strong inducers of CYP enzymes (such as barbiturates, 
carbamazepine, glucocorticoids, phenytoin, rifampin, St. John’s wort or other herbal 
medicine known with effect on CYP enzymes) within 28 days before Day 1 of this trial 
x Presence or history of significant cardiovascular, pulmonary, hematologic, neurologic, 
endocrine, immunologic, or dermatological disease 
x Presence or history of significant angina pectoris, acute myocardial infarction or ST 
segment and T wave changes other than non-clinically significant minor changes 
x Presence or history of ventricular arrhythmia (such as ventricular tachycardia or 
ventricular fibrillation) or of congestive heart failure 
x Acute conditions which might alter the renal function (eg, dehydration, severe 
infection) 
x Surgery in the previous 28 days before Day 1 of this trial 
x Any history of tuberculosis and/or prophylaxis for tuberculosis within 10 years of Day 1 
of the trial 
x Positive results to HIV antibody, hepatitis B surface antigen (HBsAg), hepatitis C 
virus (HCV) antibody, or treponema pallidum (TP) antibody tests 
x Donation of 50 mL or more of blood within 28 days before Day 1 of the trial; donation 
of 500 mL or more of blood within 56 days before Day 1 of the trial 
x History of suicidal tendency, history of or disposition to seizures, state of confusion, 
clinically relevant psychiatric diseases 
x Poor motivation, intellectual problems likely to limit the validity of consent to 
participate in the trial or limit the ability to comply with the protocol requirements or 
inability to cooperate adequately, inability to understand and to observe the instructions 
of the physician 
x Maintenance therapy with any drug, or significant history of drug dependency or 
alcohol abuse (> 3 × 14 g alcohol per day, intake of excessive alcohol, acute or chronic 
use) 
x Positive urine screening of drugs of abuse (cannabis, benzodiazepines, barbiturates, 
opiates, cocaine, and methyl amphetamine), or positive breath test of alcohol 
x Positive pregnancy test (only for females of child-bearing potential) or females breast 
feeding a child 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
15/96 
 
 
x Consumption of large quantities of methylxanthine-containing beverages (more than 
600 mg caffeine/day: 1 cup (250 mL) of coffee contains approximately 100 mg of 
caffeine, 1 cup of black or green tea contains approximately 30 mg and 1 glass of cola 
contains approximately 20 mg caffeine) 
x Volunteers who took an investigational product (in another clinical trial) by prescription 
within 2 weeks or an over-the-counter medication taken within 1 week before drug 
administration.  
Investigational Medicinal Product: dose/mode of administration/ dosing schedule: 
5 mg/5 mg bisoprolol-amlodipine combination tablet (Concor AM®) administered either as a 
single dose on Day 1 or a single dose on Day 15 of the trial. 
Reference therapy: dose/mode of administration/dosing schedule: 
5 mg bisoprolol tablet (Concor®) and 5 mg amlodipine tablet (Norvasc®) administered 
concomitantly either as a single dose on Day 1 or a single dose on Day 15 of the trial. 
Planned trial and treatment duration per subject: 
The planned treatment consists of initial screening assessments (within 7 days prior to the first 
trial drug administration) followed by 2 trial periods consisting of 8 days of blood sampling in 
a crossover trial design. Each trial period includes a single dose of trial drug administration and 
the doses are separated by a 14-day Washout period. An End of Trial visit (Day 29) will be 
conducted 14 days after administration in Period 2. The overall trial duration for each subject 
is approximately 5 weeks (or approximately 35 days) including the Screening and End of Trial 
visit. 
Statistical methods: 
Based on the results of the previously conducted BE trial, a within-subject coefficient of 
variation (CV) for AUC0-t and Cmax has been calculated. The sample size in fasting cohort 
calculation is mainly driven by AUC0-t of amlodipine due to the largest ratio (111.22%) of 
geometric least square mean and intra-subject CV (10.4%). With 12 evaluable subjects at least 
80% power can be achieved for all 4 parameter’s 90% confidence intervals of the treatment 
ratio to fall within 80.00% to 125.00%. Taking account of the possible dropout, 4 additional 
subjects will be enrolled. In the case of full completion by all 16 subjects, a power of > 90% 
may be achieved. Assume there is no difference between fasting and fed states [10, 11], a total 
of 32 subjects are planned to be enrolled. 
 






Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
C O N F I D E N T I A L
I N F O R M A T I O N
18/96
2
Sponsor, Investigators and Trial Administrative Structure 
2.1
Trial Structure 
The Sponsor’s legal representative is Merck KGaA (Darmstadt, Germany) at the address 
Frankfurter Strasse 250, 64293 Darmstadt, Germany. 
Merck will supply the bisoprolol-amlodipine 5 mg/5 mg medication. Bisoprolol-amlodipine 
5 mg/5 mg will be produced under Good Manufacturing Practice conditions by 
 
 and will be finally released by a qualified person 
of Merck. 
2.2
Trial Center/Country
The trial will be conducted in one single center in China. 
PPD


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
 
19/96 
 
 
3 
Background Information 
3.1 
Amlodipine 
Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker 
or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and 
vascular smooth muscle. It is indicated for the treatment of hypertension and for prophylaxis of 
chronic stable angina pectoris. 
The therapeutic effect of this group of drugs is believed to be related to their specific cellular action 
of selectively inhibiting transmembrane influx of calcium ions into vascular smooth muscle and 
cardiac muscle, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. 
The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on 
vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not 
been fully determined, but it reduces total ischemic burden by the following 2 actions: it dilates 
peripheral arterioles and thus reduces the total peripheral resistance (afterload) against which the 
heart works. Since the heart rate remains stable, this reduced load on the heart consequently 
reduces myocardial energy consumption and oxygen requirements. It also probably involves 
dilation of the main coronary arteries and coronary arterioles, both in normal and ischemic regions. 
This dilation increases myocardial oxygen delivery in patients with coronary artery spasm 
(Prinzmetal’s or variant angina). 
The recommended initial dose is 5 mg once daily and can be increased after 1 to 2 weeks to a 
maximum dose of 10 mg once daily. 
After oral administration of therapeutic doses of amlodipine, absorption occurs gradually with 
peak plasma concentration reached between 6 and 12 hours. Absolute bioavailability has been 
estimated to be between 64% and 90%. The absorption of amlodipine is not altered by the presence 
of food. Amlodipine is metabolized through the cytochrome P450 (CYP) system, mainly via 
CYP 3A4 isoenzyme. 
Amlodipine is extensively (about 90%) converted to inactive metabolites (via hepatic metabolism) 
with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies 
have shown that approximately 93% of the circulating drug is bound to plasma proteins in 
hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life 
(t1/2) of about 35 to 50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days 
of consecutive daily dosing. 
Following administration of recommended doses to patients with hypertension, amlodipine 
produces vasodilation resulting in a reduction of supine and standing blood pressures. These 
decreases in blood pressure are not accompanied by any significant change in heart rate or plasma 
catecholamine levels with chronic dosing. With chronic once daily oral administration (5 mg and 
10 mg once daily), antihypertensive effectiveness is maintained throughout the 24 hour dose 
interval with minimal peak to trough differences in blood pressure reduction. Since the 
vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported 
after oral administration of amlodipine. In normotensive patients with angina, amlodipine has not 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
 
20/96 
 
 
been associated with any clinically significant reductions in blood pressure or changes in heart 
rate. 
In patients with angina, once daily administration of amlodipine increases total exercise time, time 
to angina onset, and time to 1 mm ST-segment depression, and decreases the frequency of angina 
attack. 
Following the administration of amlodipine, the most frequent adverse events (AEs) were edema 
and headache. Palpitations, dizziness, flushing, nausea, abdominal pain, fatigue, rash, muscle 
cramps, paresthesia, dyspepsia, somnolence, diarrhea, flatulence, dyspnea, abnormal vision, pain, 
and asthenia were also reported. 
3.2 
Bisoprolol 
Bisoprolol is a potent, highly synthetic β1-selective (cardioselective) adrenoceptor blocking agent 
without significant membrane stabilizing activity or intrinsic sympathomimetic activity in its 
therapeutic dosage range. This preferential effect is not absolute, however, and at higher doses 
bisoprolol may also inhibit β2-adrenoceptors, located chiefly in the bronchial and vascular 
musculature. Bisoprolol is a racemic mixture and the S (-) enantiomer is responsible for most of 
the β-blocking activity. It may be used alone or in combination with other antihypertensive agents. 
It is indicated for the management of hypertension and angina pectoris. 
As with other β1-blocking agents, the mode of action in hypertension is not clear but it is known 
that bisoprolol markedly depresses plasma renin levels. Factors which may be involved include: 
antagonism of β-adrenoceptors to decreased cardiac output, inhibition of renin release by the 
kidneys, and diminution of tonic sympathetic outflow from the vasomotor centers in the brain. In 
normal 
volunteers, 
bisoprolol 
therapy 
resulted 
in 
a 
reduction 
of 
exercise 
and 
isoproterenol-inducted tachycardia. The maximal effect occurred within 1 to 4 hours postdose. 
Effects persisted for 24 hours at doses equal to or greater than 5 mg. 
Bisoprolol is well absorbed following oral administration. The absolute bioavailability after a 
10 mg dose is greater than 80%. Absorption is not affected by the presence of food. The first pass 
metabolism of bisoprolol is less than 20%. Binding to serum proteins is approximately 30%. Peak 
plasma concentrations occur within 2 to 4 hours of dosing with 5 to 20 mg, and mean peak values 
range from 16 ng/mL after a 5 mg dose to 70 ng/mL after a 20 mg dose. Once daily dosing with 
bisoprolol results in less than a 2-fold inter-subject variation in peak plasma levels. The plasma 
elimination t1/2 is 10 to 12 hours and is slightly longer in elderly patients in part because of 
decreased renal function in that population. Steady-state is attained within 5 days with once-daily 
dosing. In both young and elderly populations, plasma accumulation is low; the accumulation 
factor ranges from 1.1 to 1.3, and is what would be expected from the first order kinetics and 
once-daily dosing. Plasma concentrations are proportional to administered dose in the range of 5 to 
20 mg. Pharmacokinetic (PK) characteristics of the 2 enantiomers are similar. 
Bisoprolol is eliminated equally by renal and non-renal pathways with about 50% of the dose 
appearing unchanged in the urine and the remainder appearing in the form of inactive metabolites. 
Less than 2% of the dose is excreted in the feces. 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
 
21/96 
 
 
Following administration of bisoprolol, the most frequently reported adverse reactions were 
feeling of coldness, numbness in the extremities, tiredness, dizziness, headache, nausea, diarrhea, 
and constipation. 
3.3 
Trial Rationale 
Concor AM® is a fixed-dose-combination tablet and this formulation has been already marketed 
in multiple countries. The tablet contains bisoprolol and amlodipine. This combination allows to 
increase the antihypertensive and anti-anginal efficacy by complementary mechanism of actions 
of the 2 active compounds: vasoselective effect of the calcium channel blocker amlodipine 
(decrease of peripheral resistance) and cardioselective beta-blocker bisoprolol (decrease of cardiac 
output). 
A bioequivalence (BE) trial is proposed to support registration of Concor AM® in China. 
Bisoprolol tablet (Concor®) and amlodipine tablet (Norvasc®) have both been marketed in China 
for a long time and the clinical practice of treating hypertension and angina with co-administration 
of bisoprolol and amlodipine is already recommended by the China Food and Drug Administration 
guideline [1]. Moreover, the combination product of bisoprolol-amlodipine can fulfill a previously 
unmet healthcare need in the treatment of hypertension and angina in China. 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
 
22/96 
 
 
4 
Trial Objectives 
4.1 
Primary Objectives 
The primary objective of this trial is: 
x To demonstrate BE between the bisoprolol-amlodipine fixed-dose-combination tablet 
(investigational product) and 
bisoprolol and amlodipine tablets administered 
concomitantly (comparators) given as a single oral dose in fasting and fed state. 
4.2 
Secondary Objectives 
The secondary objectives of this trial are: 
x To compare the PK profiles of bisoprolol and amlodipine between the investigational 
product and the comparators. 
x To examine the safety and tolerability of bisoprolol and amlodipine for the 
fixed-dose-combination tablet compared with the bisoprolol and amlodipine tablets 
administered concomitantly. 
x To explore the effect of food intake on the PK of the 2 active ingredients. 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
 
23/96 
 
 
5 
Investigational Plan 
5.1 
Overall Trial Design and Plan 
The trial is designed to assess BE between a single oral dose of bisoprolol-amlodipine 
fixed-dose-combination tablet (investigational product) and bisoprolol and amlodipine (the 
comparators), each given concomitantly as a single dose in fasting or fed state. 
This is a Phase I, open-label, randomized, 2-period, 2-sequence, crossover trial where subjects will 
be randomized to receive, in each period, either 
x Treatment A: one fixed-dose-combination tablet of 5 mg/5 mg bisoprolol-amlodipine 
(Concor AM®), or 
x Treatment B: one tablet of 5 mg bisoprolol (Concor®) co-administrated with 5 mg 
amlodipine tablet (Norvasc®) 
x Drug administration will be done with or without food depending on cohort allocation to 
either fasting or fed state. The subjects will remain in the same cohort (fasting or fed) in 
both treatment periods. 
The trial has a duration of approximately 5 weeks for the fasting or fed cohort respectively for 
each subject, including: 
x Screening (assessments to determine eligibility for entry into the trial; occurring from 
Day -7 to Day -1) 
x Admission to the Clinical Research Unit (CRU) on Day -1 
x Period 1 (duration of 8 days; Day 1- Day 8) 
x Washout (duration of 14 days; Day 1- Day 14) 
x Admission to the CRU on Day 14 
x Period 2 (duration of 8 days; Day 15- Day 22) 
x Washout (duration of 14 days; Day 15- Day 28) 
x End of Trial (visit occurring after the second 14-day washout on Day 29) or premature 
withdrawal from the trial. 
A total of 32 healthy male and female Chinese subjects will be enrolled in the trial, with each 
gender representing no less than 1/3 of the total number (also evenly allocated to fasting vs. fed 
cohort). Sixteen subjects each will be enrolled into the fasting cohort and fed cohort, respectively, 
and are statistically powered to provide adequate sample size for BE testing. Each subject will be 
administered both the investigational product and comparators in this 2 × 2 crossover BE trial to 
minimize the effect of the individual difference and periodic difference of the testing results. 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
 
24/96 
 
 
Trial design and flow chart are shown in Figure 1 and Figure 2. Detailed schedule of trial 
procedures/assessments will be provided in Table 1. 
 






Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
C O N F I D E N T I A L
I N F O R M A T I O N
27/96
single agent treatment. But the current Chinese market does not include β blockers [6] as an active 
component 
in 
fixed-dose-combinations. 
Therefore, 
the 
fixed-dose-combination 
bisoprolol-amlodipine can fulfill a unique healthcare need in the Chinese fixed-dose-combination 
market for hypertension and angina treatment. 
5.2.2
Justification for Dose 
The 5 mg/5 mg dose of Concor AM® is the intended clinical dose levels and within the dose 
proportionality range for both bisoprolol and amlodipine. 
. In the current trial, a 5 mg/5 mg dose combination tablet will 
be evaluated using a similar design to the previous higher dose strength trial, it not only meets the 
medical need for registering a lower dose strength tablet in China, but also adds additional data to 
the overall fixed-dose-combination usage. 
5.2.3
Rationale for Endpoints 
The primary objective of the trial is to demonstrate the BE between the bisoprolol-amlodipine 
fixed-dose-combination tablet and the comparators (co-administrated bisoprolol and amlodipine) 
after single oral administration in healthy Chinese subjects. With this primary objective, the 
endpoints maximum plasma concentration observed (Cmax) and area under the (plasma) 
concentration-time curve from time 0 to time t (AUC0-t) are established as standard primary 
endpoints according to the Chinese guideline for BE studies [8]. The guideline states that BE 
criteria is determined by the confidence intervals (CIs) of the geometric means for AUC0-t and 
Cmax from both bisoprolol and amlodipine, which should be within in the acceptance range of 
80.00% to 125.00% for all 4 primary endpoints. 
5.3
Selection of Trial Population 
5.3.1
Inclusion Criteria 
Subjects meeting all of the following criteria will be considered for enrollment in the trial:
1.
Availability for the entire trial period and willingness to adhere to the protocol 
requirements as evidenced by the informed consent form (ICF) duly read, signed and dated 
by the volunteer 
2.
Chinese male and female volunteer
3.
Volunteer aged ≥ 18 years, but ≤ 55 years 
4.
Volunteer with a body mass index (BMI) greater than or equal to 18 and below 28 kg/m2
5.
Systolic blood pressure (in supine position) within 100 to 139 mmHg (inclusive) and 
diastolic blood pressure (in supine position) within 65 to 90 mmHg (inclusive) at 
Screening, during Admission to the Clinical Research Unit (CRU) (12 hour predose) and 
before each dosing 
CCI


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
 
28/96 
 
 
6. Clinical laboratory values (within 1 month before screening) within the laboratory's stated 
normal range; if not within this range, they must lack clinical significance (laboratory tests 
are listed in Section 7.1) 
7. Healthy according to assessment of the medical history, electrocardiogram (ECG), vital 
signs, physical examination, laboratory results, negative drug screening, and negative 
serology tests (except results after vaccination) 
8. Non-smoker or ex-smoker, not using any nicotine product; an ex-smoker being defined as 
someone who completely stopped smoking for at least 12 months before Day 1 of the trial 
9. Each subject has to be capable of understanding the trial procedures and sign the ICF prior 
to their participation in the trial 
10. Subjects must consent to adhere to the recommended contraceptive methods as detailed in 
Section 6.7.5 and Appendix I. 
5.3.2 
Exclusion Criteria 
Subjects presenting with any of the following will not be included in the trial: 
1. Significant history of hypersensitivity to bisoprolol, amlodipine, other dihydropyridines, or 
any related products (including excipients of the formulations) 
2. Significant history of severe hypersensitivity reactions (eg, angioedema) to any drugs 
3. Pulse rate (in supine position) less than 60 beats per minute (bpm) or more than 100 bpm at 
screening 
4. Presence of significant arrhythmia: QTc interval prolongation (QTc greater than 430 msec), 
severe sinus node dysfunction, or second or third atrioventricular block 
5. History of low blood pressure (< 100/65 mmHg) or vegetative dystonia 
6. History or presence of peripheral arterial occlusion or Raynaud's syndrome 
7. Presence of diabetes mellitus 
8. History or presence of asthma 
9. Presence of significant gastrointestinal, liver, kidney disease, surgery, or any other 
conditions known to interfere with the absorption, distribution, metabolism, or excretion 
of drugs or known to potentiate or predispose to undesired effects 
10. Use of any enzyme-modifying drugs, including strong inhibitors of CYP enzymes (such as 
cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, 
diltiazem, and human immunodeficiency virus [HIV] antivirals) and strong inducers of 
CYP enzymes (such as barbiturates, carbamazepine, glucocorticoids, phenytoin, rifampin, 
St. John’s wort or other herbal medicine known with effect on CYP enzymes) within 
28 days before Day 1 of this trial 
11. Presence or history of significant cardiovascular, pulmonary, hematologic, neurologic, 
endocrine, immunologic, or dermatological disease 
12. Presence or history of significant angina pectoris, acute myocardial infarction or ST 
segment and T wave changes other than non-clinically significant minor changes 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
 
29/96 
 
 
13. Presence or history of ventricular arrhythmia (such as ventricular tachycardia or ventricular 
fibrillation) or of congestive heart failure 
14. Acute conditions which might alter the renal function (eg, dehydration, severe infection) 
15. Surgery in the previous 28 days before Day 1 of this trial 
16. Any history of tuberculosis and/or prophylaxis for tuberculosis within 10 years of Day 1 
of the trial 
17. Positive results to HIV antibody, hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody, or treponema pallidum (TP) antibody tests 
18. Donation of 50 mL or more of blood within 28 days before Day 1 of the trial; donation of 
500 mL or more of blood within 56 days before Day 1 of the trial 
19. History of suicidal tendency, history of, or disposition to seizures, state of confusion, 
clinically relevant psychiatric diseases 
20. Poor motivation, intellectual problems likely to limit the validity of consent to participate 
in the trial or limit the ability to comply with the protocol requirements or inability to 
cooperate adequately, inability to understand and to observe the instructions of the 
physician 
21. Maintenance therapy with any drug, or significant history of drug dependency or alcohol 
abuse (> 3 × 14 g alcohol per day, intake of excessive alcohol, acute or chronic use) 
22. Positive urine screening of drugs of abuse (cannabis, benzodiazepines, barbiturates, 
opiates, cocaine, and methyl amphetamine), or positive breath test of alcohol 
23. Positive pregnancy test (only for females of child-bearing potential), or females breast 
feeding a child 
24. Consumption of large quantities of methylxanthine-containing beverages (more than 
600 mg caffeine/day: 1 cup (250 mL) of coffee contains approximately 100 mg of caffeine, 
1 cup of black or green tea contains approximately 30 mg and 1 glass of cola contains 
approximately 20 mg caffeine) 
25. Volunteers who took an investigational product (in another clinical trial) by prescription 
within 2 weeks or an over-the-counter medication taken within 1 week before drug 
administration. 
5.4 
Criteria for Initiation of Trial Treatment 
Not applicable. 
5.5 
Criteria for Subject Withdrawal 
5.5.1 
Withdrawal from Trial Therapy 
Subjects are free to discontinue the trial at any time without giving their reasons. A subject must 
be withdrawn in the event of withdrawal of the subject’s consent. 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
 
30/96 
 
 
Subjects who withdraw from the trial will also be withdrawn from the investigational medicinal 
product (IMP). Dropout will not be replaced for this trial as long as the minimum evaluable sample 
size is met. 
5.5.2 
Withdrawal from the Trial 
Furthermore, participation in this clinical trial can be discontinued by the Investigator for one of 
the following reasons: 
1. On Day 1 before trial drug administration of Period 1 and additionally on Day 15 before trial 
drug administration of Period 2, if the supine blood pressure before drug administration is 
below 100/65 mmHg or above 139/90 mmHg, the subject has to be withdrawn from the trial 
2. Adverse events, as assessed by the Investigator to affect the outcome of the trial endpoints 
3. Significant protocol violation such as restrictions regarding alcohol and drug use, and 
nonadherence to the fasting or fed state 
4. Difficulties with blood collection 
5. Emesis experienced within 16 hours following drug administration because of incomplete 
absorption (this period of time corresponds also to 2 times the median time of maximum 
plasma concentration observed [tmax] of amlodipine). Subjects experiencing vomiting later 
than 16 hours postdose will not be withdrawn unless otherwise decided by the Investigator 
in light of subject’s safety or trial integrity 
6. Subject is uncooperative during the trial 
7. Use of any medication 
8. Withdrawal by Investigator’s judgement. 
Concomitant medication of any drug is prohibited. Any possible drug interaction caused by a 
concomitant medication with the IMP during the trial must be completely avoided in this trial. 
Details of reasons for premature withdrawal of subjects will be recorded and documented in the 
final report. 
In case of premature withdrawal from the trial, the investigations scheduled for premature 
withdrawal visit should be performed, if possible, with focus on the most relevant assessments 
(Section 7.1, “Schedule of Assessments” and Table 1). In any case, the appropriate electronic Case 
Report Form (eCRF) section must be completed. 
Dropouts within each sequence will be replaced if the total number of evaluable subjects within 
the sequence falls below 12 (Section 8.2.1). 
5.5.3 
Withdrawal from the Investigational Medicinal Product 
Subjects who withdraw from the trial will also be withdrawn from the IMP using the same criteria 
(Section 5.5.1). 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
 
31/96 
 
 
5.6 
Premature Termination of the Trial 
This trial is to be conducted in healthy volunteers using products in which the safety profile of the 
2 products is very well known. A 30-year marketing history with a large population exposure has 
established that the safety of these products is proven in the population with the target disease. As 
the safety of these products has been demonstrated in diseased patients, the conduct of this trial in 
healthy volunteers poses very little risk of premature withdrawal of the trial due to safety issues. 
However, in every case of (premature) withdrawal, the assessments scheduled for premature 
withdrawal visit must be conducted (Section 6.15). 
5.7 
Definition of End of Trial 
The End of Trial is defined as the last contact of the last subject (usually the End of Trial visit 
[Day 29], which is scheduled for 14 days after the administration day in Period 2 [Day 15]). 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
C O N F I D E N T I A L
I N F O R M A T I O N
32/96
6
Investigational Medicinal Products and Other Drugs Used in 
the Trial 
6.1
Description of the Investigational Medicinal Products 
Investigational product: 
 
One tablet of bisoprolol-amlodipine 5 mg/5 mg (as a combination formulation of the 2 active 
ingredients) 
Manufacturer: An appropriate packaging site under the control of Merck; final release will be 
conducted by a qualified person of Merck 
Tablet description: Bispoprolol-amlodipine fixed-dose-combination tablet: equivalent to 5 mg of 
bisoprolol fumarate and 5 mg of amlodipine per tablet 
Comparator-1:  
Tablet description: Bisoprolol fumarate (Concor®), light yellow, heart-shaped biconvex film 
coated tablets, scored on both side 
Manufacturer: Bisoprolol; Merck (Darmstadt, Germany) at Frankfurter Strasse 250 64293 
Darmstadt Germany  
Comparator-2:  
Tablet description: Amlodipine besylate (Norvasc®), equivalent to 5 mg of amlodipine per tablet; 
supplied as white, octagonal tablet, scored, debossed on 1 side with "NRV 5" and with "Pfizer" on 
the opposite side 
Manufacturer: Amlodipine; 
All trial products will be sourced from respective manufacturer as listed below. A set of in-vitro 
experiment including dissolution profile and content uniformity are being planned to confirm the 
dissolution profile of the comparator are within specifications. These in-vitro testing results will 
be available before the clinical trial conduct. 
CCI


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
C O N F I D E N T I A L
I N F O R M A T I O N
33/96
Drug Treatment
Investigational Product
Comparator-1
Comparator-2
Formulation:
Concor AM®
Bisoprolol-Amlodipine 5mg/5mg
Concor®
Bisoprolol 5 mg tablet
Norvasc®
Amlodipine 5 mg tablet
Manufacturer:
 
 
Merck KGaA., Germany
Storage 
Condition
Store in original package;
Do not store above 30°C;
Protected from light.
Store 
in 
original 
package;
Do not store above 25°C;
Do not freeze;
Protected from light.
Store in original 
package;
Do not store above 25°C;
Do not freeze;
Protected from light.
6.2
Dosage and Administration 
Potential trial subjects will be examined at a screening examination to determine their eligibility 
for participation. These tests are to be conducted within 7 days before the first trial administration 
(Day 1, Period 1). 
On the evening before the dosing day in each period, subjects will be admitted to the CRU to fast 
prior to Day 1 dosing (administered the next morning). During the fast, subjects will refrain from 
all food and drinks except water from the evening after dinner of Day -1. Water will be provided 
until 2 hours predose; the drug will be given with 240 mL (8 ounces) of water at room temperature; 
water will then be allowed ad libitum beginning 1 hour after the administration of the drug. 
x
The subjects in the fasting cohort will have fasted for at least 10 hours by the time of 
predose blood sample collected after 07:00 on the first day of each period. 
x
For the fed cohort, subjects will consume a standard breakfast started from 30 minutes 
before dosing and finished by 10 minutes before dosing. The single dose of trial drug 
administration will occur 10 minutes after breakfast completion around 07:00 in the 
morning of the first day of each period. The content of the breakfast will match the high-fat, 
high-calorie recommendation based on the regulatory guideline. 
All subjects will be required to refrain from drinking water during the first 1 hour after drug 
administration and to refrain from eating during the first 4 hours. Standard diet for lunch and dinner 
will be served for both fasting and fed cohorts. Beverages should be controlled: fluid intake will 
be controlled for each in-house period for all subjects. The subjects should drink at least 2 L of 
water during the first 24 hours after drug administration. 
On Day 1 before first trial drug administration, ECG and vital signs will be assessed. If the subject 
does not meet all eligibility requirements, the subject cannot be randomized to the trial.
CCI
CCI


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
 
34/96 
 
 
6.3 
Assignment to Treatment Sequences 
Each eligible subject will receive his allocated treatment according to a computer-generated 
randomization schedule. 
Sequence A-B: 
x Day 1 (Period 1), Treatment A: the administration of a single dose of 5 mg/5 mg 
bisoprolol-amlodipine (fixed-dose-combination tablet; investigational product); 
x Day 15 (Period 2), Treatment B: the administration of a single dose of 5 mg bisoprolol 
(1 tablet) and a single dose of 5 mg amlodipine (1 tablet) given concomitantly 
(comparators). 
Sequence B-A: 
x Day 1 (Period 1), Treatment B: the administration of a single dose of 5 mg bisoprolol 
(1 tablet) and a single dose of 5 mg amlodipine (1 tablet) given concomitantly 
(comparators); 
x Day 15 (Period 2), Treatment A: the administration of a single dose of 5 mg/5 mg 
bisoprolol-amlodipine (fixed-dose-combination tablet; investigational product). 
The 2 doses will be separated by a Washout period of 14 days (Table 2). 
Table 2 
Assignment to Administration Sequences 
 
Day 1 of Period 1 
Day 1 of Period 2 
Sequence A-B 
Bisoprolol-Amlodipine  
(5 mg/5 mg × 1) 
(Investigational product) 
Bisoprolol (5 mg × 1) +  
Amlodipine (5 mg × 1) 
(Comparator) 
Sequence B-A 
Bisoprolol (5 mg × 1) +  
Amlodipine (5 mg × 1) 
(Comparator) 
Bisoprolol-Amlodipine  
(5 mg /5 mg × 1) 
(Investigational product) 
This 2 × 2 crossover design for comparison of 2 treatments complies with the Chinese guideline 
for BE trials [8]. The guideline recommends 2 sequences in order to minimize the effect of 
individual and periodic differences. The guideline suggests that the duration of Washout period 
should be at least 7 times t1/2. Therefore, 14 days have been assigned as the Washout period 
duration to assure that the main collection times in Period 2 can occur on a weekday. 
 


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6.4 
Non Investigational Medicinal Products to be Used 
No other drugs are required by the protocol. 
6.5 
Concomitant Medications and Therapies 
Concurrent administration of any medication is prohibited during the trial. 
Subjects enrolled in this trial should be in good general health and therefore should not be taking 
any other medication. No concomitant medication (including nonprescription medication or 
multi-vitamin preparations or herbal medications, including traditional Chinese medicines) will be 
permitted during the trial (that is, within the period of time from the screening examination to the 
End of Trial examination). 
Upon use of any concomitant medication the subject shall then discontinue his/her participation in 
the trial treatment. 
The concomitant medication shall be documented in the eCRF stating the international 
nonproprietary name and trade name of the medication, its dose, duration, galenic form, route of 
administration, date and time of all administrations and indication. The data recorded up to the 
time at which the subject in question will be withdrawn shall be taken for the evaluation of the 
trial substance’s safety and tolerability. 
Any additional concomitant therapy that becomes necessary during the trial must be recorded in 
the corresponding section of the eCRF, noting the name, dose, duration and indication of each 
drug. 
6.5.1 
Permitted Medicines 
No concomitant medication is allowed during the trial. 
Any additional concomitant therapy that becomes necessary during the trial must be recorded in 
the corresponding section of the eCRF. 
6.5.2 
Prohibited Medicines 
Prohibitive medications also include cold preparations, aspirin, antacid preparations, vitamins, and 
natural products used for therapeutic benefits. 
The following medications are specifically mentioned in the exclusion criteria for the trial: 
x Maintenance therapy with any drug or significant history of drug dependency 


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x Use of any enzyme-modifying drugs, including strong inhibitors of CYP enzymes (such as 
cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, 
diltiazem, and HIV antivirals) and strong inducers of CYP enzymes (such as barbiturates, 
carbamazepine, glucocorticoids, phenytoin, rifampin, St. John’s wort or other herbal 
medicine known with effect on CYP enzymes) within 28 days before Day 1 of this trial. 
6.6 
Food Restriction and Standardization Diet 
Fluids 
Subjects are not allowed to excessively consume beverages containing xanthine (> 5 cups of coffee 
a day or equivalent) and need to stop caffeine consumption from 48 hours prior to drug 
administration until collection of the last PK sample in each period. Subjects also need to stop 
intake of grapefruit, cranberry or juices of these 2 fruits, from 14 days prior to drug administration 
until collection of the last PK sample in each period. During the hospitalization periods (evening 
of Day -1 to Day 8 of each period), water is allowed as desired, except for 2 hours before and until 
1 hour after drug administrations on Day 1 or Day 15 respectively. 
Food 
Subjects included in the fed cohort must agree to consume the trial high-fat breakfast. In the fed 
cohort, the breakfast should be similar in fat and caloric composition of the recommended high-fat 
(approximately 50% of total caloric content of the meal), high-calorie (approximately 800 to 1000 
calories) Chinese breakfast according to the standard of the trial center. During the hospitalization 
periods, subjects will receive breakfast, lunch, and dinner at regular times (as applicable). 
Prior to each drug administration (ie, Day 1 or Day 15), subjects in both cohorts need to fast 
overnight for at least 10 hours. 
Fasting cohort: In the morning of Day 1 or Day 15, after drug intake, the subjects should observe 
a fasting period of 4 hours until a standard lunch will be served. The dinner will be served 
approximately 12 hours after dosing. 
Fed cohort: In the morning of Day 1 or Day 15, subjects in fed cohort need to start the intake of 
the high-fat breakfast 30 minutes prior to drug administration and complete by 10 minutes before 
dosing. The drug will be administered 10 minutes after the end of the meal with 240 mL of water. 
After administration, subjects should observe a fasting period of 4 hours until a standard lunch will 
be served. The dinner will be served approximately 12 hours after dosing. 
6.7 
Special Precautions 
6.7.1 
Alcohol Prohibition 
The subjects have to abstain from alcohol from 2½ days (~60 hours) prior to dosing and through 
the End of Trial visit. 


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In case of any suspicion of alcohol consumption, a test for alcohol may be performed to confirm 
the Investigator's judgment. 
6.7.2 
Smoking Prohibition 
Smoking is included as an exclusion criterion barring eligibility into the trial and smoking is also 
prohibited during the trial. 
6.7.3 
Clinical Research Unit Inpatient Procedures 
Overnight Fast 
In the evening before the dosing day, subjects will be admitted to the CRU at ~12 hours prior to 
Day 1 or Day 15 dosing respectively. Subjects will refrain from all food and drinks except water 
from the evening following dinner of Day -1 or Day 14 respectively, and they will have fasted for 
at least 10 hours at the time of Baseline sampling (fasting cohort) or breakfast (fed cohort) the next 
morning. Water will be provided until 2 hours predose; water will be allowed beginning 1 hour 
after the administration of the drug. Beverages should be controlled: fluid intake will be controlled 
for each in-house period for all subjects. The subjects should drink at least 2 L of water during the 
first 24 hours after drug administration. 
Trial Drug Administration 
The single dose of trial drug administration will occur after 07:00 on the first day of each period. 
Subjects will take the medication in a seated position. A total volume of 240 mL water will be 
consumed with the medication. Following the administration of the drug, hands and mouth will be 
checked in order to confirm the consumption of the medication. All subjects will be required to 
refrain from drinking water during the first 1 hour after drug administration and refrain from eating 
during the first 4 hours. Standard diet for lunch and dinner will be served. The fluid intake will be 
controlled during the in-house stay. 
Posture and Physical Activities 
Subjects will remain in bed in an upright or semi-reclined position for at least the first 4 hours 
following drug administration. During this interval and under supervision, subjects are permitted 
to leave their bed for brief periods, eg, to use the washroom facilities. After this 4-hour period, 
subjects may get up, but only under supervision. Furthermore, subjects will be advised to exercise 
caution with their activities throughout the rest of each period of the trial. Subjects will not engage 
in strenuous activity at any time during the trial periods. 
6.7.4 
Safety Considerations 
On the last assessment day of each period, the Investigator will decide whether or not the subjects 
need to return for additional visits to the clinic. At any visit, subjects will be advised to remain at 
the clinical site if significant AEs are present. 


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6.7.5 
Contraception 
Male participants: 
A male participant must agree to use and to have their female partners to use a highly effective 
contraception (ie, methods with a failure rate of less than 1% per year) as detailed in Appendix I 
of this protocol during the treatment period and for at least 14 days after the last dose of trial 
treatment and refrain from donating sperm during this period. 
Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix I), not 
breastfeeding, and at least one of the following conditions applies: 
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix I 
OR 
b. A WOCBP who agrees to use a highly effective contraception (ie, methods with a failure rate 
of less than 1% per year) as detailed in Appendix I of this protocol during the treatment period 
and for at least 14 days after the last dose of trial treatment. 
6.8 
Packaging and Labeling of the Investigational Medicinal 
Product 
The packaging, labeling and documentation of IMP will be done according to Annex 13 and GMP 
requirements, so that it shall be possible to retrace the composition and pharmaceutical quality. 
6.9 
Preparation, Handling and Storage of the Investigational 
Medicinal Product 
Instructions for the preparation, handling, and storage of the IMPs will be provided. Additional 
details on the preparation and administration of the IMPs will be provided in the IMP Manual. 
All IMP treatment boxes supplied to the trial center must be stored carefully, safely, and separately 
from other drugs. 
Trial medication must not be used for any purpose other than the trial. The administration of trial 
medication to subjects who have not been enrolled into the trial is not covered by the subject’s trial 
insurance. 
The Investigator (or the pharmacist or another person who is designated by the Investigator) will 
maintain the following records for the trial medication: 
Upon receipt of trial treatment boxes at the trial center, the following must be performed by the 
trial staff: 
x Inventory at the center 
x Administration to each subject 
x Destruction of unused medication. 


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It must be ensured that the trial drug is not used at the trial site: 
x After the expiry date or 
x After the retest date unless the trial drug is reanalyzed and its release date extended. 
These procedures are to be closely monitored by the trial monitor and trial manager. 
Instruction of destruction of IMP will be provided in the IMP Manual. The unused and remained 
trial medication and the expired testing sample has to be destroyed under Sponsor’s greenlight and 
follow the instruction in IMP Manual. 
6.10 
Investigational Medicinal Product Accountability 
The Investigator is responsible for ensuring accountability for IMP, including reconciliation of 
drugs and maintenance of drug records. 
x Upon receipt of IMP, the Investigator (or designee) will check for accurate delivery and 
acknowledge receipt by signing (or initialing) and dating the documentation provided by 
the Sponsor and returning it to the Sponsor. A copy will be retained for the Investigator 
File. 
x The dispensing of the IMP will be carefully recorded on the appropriate drug accountability 
forms provided by the Sponsor and an accurate accounting will be available for verification 
by the Sponsor Monitor at each monitoring visit. 
x IMP accountability records will include: 
x Confirmation of IMP delivery to the trial site. 
o The inventory at the site of IMP provided by the Sponsor and prepared at the site. 
o The use of each dose by each subject. 
o The return to the Sponsor or alternative disposition of unused IMP. 
o Dates, quantities, batch numbers, expiry dates and formulation, as well as the 
subjects’ trial numbers. 
x The Investigator should maintain records that adequately document: 
o That the subjects were provided the doses specified by the clinical trial 
protocol/amendment(s), and 
o That all IMP provided by the Sponsor was fully reconciled. 
Unused IMP must not be discarded or used for any purpose other than the present trial. 
Investigational medicinal product that has been dispensed to a subject must not be redispensed to 
a different subject. 
The Sponsor Monitor will periodically collect the IMP accountability forms and will check all 
returns (both unused and used containers) before arranging for their return to the Sponsor or 
authorizing their destruction by the trial site. Following the administration of the drug, hands and 
mouth will be checked in order to confirm the consumption of the medication. 


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6.11 
Assessment of Investigational Medicinal Product Compliance 
The trial treatments will be administered either by the Investigator or under his or her direct 
supervision in a CRU. 
Investigational medicinal product administration and any reason for non-compliance should be 
recorded in the eCRF. 
6.12 
Blinding 
This trial is an open-label trial design. Blinding is not applicable. 
6.13 
Emergency Unblinding 
Not applicable. 
6.14 
Treatment of Overdose 
This is a trial where the IMPs will be administered by the Investigator/Clinical Trial Coordinator. 
Therefore, the risk of overdose will be negligible. In case of unexpected events, the supervising 
physician is responsible for diagnosis and treatment of unexpected adverse reactions according to 
accepted standard medical care and full documentation. The following actions should be 
considered. 
Amlodipine 
If any unforeseen overdose should occur, active cardiac and respiratory monitoring should be 
instituted. Frequent blood pressure measurements are essential. Should hypotension occur, 
cardiovascular support including elevation of the extremities and the judicious administration of 
fluids should be initiated. If hypotension remains unresponsive to these conservative measures, 
administration of vasopressors (such as phenylephrine) should be considered with attention to 
circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects 
of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be 
of benefit. 
Bisoprolol 
In general, if overdose occurs, supportive and symptomatic treatment should be provided. Limited 
data suggest that bisoprolol fumarate is not dialyzable. Based on the expected pharmacologic 
actions and recommendations for other beta-blockers, the following general measures should be 
considered when clinically warranted. 
Bradycardia: 
Administer intravenous atropine. If the response is inadequate, 
isoproterenol or another agent with positive chronotropic properties 
may be given cautiously. Under some circumstances, transvenous 
pacemaker insertion may be necessary. 


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Hypotension: 
Intravenous fluids and vasopressors should be administered. 
Intravenous glucagon may be useful. 
Heart Block: 
For second or third degree heart block, patients should be carefully 
monitored and treated with isoproterenol infusion or transvenous 
cardiac pacemaker insertion, as appropriate. 
Congestive Heart Failure: Initiate conventional therapy (ie, digitalis, diuretics, inotropic agents, 
vasodilating agents). 
Bronchospasm: 
Administer bronchodilator therapy such as isoproterenol and/or 
aminophylline. 
Hypoglycemia: 
Administer intravenous glucose. 
6.15 
Medical Care of Subjects after End of Trial 
After a subject has completed the second Washout of the trial (14 days after last dose) or has 
withdrawn prematurely, an End of Trial visit (Day 29, if subject completed the trial) or premature 
withdrawal visit will be conducted and safety assessments will be performed. 
Upon the careful screening for healthy subjects such as detailed in the eligibility criteria for this 
trial, no serious AEs are expected during this trial. However, in case of any ongoing AE at the End 
of Trial visit or Premature Withdrawal visit, these AEs must be monitored until they have either 
returned to normal or are no longer considered as clinically relevant by the Investigator or can be 
explained. If necessary, other medical disciplines should be consulted. 


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7 
Trial Procedures and Assessments 
7.1 
Schedule of Assessments 
The schedule of assessments will include: 
x Screening (determining eligibility to the trial, including assessments during admission to 
CRU; Day -7 to Day -1) 
x Admission to the CRU before Period 1 (Day -1) 
x Period 1 (Day 1 to Day 8) 
x Washout Period 1 
x Admission to the CRU before Period 2 (Day 14) 
x Period 2 (Day 15 to Day 22) 
x Washout Period 2 
x End of Trial (Day 29)/Premature Withdrawal (Table 1). 
Subject will participate in the clinical trial on an in-house basis during Day -1 to Day 8 and also 
during Days 14 to Day 22. 
The description of these trial intervals are as follow. 
7.1.1 
Screening (Day -7 to Day -1) 
The following assessments will be conducted during Screening (between Day -7 and  
Day -1) to determine eligibility of the subject for randomization to the trial. 
Informed Consent (ICF) 
Prior to performing any trial assessments, the Investigator will ensure that the subject or the 
subject’s legal representative has provided written informed consent according to the 
procedure described in Section 9.2. The ICF will be signed by the subject prior to the 
subject’s inclusion into the trial. 
Inclusion/exclusion Criteria 
Potential trial subjects will be examined at screening to determine their eligibility for clinical 
trial participation. The inclusion and exclusion criteria will be reviewed to determine 
eligibility for the trial while collecting the necessary information. All screening assessments 
are to be conducted within 7 days before the start of the trial. 
Demographic Information 
Demographic information will consist of data collected for age, sex, race (Chinese, 
non-Chinese), height and weight. The BMI (kg/m2) will be calculated. 


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Other Baseline Information 
Other baseline information will include inquiry for the history of alcohol and nicotine 
consumption plus the baseline assessments described in more detail below: physical 
examination, vital signs, ECG recordings, medical history, and laboratory tests. 
Medical history will include screening for past illnesses associated with allergic disorders; 
eyes, ears, nose, and throat; and past illnesses describing the cardiac, vascular, pulmonary, 
musculoskeletal, gastrointestinal, genitourinary, neurological, endocrine, psychiatric, 
dermatological, hematological systems of the body, and previous treatments. 
Prior medications within 1 month before the date of first signature of informed consent will 
be collected.  
Concomitant medications, treatments, and AEs will be collected from the date of first 
signature of informed consent. 
Physical Examination 
A detailed physical examination will be performed. This examination includes assessments 
of the general appearance, skin and mucosa, superficial lymph nodes, head and neck, chest, 
abdomen, musculoskeletal, and neurological systems. 
Vital Signs 
Blood pressure (systolic and diastolic pressures), pulse rate, body temperature, and 
respiration (frequency per minute) will be measured and recorded. Blood pressure and pulse 
rate will be recorded in a supine position after the subject has rested comfortably for at least 
5 minutes. 
Electrocardiogram Recording 
A 12-lead ECG (including QTc evaluation) will be performed. 
Results of the ECG recordings will be included in the subject's eCRF. Printouts for each 
ECG will include date, time, initials of the technician/nurse, and initials of the Investigator 
who reviewed the printout. At least 5 to 7 beats will be monitored at a speed of 25 mm/sec 
for each lead and a single lead (V2) run (see Section 7.3.4 for specific ECG determinations 
and procedures).  
Chest X-ray 
A chest X-ray examination will be performed. 


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Laboratory Tests 
Hematology assessments 
Parameter 
Dimension/Unit 
 
Erythrocytes 
 
×1012/L 
 
Hemoglobin  
 
g/L 
 
Hematocrit  
 
% 
 
Mean corpuscular volume 
 
fL 
 
Mean corpuscular hemoglobin 
 
pg 
 
Mean corpuscular hemoglobin  
 
concentration 
 
g/L 
Red blood cell distribution width 
%  
Platelets 
×109/L 
Mean platelet volume 
fL 
Thrombocytocrit 
% 
Platelet distribution width 
% 
 
White blood cells 
 
×109/L 
Hematology assessments for differential white blood cell counts 
Parameter 
Dimension/Unit 
 
Neutrophils 
 
109/L and % 
 
Monocytes 
 
109/L and % 
 
Lymphocytes 
 
109/L and % 


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Biochemistry assessments 
Parameter 
Dimension/Unit 
Alanine aminotransferase 
IU/L 
Aspartate aminotransferase 
IU/L 
Total bilirubin 
μmol/L 
Direct bilirubin 
μmol/L 
Indirect bilirubin 
μmol/L 
Protein total 
g/L 
Albumin 
g/L 
Globulin 
g/L 
A/G 
(Not applicable) 
Alkaline phosphatase 
IU/L 
Glutamyl transpeptidase 
IU/L 
Urea nitrogen 
mmol/L 
Creatinine 
μmol/L 
Cholesterol 
mmol/L 
Triglycerides 
mmol/L 
Glucose 
mmol/L 
Creatine kinase 
IU/L 
Lactate dehydrogenase 
IU/L 
Calcium 
mmol/L 
Phosphorus 
mmol/L 
α-Amylase 
U/L 
Sodium 
mmol/L 
Potassium 
mmol/L 
Chloride 
mmol/L 
Note: If creatine kinase is above the upper limit of normal and evaluated as clinically 
relevant, a retest should be done and the creatine phosphokinase MB isoenzyme should be 
determined. 


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Urinalysis 
Appearance, blood, glucose, ketones, nitrite, pH, protein, and leukocytes will be assessed. 
Microscopic examination will only be performed if dipstick test is positive for leukocytes, 
blood, nitrites, or proteins. 
Serum pregnancy test 
Pregnancy testing for females of childbearing potential only (Human Chorionic 
Gonadotropin in serum) 
Other laboratory tests 
Serology 
HIV antibody 
HBsAg 
HCV antibody 
TP antibody 
Urine screening of drugs of abuse 
The following urine tests for drug abuse will be conducted: levels for other drugs of abuse 
(eg, cannabis, benzodiazepines, barbiturates, opiates, cocaine, and methyl amphetamine). 
Breath test of alcohol 
Levels of alcohol in breath will be tested. 
Urine nicotine 
Levels of nicotine in urine will be tested. 
7.1.2 
Admission to Clinical Research Unit (Day -1) 
In the evening before the dosing day, subjects will be admitted in an in-house status to the CRU at 
least 12 hours prior to Day 1 dosing for an overnight fast. Subjects will refrain from all food and 
drinks except water from the evening after dinner of Day -1. They will have fasted for at least 
10 hours by the time of drug administration (fasting cohort) or standard breakfast (fed cohort) next 
morning (see Section 6.7.3). 
Trial eligibility assessments will be performed including: physical examination, vital signs, ECG 
and concomitant medications, treatments and diseases as well as testing for drug abuse. 
If the subject is determined to be ineligible for the trial due to any of the above assessments, the 
subject will be considered a screening failure and will not continue to randomization to the trial. 
Adverse events will be collected and recorded on the eCRF. 


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7.1.3 
Period 1 (Day 1 to Day 8) 
Day 1, Trial Drug Administration 
On Day 1, the following assessments will be conducted and/or collected and recorded on the eCRF. 
Trial Eligibility Assessments 
Subjects will be assessed for vital signs (blood pressure, pulse rate, temperature and 
respiration). Blood pressure assessments determine eligibility to be randomized to the trial. 
The blood pressure (measured in supine position after at least 5 minutes rest) must not be 
below 100 mmHg and/or 65 mmHg or above 139 mmHg and/or 90 mmHg. 
A 12-lead ECG (including QTc evaluation) will be performed. 
Any concomitant medications, diseases and treatments should be documented. Concurrent 
administration of any medication will be prohibited during the trial (Section 6.5). 
If the subject is determined to be ineligible for any of the above assessments, the subject will 
not be randomized to the trial. 
Any AEs and serious adverse events (SAEs) should also be recorded. 
Randomization 
Eligible subjects will then be randomly assigned to one of 2 sequences (Table 2). 
Baseline Sampling 
Eligible subjects will have their baseline blood sample collected before IMP administration 
in Period 1. 
Trial Drug Administration 
As per randomization, each subject will receive a single dose of bisoprolol-amlodipine 
5 mg/5 mg (given as 1 tablet of 5 mg/5 mg) or a single dose of 5 mg bisoprolol and 5 mg 
amlodipine (given as 1 tablet of 5 mg bisoprolol and 1 tablet of 5 mg amlodipine, 
co-administrated) accordingly. 
The single dose of trial drug administration will occur after 07:00 in the morning of the first 
day of each period. A total volume of 240 mL water will be consumed with the medication. 
All subjects will be required to refrain from drinking water during the first 1 hour after drug 
administration and refrain from eating during the first 4 hours. Standard diet for lunch and 
dinner will be served. Beverages should be controlled: fluid intake will be controlled for 
each in-house period for all subjects. The subjects should drink at least 2 L of water during 
the first 24 hours after drug administration. 


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Blood Sampling (Postdose) 
Blood samples for the determination of bisoprolol and amlodipine will be taken at the 
specified times (Table 3). 
Pharmacokinetic Sampling procedure 
For bisoprolol and amlodipine, whole blood samples will be collected in coded, precooled 
ethylenediamine tetraacetic acid dipotassium salt coated vacutainers by indwelling cannula 
(short-term peripheral catheter) for the first day and by direct venipuncture for the rest of the 
time. Blood samples will be kept in an ice water bath pending processing. 
For every subject, during each treatment period, a total of 20 samples, approximately 4 mL 
each whole blood, will be collected at the following times: at predose (Baseline) and at 0.5, 
1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing. One 
sample will be collected at End of Trial (Day 29)/Premature Withdrawal. The PK collection 
time is based on known single-dose PK profiles of both drugs and should be frequent and 
long enough to characterize the peak and extent of exposure. Plasma samples will be 
prepared, divided into 2 aliquots and stored at -20 ºC. 
Subjects who complete both treatment periods will have a total of 41 samples (4 mL whole 
blood each sample) collected. Total blood volume collection for PK sampling is 
approximately 164 mL over 5 weeks. 
A validated bioanalytical method, using HPLC with MS/MS detection, will be applied to 
analyze plasma concentration of bisoprolol and amlodipine. The assay and all related 
procedure will be developed and cross-validated with previously established methods to 
ensure quality standard and technical specifications are met. Based on previous method, the 
following criteria are expected: 
Analytes: bisoprolol and amlodipine in human plasma 
Assay range: bisoprolol 0.500 – 75.000 ng/mL; amlodipine 50.0 – 15000.0 pg/mL 
Details of the assay may differ from above and will be provided in the Analytical plan 
separately. 
The complete schedule for each trial period is presented in Table 3. The clock time of all 
blood draws will be recorded and reported for each subject in the eCRF. The actual sampling 
times, if available, will always be used for calculation. 




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Concurrent administration of any medication will be prohibited during the trial (Section 6.5.1). 
Day 2 to Day 8, Period 1 
Pharmacokinetic Blood Sampling (Postdose, continued) 
During the 7 days following Day 1, blood samples will be taken according to the trial 
schedule (Table 3). On Day 2, sampling will be conducted at 24 and 36 hours; from Day 4 
to Day 8, sampling will be conducted every 24 hours. Subjects will be allowed to leave the 
CRU on Day 8 after the morning blood sampling collection (168-hour sample). 
Safety Monitoring 
Any concomitant diseases and treatments have to be documented. Concurrent administration 
of any medication will be prohibited during the trial. Any AEs and SAEs should also be 
recorded. 
Vital signs (blood pressure, pulse rate, temperature and respiration) will be assessed before 
blood sampling from Day 2 to Day 8. 
A 12-lead ECG (including QTc evaluation) will be performed 48 hours postdose at Day 3. 
At the day of discharge, a blood sample for determination of hematology and biochemistry 
will be taken and a urinalysis will be performed. Serum pregnancy test will be performed for 
females of childbearing potential only. Physical examination, ECG, and chest X-ray will be 
performed. 
On the morning of Day 8 in the CRU after the blood sampling collection (168-hour sample), 
the Investigator will decide whether or not the subject needs to stay for any additional time 
in the clinic. If there are no safety concerns based on the assessment by the Investigator, the 
subject will be allowed to leave the CRU. 
7.1.4 
Washout Period 1 
The 2 administrations of trial drug are separated by a washout of 14 days. Washout begins postdose 
on Day 1 and continues for 14 days. 
7.1.5 
Admission to Clinical Research Unit (Day 14) 
In the evening before the dosing day, subjects will be admitted to the CRU at least 12 hours prior 
to Day 15 dosing for an overnight fast. Subjects will refrain from all food and drinks except water 
from the evening after dinner of Day 14. They will have fasted for at least 10 hours at the time of 
drug administration (fasting cohort) or standard breakfast (fed cohort) next morning (see 
Section 6.6). 
Trial eligibility assessments will include: physical examination, vital signs (blood pressure, pulse 
rate, temperature and respiration), ECG, and concomitant medications (Table 1). Testing for drug 


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abuse will be performed. In addition, a blood sample for determination of hematology and 
biochemistry will be taken and a urinalysis will be performed. 
If the subject is determined to be ineligible for any of the above assessments, the subject will be 
dismissed from the CRU and will not continue with the trial. 
Any AEs will be collected and recorded on the eCRF. 
7.1.6 
Period 2 (Day 15 to Day 22) 
Day 15, Trial Drug Administration 
Procedures outlined on Day 1 in Period 1 will be repeated on Day 15 for continuing trial eligibility 
into Period 2 (except for randomization). 
Baseline Sampling 
Eligible subjects will have their baseline blood sample collected before trial drug 
administration in Period 2. 
Trial Drug Administration 
Each subject will receive the trial medication according to the randomization plan 
(investigational product and comparators). 
The single dose of trial drug administration will occur after 07:00 in the morning of Day 15. 
A total volume of 240 mL water will be consumed with the medication. All subjects will be 
required to refrain from drinking water during the first 1 hour after drug administration and 
refrain from eating during the first 4 hours. Standard diet for lunch and dinner will be served. 
Beverages should be controlled: fluid intake will be controlled for each in-house period for 
all subjects. The subjects should drink at least 2 L of water during the first 24 hours after drug 
administration. 
Pharmacokinetic Blood Sampling (Postdose) 
Blood samples for the determination of bisoprolol and amlodipine will be taken at the 
specified times: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 15 hours (Table 3). 
Safety Monitoring 
Any concomitant diseases and treatments have to be documented. Concurrent administration 
of any medication will be prohibited during the trial (Section 6.5.1). 
Any AEs and SAEs are also to be recorded. 
Vital signs (blood pressure, pulse rate, temperature and respiration) will be taken prior to 
dosing and also at 4, 8, and 12 hours postdose. 
A 12-lead ECG (including QTc evaluation) will be performed 4 hours postdose. 


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Day 16 to Day 22 
Pharmacokinetic Blood Sampling (Postdose, continued) 
Blood samples for the determination of bisoprolol and amlodipine will be taken at the 
specified times (Table 3). 
On Day 16, sampling will be conducted at 24 and 36 hours; from Day 18 to Day 22, sampling 
will be conducted every 24 hours. The subject is allowed to leave the CRU on Day 22 after 
the morning blood sampling (168 hour sample). 
Safety Monitoring 
Any concomitant diseases and treatments have to be documented. Concurrent administration 
of any medication will be prohibited during the trial (Section 6.5.1). 
Any AEs and SAEs should also be recorded. 
Vital signs (blood pressure, pulse rate, temperature and respiration) will be assessed before 
blood sampling from Day 16 to Day 22. 
A 12-lead ECG (including QTc evaluation) will be performed 48 hours postdose at Day 17. 
At the day of discharge, a blood sample for determination of hematology and biochemistry 
will be taken and a urinalysis will be performed. Serum pregnancy test will be performed for 
females of childbearing potential only. Physical examination, ECG, and chest X-ray will be 
performed. 
On the morning of Day 22 in the clinic after the morning blood sampling collection 
(168-hour sample), the Investigator will decide whether or not the subject needs to stay for 
any additional time in the clinic. If there are no safety concerns based on the assessment by 
the Investigator, the subject will be allowed to leave the clinic. 
7.1.7 
Washout Period 2 
Washout in Period 2 begins postdose on Day 15 and continues for 14 days through Day 28. 
7.1.8 
End of Trial (Day 29)/Premature Withdrawal 
End of Trial 
At End of Trial (Day 29), AEs will be assessed. The case conclusion has to be filled in. 
If AEs or pathological findings, ie, clinically relevant deviations from baseline findings are 
obtained during the final examination, these findings must be monitored until they have either 
returned to normal or are no longer considered as clinically relevant or can be explained. If 
necessary, other medical disciplines should be consulted. 


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Pharmacokinetic Blood Sampling 
Blood samples for the determination of bisoprolol and amlodipine will be taken (Table 3). 
Premature Withdrawal 
The assessments at Premature Withdrawal visit include: physical examination, vital signs (blood 
pressure, pulse rate, temperature, and respiratory), ECG, laboratory tests (hematology, 
biochemistry, and urinalysis), Chest X-ray, and AEs (Table 1). The case conclusion has to be filled 
in. Serum pregnancy test will be performed for females of childbearing potential only. 
If AEs or pathological findings, ie, clinically relevant deviations from baseline findings are 
obtained during the final examination, these findings must be monitored until they have either 
returned to normal or are no longer considered as clinically relevant or can be explained. If 
necessary, other medical disciplines should be consulted. 
Pharmacokinetic Blood Sampling 
Blood samples for the determination of bisoprolol and amlodipine will be taken (Table 3). 
7.1.9 
Estimated Blood Sample Volumes per Subject 
The blood sample volumes of each subject are estimated in Table 4. 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
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Table 4 
Estimated Blood Sample Volumes per Subject 
Time Points 
Evaluation Indexes 
Total Blood Volume (mL) 
Screening 
Serum virology 
4 
Hematology 
2 
Biochemistry 
4 
Serum Pregnancy Test (if 
applicable) 
4 
Approximate Total 
14 
Period 1 
Hematology 
2 
Biochemistry 
4 
Serum Pregnancy Test (if 
applicable) 
4 
Pharmacokinetics 
4*20 
Approximate Total 
90 
Period 2 
Hematology 
2*2 
Biochemistry 
4*2 
Serum Pregnancy Test (if 
applicable) 
4 
Pharmacokinetics 
4*20 
Approximate Total 
96 
End of Trial 
 
Pharmacokinetics 
4 
Approximate Total 
4 
Premature Withdrawal 
Hematology 
2 
Biochemistry 
4 
Serum Pregnancy Test (if 
applicable) 
4 
Pharmacokinetics 
4 
Approximate Total 
14 
Approximate Total of Each Subject (without premature 
withdrawal) 
204 
 
 
7.2 
Demographic and Other Baseline Characteristics 
At screening, the following demographic data will be collected: date of birth, sex, race, and height 
and weight. The BMI (kg/m2) will be calculated. 


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7.3 
 Assessment of Safety 
The safety profile of the IMP will be assessed through the recording, reporting and analyzing of 
baseline medical conditions, physical examination findings, vital signs (blood pressure, pulse rate, 
temperature and respiration), ECG, laboratory tests, and AEs. 
Comprehensive assessment of any apparent toxicity experienced by the subject will be performed 
throughout the course of the trial, from the time of the subject’s signature of informed consent. 
Trial site personnel will report any AE, whether observed by the Investigator or reported by the 
subject (Section 7.3.1.2, “Methods of Recording and Assessing Adverse Events”). 
The reporting period for collecting AEs is described in Section 7.3.1.3. 
7.3.1 
Adverse Events 
7.3.1.1 
Adverse Event Definitions 
Adverse Event 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself. 
In case of a fatality, the cause of death is considered an AE, and the death is considered the outcome 
of the AE. 
Investigators must assess the severity/intensity of AEs according to the Qualitative Toxicity Scale 
as one of the following: 
Mild: 
The subject is aware of the event or symptom, but the event or symptom is easily 
tolerated. 
Moderate: The subject experiences sufficient discomfort to interfere with or reduce his or her 
usual level of activity. 
Severe: 
Significant impairment of functioning: the subject is unable to carry out usual 
activities. 
Investigators must also systematically assess the causal relationship of AEs to the 
bisoprolol-amlodipine fixed-dose-combination tablet and the comparators (bisoprolol and 
amlodipine) using the following definitions. Decisive factors for the assessment of causal 


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relationship of an AE to the treatments include, but may not be limited to, temporal relationship 
between the AE and the treatments, known side effects of treatments, medical history, concomitant 
medication, course of the underlying disease, or trial procedures: 
Not related: Not 
suspected to 
be 
reasonably 
related 
to the 
bisoprolol-amlodipine 
fixed-dose-combination tablet or the comparators. Adverse event could not 
medically (pharmacologically/clinically) be attributed to the bisoprolol-amlodipine 
combination tablet or the comparators under trial in this clinical trial protocol. A 
reasonable alternative explanation must be available. 
Related: 
Suspected to be reasonably related to bisoprolol-amlodipine fixed-dose-combination 
tablet 
and 
the 
comparators. 
Adverse 
event 
could 
medically 
(pharmacologically/clinically) 
be 
attributed 
to 
the 
bisoprolol-amlodipine 
fixed-dose-combination tablet and the comparators under trial in this clinical trial 
protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings 
Abnormal laboratory findings and other abnormal investigational findings (eg, on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead to 
treatment discontinuation, or are considered otherwise medically important by the Investigator. If 
an abnormality fulfills these criteria, the identified medical condition (eg, anemia and increased 
alanine aminotransferase must be reported as the AE rather than the abnormal value itself. 
Adverse Drug Reaction 
In accordance with Good Clinical Practice (GCP), an adverse drug reaction (ADR) is defined in 
this study as any AE considered to be related to drug treatment. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
x Results in death 
x Is life-threatening. 
NOTE: The term “life-threatening” in this definition refers to an event in which the subject is at 
risk of death at the time of the event; it does not refer to an event that hypothetically might cause 
death if it were more severe, that is as follows: 
x Requires inpatient hospitalization or prolongation of existing hospitalization 
x Results in persistent or significant disability/incapacity 
x Is a congenital anomaly/birth defect 
x Is otherwise considered as medically important. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered as SAEs when, based upon appropriate medical judgment, they may jeopardize 


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the subject or may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias, or convulsions that do not result in 
inpatient hospitalization, in the development of drug dependency, or in drug abuse. 
Events that Do Not Meet the Definition of a Serious Adverse Event 
Elective hospitalizations to simplify trial treatment or trial procedures (eg, an overnight stay to 
facilitate related hydration therapy applications) are not considered an SAE. However, all events 
leading to unplanned hospitalizations or unplanned prolongation of an elective hospitalization (eg, 
undesirable effects of any administered treatment) must be documented and reported as SAEs. 
7.3.1.2 
Methods of Recording and Assessing Adverse Events 
At each trial visit, the subject will be queried on changes in his condition. During the reporting 
period of the trial any unfavorable changes in the subject’s condition will be recorded as AEs, 
whether reported by the subject or observed by the Investigator. 
All AEs must be documented in the appropriate section of the eCRF. Complete, accurate and 
consistent data on all AEs experienced for the duration of the reporting period (defined below) will 
be reported on an ongoing basis. Among these AEs, all serious AEs must be additionally 
documented and reported using an SAE Report Form (Clinical Trial) as described in  
Section 7.3.1.4. 
The following aspects must be recorded for each AE in the eCRF: 
1) Description of the AE in medical terms, not as reported by the subject 
2) Date/time of onset (only in relation to administration of IMP: before, during, or after) 
3) Severity grade (Section 7.3.1.1), assessed by the Investigator according to the Qualitative 
Toxicity Scale 
4) Causal relationship to the IMP applied per protocol, assessed by the Investigator 
5) Action taken with regard to trial treatments 
6) Concomitant medication 
7) Outcome 
8) Seriousness (appropriate criteria documented). 
Specific guidance can be found in the eCRF Completion and Monitoring Conventions provided 
by the Sponsor. 
7.3.1.3 
Definition of the Adverse Event Reporting Period 
The AE reporting period for safety surveillance begins when the subject is included into the trial 
(date of first signature of informed consent) and continues through the trial’s post treatment period. 
The complete trial duration for collecting AEs is defined as beginning with the date of the signing 
of the consent form (up to 7 days before Day 1 of trial Period 1), continuing during the 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
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investigational trial drug administration, and collection continued until 14 days after the day of the 
last investigational trial drug administration (that is, End of Trial visit, Day 29). In case of early 
termination, AEs until Premature Withdrawal visit will be collected. 
7.3.1.4
Procedure for Reporting Serious Adverse Events and 
Non-serious Adverse Drug Reactions 
In the event of any SAE occurring in Treatment A or B group during the reporting period, and in 
the event of any non-serious ADRs related with Treatment B, the Investigator must inform Sponsor 
or its designee in writing, within a maximum of 24 HOURS after becoming aware of the event. 
All written reports should be transmitted using the AE Report Form, which must be completed by 
the Investigator following specific completion instructions.  
To do so, the Investigator/reporter must complete a Sponsor SAE report following specific 
instructions (SAE report Completion Instruction) and using preferably the electronic template, and 
send it directly to the Sponsor’s designee by electronic mail or facsimile. Name, address, 
telephone, and fax numbers for SAE reporting will be included in the trial specific AE Report 
Form as shown below: 
E-mail: 
Facsimile: 
When an event (or follow-up information) is reported by telephone, a written report must be sent 
immediately thereafter by fax or e-mail. All written reports should be transmitted using the SAE 
Report Form (Clinical Trials), which must be completed by the Investigator following specific 
completion instructions. 
Reporting procedures and timelines are reported in the same manner as for follow-up information 
for any new information for a subject as was collected on a previously reported SAE. 
Specific guidance can be found in SAE Report Form Instructions provided by the Sponsor. 
The Investigator or reporter must respond to any request for follow-up information (eg, additional 
information, outcome and final evaluation, specific records where needed) or to any question the 
Sponsor may have on the AE within the same timelines as described for initial reports. This is 
necessary to permit a prompt assessment of the event by the Sponsor and (as applicable) to allow 
the Company to meet strict regulatory timelines associated with expedited safety reporting 
obligations. 
Requests for follow-up will usually be made by the responsible Monitor, although in exceptional 
circumstances the Sponsor’s Drug Safety department or its designee may contact the Investigator 
directly to obtain clarification or to discuss a particularly critical event. 
PPD
PPD


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
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7.3.1.5 
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators 
In the event of any SAE occurring during the reporting period, the Investigator must immediately 
(ie, within 24 hours of becoming aware of the event) report to regulatory authorities in accordance 
with applicable laws and regulations. 
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (and in particular SAEs with outcome of death) involving his/her subjects to the 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the trial. 
The Sponsor will send appropriate safety notifications to regulatory authorities in accordance with 
applicable laws and regulations. 
The Sponsor 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 these Safety reports in the 
Investigator Site File. National regulations will be taken into account with regard to safety report 
notifications to Investigators. 
When specifically required by regulations and guidelines, the Sponsor will provide appropriate 
Safety reports directly to the concerned lead IEC/IRB and will maintain records of these 
notifications. When direct reporting by the Sponsor is not clearly defined by national or 
site-specific regulations, the Investigator will be responsible for promptly notifying the concerned 
IEC/IRB of any Safety reports provided by the Sponsor and of filing copies of all related 
correspondence in the Investigator Site File. 
7.3.1.6 
Monitoring of Subjects with Adverse Events 
Any AE that occurs during the course of the clinical trial and is considered to be related to 
Concor AM®, Concor® or Norvasc® must be monitored and followed up until the outcome is 
known, unless the subject is documented as “lost to follow-up.” Reasonable attempts to obtain this 
information must be made and documented. It is the responsibility of the Investigator to ensure 
that any necessary additional therapeutic measures and follow-up procedures are performed. 
7.3.2 
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to trial treatment (eg, resulting from 
a drug interaction with a contraceptive medication) are considered to be AEs. However, all 
pregnancies with an estimated conception date during the period defined in Section 7.3.1.3 must 
be recorded by convention in the AE page/section of the eCRF. The same rule applies to 
pregnancies in female subjects and to pregnancies in female partners of male subjects. The 
Investigator must notify the Sponsor/designee in an expedited manner of any pregnancy using the 
Pregnancy Report Form, which must be transmitted according to the same process as described 
for SAE reporting in Section 7.3.1.4. 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
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Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial. 
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the subject sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event. 
Any abnormal outcome must be reported in an expedited manner as described in Section 7.3.1.4, 
while normal outcomes must be reported within 45 days after delivery. 
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from trial medication immediately. The Sponsor/designee must be notified 
without delay and the subject must be followed as mentioned above. 
7.3.3 
Clinical Laboratory Assessments 
Safety and tolerability will be assessed by monitoring laboratory measurements. 
It is essential that Merck Serono be provided with a list of laboratory normal ranges before 
shipment of trial drug. Any change in laboratory normal ranges during the trial will additionally 
be forwarded to Merck Serono. 
7.3.4 
Electrocardiogram 
A 12-lead ECG (including QTc evaluation) will be performed. 
After the subject has rested for at least 5 minutes in the supine position, a 12-lead ECG will be 
conducted by placing peripheral leads I, II, III, aVR, aVL, aVF followed by the precordial leads 
V1-V6 and all 12 leads recorded. At least 2 to 3 beats will be monitored at a speed of 25 mm/sec 
for each lead and a single lead (V2) run. Printouts for each ECG will include date, time, initials of 
the technician/nurse who performed the test and initials of the personnel who reviewed the printout 
(ie, a medical physician). Results of the ECG recordings will be included in the subject's eCRF. 
The following parameters will be assessed: 
x RR-Interval [ms] 
x PR-Interval [ms] 
x QRS-Duration [ms] 
x QT-Interval [ms] 
x QTc (Bazett) [ms] 
x QTcF (Fridericia) [ms] 
x Heart Rate [bpm] 
x Rhythm (sinusal - other) 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
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QT / QTc interval will be automatically computed using the Bazett correction formula (QTcB = 
QT / √RR) and the Fridericia correction formula (QTcF = QT / 3√RR) by the ECG device 
according to the recently approved International Council for Harmonisation (ICH) guidance E1. 
In case of QTc values outside of the normal range, ECGs will be manually re-evaluated by a
physician.
7.3.5
Vital Signs, Physical Examinations, and Other Assessments 
Safety and tolerability will be assessed by monitoring of vital signs (blood pressure, pulse rate, 
temperature and respiration) and physical examinations. 
Despite the fact that bisoprolol and amlodipine are usually safe and well tolerated, one cannot fully 
exclude the possibility of an incidence of bradycardia or hypotension. 
7.3.6
Pharmacokinetics 
7.3.6.1
Sample Processing, Labeling and Storage 
At each sampling time point (Section 7.1, Schedule of Assessments), the following process will 
be followed for the collection of plasma samples for quantification of bisoprolol and amlodipine. 
x
Approximately 4 mL venous blood will be taken from the subject into a precooled 
vacutainer. 
x
Completely and gently invert the vacutainer 8 to 10 times and then centrifuge at 1,500 to 
2,000 g for 15 min at 4 C. This must be conducted within 30 min after blood draw. The 
samples will be kept in an ice bath at all times before centrifugation. 
x
The resulting plasma will be split equally into 2 × 1.8 mL transfer vials using a calibrated 
pipette. The vials will be labeled Vial A and Vial B, respectively. Vial A should contain a 
minimum of 1 mL; Vial B will be reserved as the back-up sample. 
x
These tubes will be labeled containing the following information. 
o
Test subject ID 
o
Plasma 
o
Visit Name 
o
Sampling date 
o
Vial A or Vial B 
x
The samples will be frozen upright at -20 C or below until shipment. The Vial A and Vial B
samples from the same subject should always be stored in separate boxes. 
x
The samples will be stored at the site for not more than 1 month. Storage of the samples 
should be monitored closely by the site and the site should complete the Freezer 
Temperature Logs on a weekly basis. 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
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7.3.6.2
Sample Shipment 
All frozen plasma samples will be shipped in dry ice to 
. Vial A and Vial 
B samples from the same subject / time point will never be shipped together. Dry ice shipments 
can only be made from Mondays to Wednesdays and is not to be made on the day before Local 
Public Holidays or on Local Public Holidays. 
Before shipments are conducted, the site should perform a review to ensure all samples are present 
and are labeled correctly. Shipment will be made to the following address: 
7.4
Information to be Collected on Clinical Screening Failures 
Subjects who sign the ICF but do not start trial treatment for any reason will be considered Clinical 
Screening Failures. The following eCRF pages must be completed for all Clinical Screening 
Failures: 
x
Clinical screening Disposition page (including reason for the subject not starting study 
treatment) 
x
Informed consent 
x
Demography 
x
Adverse events (only if an SAE occurs) 
x
Inclusion/exclusion criteria. 
PPD
PPD


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
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8
Pharmacokinetic and Statistical Analyses
8.1
Pharmacokinetic Analysis 
The following PK parameters will be calculated from plasma concentrations of bisoprolol and 
amlodipine by applying non-compartmental analysis methods according respective Standard 
Operating Procedures (SOPs). 
Cmax 
the maximum plasma concentration observed 
tmax 
time of maximum plasma concentration observed 
AUC0-t 
area under the (plasma) concentration-time curve from time 0 to the last sampling time 
at which the concentration is at or above the lower limit of quantification, calculated 
using mixed log-linear trapezoidal rule 
AUC0-f 
area under the plasma concentration-time curve from time zero to infinity 
AUCextra 
extrapolated part of AUC0-f calculated by Clast/λz, expressed in percent
λz 
terminal elimination rate constant
t1/2
half-life
CL/f 
total clearance following extravascular administration 
Vss/f
apparent volume of distribution at steady-state after extravascular administration
The PK parameter evaluation will be performed using the validated PK software tool 
Phoenix/WinNonlin. 
8.2
Statistical Analysis 
8.2.1
Sample Size 
The BE is declared if all comparisons in primary hypothesis achieve the criteria – the 90% CIs for 
the ratios between the investigational product and comparators of geometric means of both AUC0-t
and Cmax for bisoprolol and amlodipine in plasma are within 80.00% to 125.00%. 
Based on the results of a BE trial conducted in 2008 by 
 where 
a higher dose strength 10 mg/10 mg fixed-dose-combination tablet was tested against respective 
single agent of bisoprolol and amlodipine, the expected effects in fasting state is presented below. 
PPD




Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
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Sensitivity analysis has been performed to explore impact of potentially different variability on the 
sample size and power calculation. The outcome, as selectively displayed in the tables below, 
suggests that consistently high power (80%+) can be obtained with the proposed sample size. 
Sensitivity Analysis 1: 
Assume 5% variation for all ratios (95% ~ 105%) and 10% all intra-subject CV. 
Sample Size 
Power (%) for Bisoprolol 
Power (%) for Amlodipine 
Joint Power (%) 
Cmax 
AUC0-t 
Cmax 
AUC0-t 
10 
96.83 
96.83 
96.83 
96.83 
87.89 
12 
98.83 
98.83 
98.83 
98.83 
95.42 
14 
99.58 
99.58 
99.58 
99.58 
98.34 
16 
99.85 
99.85 
99.85 
99.85 
99.42 
AUC0-t = area under the (plasma) concentration-time curve from time 0 to time t; CV = coefficient of variation; Cmax = the 
maximum plasma concentration observed 
Sensitivity Analysis 2: 
Assume 5% variation for all ratios (95% ~ 105%) except of Amlodipine AUC0-t (90% ~ 110%), 
and 10% all intra-subject CVs. 
Sample Size 
Power (%) for Bisoprolol 
Power (%) for Amlodipine 
Joint Power (%) 
Cmax 
AUC0-t 
Cmax 
AUC0-t 
10 
96.83 
96.83 
96.83 
77.74 
70.56 
12 
98.83 
98.83 
98.83 
85.17 
82.23 
14 
99.58 
99.58 
99.58 
90.25 
89.13 
16 
99.85 
99.85 
99.85 
93.66 
93.26 
AUC0-t = area under the (plasma) concentration-time curve from time 0 to time t; Cmax = the maximum plasma concentration 
observed 
Randomization 
Each eligible subject will be allocated to a treatment sequence according to a computer-generated 
randomization schedule. Subjects will be identified only by their assigned subject number. The 
subjects will receive consecutive subject numbers in the order of their enrollment into the trial. 
A total of 32 eligible healthy male and female Chinese subjects (16 in fasting cohort and 16 in fed 
cohort) who meet the eligibility criteria will be randomized (with each gender representing no less 
than 1/3 of the total number) on Day 1 in a 1:1 ratio to one of 2 treatment sequences: Sequence 
A-B or Sequence B-A as presented in Table 5. 
In sequence A-B, subjects will receive bisoprolol-amlodipine 5 mg/5 mg combination tablets 
(Treatment A) in Period 1 and bisoprolol 5 mg tablets and amlodipine 5 mg tablets given 
concomitantly (Treatment B) in Period 2. In sequence B-A, subjects will receive bisoprolol 5 mg 
tablets and amlodipine 5 mg tablets given concomitantly (Treatment B) in Period 1 and 
bisoprolol-amlodipine 5 mg/5 mg combination tablets (Treatment A) in Period 2. 


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Table 5 
Randomization Allocation 
 
Day 1 of Period 1 
Day 1 of Period 2 
Fasting cohort (n= 16)  
Treatment A (n= 8) 
Treatment B (n= 8) 
Treatment B (n= 8) 
Treatment A (n= 8) 
Fed cohort (n= 16)  
Treatment A (n= 8) 
Treatment B (n= 8) 
Treatment B (n= 8) 
Treatment A (n= 8) 
The first 4 discontinued subjects of each cohort not be replaced. Subjects will only be replaced if 
the number of subjects within a sequence falls below 12. The subject who is replacing a 
discontinued subject will then be allocated to the treatment sequence of the subject who 
discontinued. 
8.2.2 
Endpoints 
8.2.2.1 
Primary Endpoints 
The primary endpoints are the following PK parameters calculated from bisoprolol and amlodipine 
plasma concentrations: 
x AUC0-t of bisoprolol 
x Cmax of bisoprolol 
x AUC0-t of amlodipine 
x Cmax of amlodipine 
8.2.2.2 
Secondary Endpoints 
The secondary endpoints are the following PK parameters determined from plasma concentrations 
of both analytes, bisoprolol and amlodipine: 
x tmax 
x t1/2 
x AUC0-∞ 
x AUCextra 
x λz 
x CL/f 
x Vss/f 
All PK parameters (primary endpoints and secondary endpoints) will be calculated from plasma 
concentrations of bisoprolol and amlodipine by applying non-compartmental analysis methods 
according to respective SOPs. 


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8.2.2.3 
Safety Endpoints 
Safety and tolerability will be assessed by monitoring of: 
x Assessment of general safety and tolerability 
x Adverse Events 
x Vital signs (blood pressure, pulse rate, temperature and respiration) 
x Biochemistry, hematology, and urinalysis 
x Computerized 12-lead ECG recordings (including QTc evaluation) 
x Physical examination 
8.2.3 
Analysis Sets 
Per-protocol population 
The per-protocol population includes all randomized subjects who have been treated according to 
protocol and fulfill the following criteria: 
x All inclusion/exclusion criteria satisfied, unless some criteria were waived by the 
Investigator/Sponsor 
x Absence of relevant protocol violations with respect to factors likely to affect the 
comparability of PK results 
x Adequate investigational product compliance 
x Primary PK variables AUC0-t and Cmax of bisoprolol or amlodipine in plasma should be 
available for both trial treatments 
If subjects received concomitant medication for the treatment of AEs within 48 hours after dosing, 
their inclusion in the per-protocol population should be approved by the Sponsor. 
Safety population 
The safety population includes all subjects who received at least 1 dose of trial drug. In general, 
clinical data will be analyzed for the safety population. 
Pharmacokinetic population 
The PK Population may include all subjects who completed the trial with adequate trial medication 
compliance, without any relevant protocol violations with respect to factors likely to affect the 
comparability of PK results, and with sufficient evaluable data to determine primary endpoints 
(AUC0-t and Cmax) for both treatments in both cohorts. If subjects would receive concomitant 
medication for the treatment of an AE, their inclusion in the PK Population will be decided on a 
case-by-case basis. All PK analyses will be based on this population analysis set. 


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8.2.4 
Description of Statistical Analyses 
8.2.4.1 
General Considerations 
Details of the statistical analysis will be presented in a statistical analysis plan prior to database 
lock. 
The statistical analysis will not be started until all data have been corrected and checked for 
plausibility, and until all necessary coding and assessments have been completed. 
All data recorded during the trial will be presented in individual data listings performed on the 
safety population. All data will be evaluated as observed values; no imputation method for missing 
values will be used. Methods for concentration data below the lower limit of quantification will be 
described in the statistical analysis plan. The consideration of covariates in the mixed effect model 
is not planned. 
All statistical analyses will be performed by Merck (Darmstadt, Germany). 
8.2.4.2 
Analysis of Primary Endpoints 
The null and alternative hypotheses are the following, to be applied to both treatments: 
25
.1
/
8.0
/
25
.1
/
8.0
/
:
max
0
0
t
d
t
d

C
T
C
T
C
T
C
T
t
or
C
for
or
AUC
for
H
P
P
P
P
P
P
P
P
, for at least 1 primary endpoint 
25
.1
/
8.0
25
.1
/
8.0
:
max
0
1





C
T
C
T
t
C
for
AUC
for
H
P
P
P
P
 , for all 4 primary endpoints 
where 
 and 
 are the means of primary endpoints following investigational product and 
comparators (Treatment A and Treatment B), respectively. 
The analysis of primary endpoints will be based on PK Population (Section 8.2.3) 
The primary variable, Cmax and AUC0-t in fasting or fed cohort will be log-transformed and mixed 
effect model will be applied. The model will include effects for sequence, treatment and period. 
Subject within sequence will be included as random effect. 
Based on the residual (within-subject) variation, 90% CIs for the ratio of geometric means will be 
calculated. The BE can be established if all the 4 sets of the 90% CIs on the ratios between 
investigational product and comparators of the geometric means fall within 80.00% to 125.00%. 
8.2.4.3 
Analysis of Secondary Endpoints 
For tmax, the Hodges-Lehmann estimates [9] for the pairwise treatment differences and the 
corresponding 90% CIs according to the Tukey method will be calculated. 
T
P
C
P


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The mixed model as described above will also be applied to AUC0-∞. A 90% CI will be calculated 
for the ratios of geometric means of the investigational product and comparators (eg, 
Treatment A/Treatment B). 
Summaries using descriptive analyses for the remaining PK parameters and the safety variables 
will be performed as described in Section 8.2.4.4 and Section 8.2.4.5. 
8.2.4.4 
Analysis of Safety Endpoints 
All data recorded during the trial will be presented in individual data listings performed on the 
safety population. 
All safety variables will be analyzed using descriptive statistics. 
For the evaluation of safety parameters, the continuous variables will be summarized descriptively 
per treatment, period, time point, and overall by N, arithmetic mean, median, standard deviation 
(SD), standard error of the mean (SEM), and minimum and maximum values. Categorical 
variables will be presented in frequency tables with the counts of observations and corresponding 
percentages. 
Blood pressures, pulse rate measurements and ECG recordings will be individually listed by 
treatment, subject number, period, and time point, and the abnormal values flagged according to 
reference laboratory ranges. All hematology and biochemistry parameters will be listed and 
summarized using descriptive statistics by treatment, period, and time point on observed values. 
Urinalysis will be summarized in frequency tables. 
After coding of AEs according to the Medical Dictionary for Regulatory Activity classification 
(current version) and assignment to a system organ class and preferred term, all AEs recorded 
during the course of the trial will be listed by treatment and subject number. 
The AE listings will include the following items: 
x System organ class 
x Preferred term 
x Investigator’s description 
x Whether the event is treatment-emergent 
x Trial treatment at onset of event 
x Date and time of onset and resolution 
x Duration of the event 
x Date and time of last administration before AE 
x Intensity 
x Causality relationship to investigational product 
x Outcome 


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x Action taken to investigational product 
x Other action 
x Seriousness 
Incidence of treatment-emergent adverse events will be summarized using frequency of events and 
number of subjects experiencing these events per treatment, preferred term, and system/organ 
class. 
In addition, all treatment-emergent adverse events will be tabulated by intensity and relationship 
to drug per treatment and cohort. An AE will be considered “treatment-emergent” if it occurred 
after the first investigational product administration or if it occurred before the first investigational 
product administration and worsened after. 
Results of physical examination will only be listed by treatment, subject, period, time point, and 
body system. 
Handling of discontinued subjects and missing data 
If 4 subjects within one sequence have already discontinued and 12 subjects remain in that 
sequence, any further discontinued subjects will be replaced in this sequence. 
8.2.4.5 
Analysis of Further Endpoints 
Analyses described in this subsection will be performed in general for the PK population. 
Demographic parameters (age, height, and weight) will be summarized by means of tabulated 
descriptive statistics (the number of observations [N], arithmetic mean, median, SD, SEM, 
minimum and maximum) by treatment, cohort, and overall. 
Plasma concentrations below lower limit of quantitation will be analyzed as zero for descriptive 
statistics. Plasma concentration data will be summarized by treatment, analyte and scheduled time 
point showing the number of observations (N), arithmetic mean, SD, SEM, CV(%), minimum, 
median and maximum. 
Mean plasma concentrations per treatment and analyte will be plotted (linear scale with SD, and 
semi-logarithmic scale) using scheduled time points for bisoprolol. 
Mean plasma concentrations per treatment and analyte will be plotted (linear scale with SD, and 
semi-logarithmic scale) using scheduled time points for amlodipine. 
Results of subjects not in the per-protocol population will be annotated and listed together with the 
data of the other subjects, but will not be used for descriptive statistics and mean curves. 
Individual plasma concentrations (linear and semi-logarithmic scales) will be plotted by treatment 
(showing all subjects simultaneously) and by subject (showing all treatments simultaneously). 


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8.2.5 
Interim and Additional Planned Analyses 
Not applicable. 


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9 
Ethical and Regulatory Aspects 
9.1 
Responsibilities of the Investigator 
The Investigator is responsible for the conduct of the trial at his/her site. He/she will ensure that 
the trial is performed in accordance with the clinical trial protocol and with the ethical principles 
that have their origin in the Declaration of Helsinki, as well as with the ICH Note for Guidance on 
GCP (ICH Topic E6, 1996) and applicable regulatory requirements. In particular, the Investigator 
must ensure that only subjects who have given their informed consent are included into the trial. 
9.2 
Subject Information and Informed Consent 
An unconditional prerequisite for a subject’s participation in the trial is his/her written informed 
consent. The subject’s written informed consent to participate in the trial must be given before any 
trial-related activities are carried out. 
Adequate information must therefore be given to the subject by the Investigator before informed 
consent is obtained (a person designated by the Investigator may give the information, if permitted 
by local regulations). A subject information sheet in the local language and prepared in accordance 
with the Note for Guidance on GCP (ICH Topic E6, 1996) will be provided by the Sponsor for the 
purpose of obtaining informed consent. In addition to providing this written information to a 
potential subject, the Investigator or his/her designate will inform the subject verbally of all 
pertinent aspects of the trial. The language used in doing so must be chosen so that the information 
can be fully and readily understood by lay persons. 
Depending on national regulations, a person other than the Investigator may inform the subject 
and sign the ICF, as above. 
Where the information is provided by the Investigator, the ICF must be signed and personally 
dated by the subject and the Investigator. 
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived by the Investigator so that the forms can be retrieved at any time for 
monitoring, auditing and inspection purposes. A copy of the signed and dated information and ICF 
should be provided to the subject prior to participation. 
Whenever important new information becomes available that may be relevant to the subject’s 
consent, the written subject information sheet and any other written information provided to 
subjects will be revised by the Sponsor and be submitted again to the IEC/IRB for review and 
favorable opinion. The agreed, revised information will be provided to each subject in the trial for 
signing and dating. The Investigator will explain the changes to the previous version. 


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9.3 
Subject Identification and Privacy 
Immediately after informed consent has been obtained, a unique subject number will be assigned 
to each subject at inclusion into the trial. This number will serve as the subject’s identifier in the 
trial as well as in the clinical trial database. 
The subject’s data collected during the trial will be stored under this number. Only the Investigator 
will be able to link the subject’s trial data to the subject via an identification list kept at the site. 
The subject’s original medical data that are reviewed at the site during source data verification by 
the Monitor, audits and Health Authority inspections will be kept strictly confidential. 
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing subject data. Subjects will be informed accordingly, and will be requested to give their 
consent on data handling procedures in accordance with national regulations. 
9.4 
Emergency Medical Support and Subject Card 
Subjects enrolled in this clinical trial will be provided with Emergency Medical Support cards 
during their trial participation, which will be furnished by the Sponsor. The Emergency Medical 
Support card is based on the need to provide clinical trial subjects with a way of identifying 
themselves as participating in a clinical trial, and subsequently to give health care providers access 
to the information about this participation that may be needed to determine the course of the 
subject’s medical treatment. 
This service is designed to provide information to health care providers who are not part of the 
clinical trial. 
Clinical trial Investigators, who are already aware of the clinical trial protocol and treatment, have 
other means of accessing the necessary medical information for the management of emergencies 
occurring in their subjects. 
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected subject. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose and to answer any questions. Any subsequent action will follow the 
standard processes established for the Investigators. 
Merck Serono/EMD Serono will provide the appropriate information to contact a physician. This 
includes the provision of a 24 hour contact number at the facility, whereby the health care providers 
will be given access to an appropriate physician to assist with the medical emergency. 
9.5 
Clinical Trial Insurance and Compensation to Subjects 
Insurance coverage will be provided for each subject participating to the trial. Insurance conditions 
will meet good local standards, as applicable. 


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9.6 
Independent Ethics Committee or Institutional Review Board 
Prior to commencement of the trial at a given site, the clinical trial protocol will be submitted 
together with the ICF to the responsible IEC/IRB for its favorable opinion/approval. The written 
favorable opinion/approval of the IEC/IRB will be filed in the Investigator Site File, and a copy 
will be filed in the Trial Master File by the Sponsor. 
The trial must not start at a site before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IEC/IRB. The IEC/IRB will be asked to provide 
documentation of the date of the meeting at which the favorable opinion/approval was given, and 
of the members and voting members present at the meeting. Written evidence of favorable 
opinion/approval that clearly identifies the trial, the clinical trial protocol version and the Subject 
Information and ICF version reviewed should be provided. Where possible, copies of the meeting 
minutes should be obtained. 
Amendments to the clinical trial will also be submitted to the concerned IEC/IRB, before 
implementation in case of substantial changes (Section 10.5). Relevant safety information will be 
submitted to the IEC/IRB during the course of the trial in accordance with national regulations and 
requirements. 
9.7 
Health Authorities 
The clinical trial protocol and any applicable documentation (eg, IMP Dossier, Subject 
Information and ICF) will be submitted or notified to the Health Authorities in accordance with 
the regulations of the country involved in the trial. 


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10 
Trial Management 
10.1 
Case Report Form Handling 
The Investigator or designee will be responsible for entering trial data in the eCRF provided by 
the designated Contracted Research Organization. It is the Investigator’s responsibility to ensure 
the accuracy of the data entered in the eCRFs. 
The data will be entered into a validated database. The data management department of the 
designated Contracted Research Organization will be responsible for data processing, in 
accordance with the defined data management procedures under the supervision of the Sponsor. 
Database lock will occur once quality control procedure, and quality assurance procedures (if 
applicable) have been completed. Portable document format files of the eCRFs will be provided 
to the Investigators at the completion of the trial. 
10.2 
Source Data and Subject Files 
The Investigator must keep a subject file (medical file, original medical records) on paper or 
electronically for every subject included in the trial. This file will contain the available 
demographic and medical information for the subject, and should be as complete as possible. In 
particular, the following data should be available in this file: 
x Subject’s full name 
x Date of birth 
x Sex 
x Height 
x Weight 
x Medical history and concomitant diseases 
x Prior and concomitant therapies (including changes during the trial) 
x Trial identification 
x Date of subject’s inclusion into the trial (ie, date of giving informed consent) 
x Subject number in the trial 
x Dates of the subject’s visits to the site 
x Any medical examinations and clinical findings predefined in the clinical trial protocol 
x All AEs observed in the subject 
x Date of subject’s End of Trial visit, or 
x Date of premature withdrawal and reason for premature withdrawal of the subject from the 
trial or from IMP, if applicable. 
It must be possible to identify each subject by using this subject file. 


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Additionally, any other documents containing source data must be filed. Such documents must 
bear at least the subject number and the date when the procedure was performed. Information 
should be printed by the instrument used to perform the assessment or measurement, if possible. 
Information that cannot be printed by an automated instrument will be entered manually. Medical 
evaluation of such records should be documented as necessary and the documentation signed and 
dated by the Investigator. 
Electronic subject files (if applicable) will be printed whenever the Monitor performs source data 
verification. Printouts must be signed and dated by the Investigator, countersigned by the Monitor 
and kept in a safe place at the site. 
10.3 
Investigator Site File and Archiving 
The Investigator will be provided with an Investigator Site File upon initiation of the trial. This 
file will contain all documents necessary for the conduct of the trial and will be updated and 
completed throughout the trial. It must be available for review by the Monitor, and must be ready 
for Sponsor audit as well as for inspection by Health Authorities during and after the trial, and 
must be safely archived for at least 15 years (or per local requirements or as otherwise notified by 
the Sponsor) after the end of the trial. The documents to be thus archived include the Subject 
Identification List and the signed subject ICFs. If archiving of the Investigator Site File is no longer 
possible at the site, the Investigator must notify the Sponsor. 
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per ICH 
GCP guidelines, whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor. 
10.4 
Monitoring, Quality Assurance and Inspection by Health 
Authorities 
This trial will be monitored in accordance with the ICH Note for Guidance on GCP (ICH Topic 
E6, 1996). The site Monitor will perform visits to the trial site at regular intervals. 
Representatives of the Sponsor’s Quality Assurance unit or a designated organization, as well as 
Health Authorities, must be permitted to inspect all trial-related documents and other materials at 
the site, including the Investigator Site File, the completed eCRFs, the IMP(s), and the subjects’ 
original medical records/files. 
Independent Quality Assurance activities will be performed on the clinical trial protocol, each step 
of the data capture procedure, and the handling of the data, including the final clinical trial report. 
Audits may be conducted at any time during or after the trial to ensure the validity and integrity of 
the trial data. 
10.5 
Changes to the Clinical Trial Protocol 
Changes to the clinical trial protocol will be documented in written protocol amendments. Major 
(substantial, significant) amendments will usually require submission to the Health Authorities and 


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to the relevant IEC/IRB for approval or favorable opinion. In such cases, the amendment will be 
implemented only after approval or favorable opinion has been obtained. 
Minor (non-substantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the Site. They will be submitted to the relevant IEC/IRB or to Health Authorities 
only where requested by pertinent regulations. 
Any amendment that could have an impact on the subject’s agreement to participate in the trial 
requires the subject’s informed consent prior to implementation (Section 9.2). 
10.6 
Clinical Trial Report and Publication Policy 
10.6.1 
Clinical Trial Report 
After completion of the trial, a clinical trial report according to ICH Topic E3 will be written by 
the Sponsor/designee in consultation with the Principal Investigator and other relevant committees 
or cohorts. 
10.6.2 
Publication 
The Investigator will inform the Sponsor in advance about any plans to publish or present data 
from the trial. Any publications and presentations of the results (abstracts in journals or 
newspapers, oral presentations, etc.), either in whole or in part, by Investigators or their 
representatives will require presubmission review by the Sponsor. 
The Sponsor will not suppress or veto publications, but maintains the right to delay publication in 
order to protect intellectual property rights. Any publications of the results, either in part or in total 
(abstracts in journals or newspapers, oral presentations, etc.) by Investigators or their 
representatives will require presubmission review by the Sponsor. The Sponsor is entitled to delay 
publication in order to obtain patent protection. 


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11
References Cited in the Text 
1. Chinese Food and Drug Administration Guideline: “Technical Guidelines for 
Human Bioequivalence Studies with Pharmacokinetic Endpoints for Chemical 
Generic Drugs” Released March 2016.
2. Geddes JS. Calcium antagonists and beta blockade-a useful combination. Postgrad 
Med 1. 1983; 59:62-9.
3. Dahlof B et al. Improved antihypertensive efficacy of the felodipine metoprolol 
extended release tablet compared to each drug alone. Blood Press 1993; 2:37-45.
4. Smith SC, Blair SN, Bonow RO et al. AHA/ACC Guidelines for preventing heart 
attack and death in patients with atherosclerotic cardiovascular disease: 2001 
update. A statement for health care professionals from the American Heart 
Association and the American College of Cardiology. Circulation 2001; 
104:1577-9.
5. De Backer G, Ambrosioni E, Borch-Johnsen K et al. European guidelines on 
cardiovascular disease prevention in clinical practice. Eur Heart J 2003; 24:1601-10.
6. Wu Yiqun et al. Medication status of out-patients with primary hypertension in 
urban community. Chinese Journal of Public Health Mar 2010; 26:282-3.
 
8. Chemical pharmaceutical preparations human bioavailability and bioequivalence 
studies technical guidelines. [H]GCL2-1, Mar 2005.
9. Lehmann, Erich L. Nonparametrics: Statistical methods based on ranks (Reprinting 
of 1988 revision of 1975 Holden-Day ed.). NewYork: Springer 2006. pp.xvi+463. 
ISBN978-0-387-35212-1.
10. Leopold G., Pabst J., Ungethüm W., et al. Basic Pharmacokinetic of Bisoprolol, a 
New Highly Beta1-selective Adrenoceptor Antagonist. Journal of Clinical 
Pharmacology 1986; 26: 616-21.
11. Chung M., Calcagni A., Glue P., et al. Effect of Food on the Bioavailability of 
Amlodipine Besylate/Atorvastatin Calcium Combination Tablet. Journal of Clinical 
Pharmacology 2006; 46: 1212-6.
12. Insert package of Concor®. Merck Serono Co., Ltd. Revised date: 7 July 2012.
13. Insert package of Norvasc®. Pfizer Inc. Revised: 4/2016.
C
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12 
Appendices 
Appendix I 
Contraceptive Guidance and Woman of Childbearing 
Potential 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered WOCBP 
1. Premenopausal female with 1 of the following: 
x Documented hysterectomy 
x Documented bilateral salpingectomy 
x Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of participant’s medical 
records, medical examination, or medical history interview. 
2. Premenarchal (not applicable) 
3. Postmenopausal female 
x Females who are postmenopausal (age-related amenorrhea ≥ 12 consecutive months and 
increased follicle-stimulating hormone [FSH] > 40 mIU/mL), or who have undergone 
hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary to 
confirm postmenopausal status, an FSH will be drawn at Screening. 
x Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the trial. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before trial enrollment. 
Contraceptive Guidance 
Taken from the CTFG guidelines, which are the guidelines referenced by the EMA. Deviations 
from use of “highly effective” are possible under certain situations as detailed in the CTFG 
guidelines.  


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
80/96 
 
 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of < 1% per year when used consistently and correctly.  
x 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of ovulationb 
x 
oral (not allowed for women taking part in the study but allowed for female partners of male volunteers) 
x 
intravaginal 
x 
transdermal  
x 
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
x 
oral 
x 
injectable  
Highly Effective Methods That Are User Independent  
x 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb 
x 
Intrauterine device (IUD) 
x 
Intrauterine hormone-releasing system (IUS) 
x 
bilateral tubal occlusion 
x 
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should 
be used.  
x 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the trial drug. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the trial and the preferred and usual lifestyle of the participant.)  
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local 
regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b) Hormonal contraception may be susceptible to interaction with the trial drug, which may reduce the efficacy of the 
contraceptive method. In this case 2 highly effective methods of contraception should be utilized during the treatment period and 
for at least 14 days  after the last dose of trial treatment  
 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
81/96 
 
 
Appendix II: 
Signature Pages and Responsible Persons for the Trial 
 






Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
C O N F I D E N T I A L
I N F O R M A T I O N
84/96
Sponsor Responsible Persons not Named on the Cover Page 
Name, academic degree 
Function / Title:
Biostatistician
Institution
Merck Serono (Beijing) Pharmaceutical R&D Co., Ltd. 
Address
Merck Serono Co., Ltd.
Telephone number
Fax number
E-mail address
Name, academic degree 
Function / Title:
Institution
Merck Serono Co., Ltd.
Address
Telephone number
Fax number
E-mail address
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
85/96 
 
 
Appendix III: 
Protocol Amendments and List of Changes 
Table of Previous Protocol Amendments 
Protocol amendment included in this clinical trial protocol: 
Amendment Number 
Substantial 
(Y/N) 
Date 
Region or Country 
Included in the 
current document 
(Y/N) 
1.0 
Y 
16 February 2017 
China 
Y 
Amendment 2.0 
Rationale 
The purposes of this protocol amendment (Amendment 2.0, 03 May 2017) are to: 
x Change the blood volume for PK sample based on the recommendation from Ethics 
Committee and justified technical requirement. 
x Remove ‘orange’ and ‘orange juice’ from food restriction based on the internal scientific 
feedback, which is deemed as not relevant with study medication. 
x Update the storage conditions for IMPs according to the label of study medications. 
x Addition of non-serious ADRs related with Treatment B according to the requirement from 
China Health Authority. 
This amendment is not considered substantial as these changes are related with operational details, 
which will not influence the study design. 
Major Scientific Changes 
The major scientific changes of this protocol amendment (Amendment No.2.0) are: 
x Changed the blood volume for PK sample from 5 mL to 4 mL whole blood; 
x Removed the wording of ‘orange’ and ‘orange juice’ from food restriction; 
x Updated the details of storage conditions for IMPs; 
x Added the procedure for reporting non-serious ADRs related with Treatment B. 
Administrative and Editorial Changes 
Correction of administrative, minor editorial changes and inconsistencies throughout the document 
that have been identified since the finalization of the clinical trial protocol. 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
86/96 
 
 
Changes to the clinical trial protocol text are presented in the table below. Additions and amended 
text are shown in bold. If the original clinical trial protocol text was already bold, changes are 
shown in bold and underlined, deletions are marked using strike through.


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
87/96 
 
 
Comparison with Clinical Trial Protocol Version 2.0, 16 February 2017 (Amendment No. 1.0) 
Change 
Section 
Page 
Previous Wording 
New Wording 
Updated the 
protocol 
number 
Cover page 
Synopsis 
headers 
1 
10 
All 
pages 
EMR200006-0001 
EMR200006-0001 
Specified the 
duration of 
prior 
medication, 
concomitant 
therapies, and 
AEs 
Table 1 
Schedule of 
Assessments 
Section 7.1.1 
Screening 
(Day -7 to 
Day -1) 
16-17 
 
 
43 
 
 
 
Prior medication within 1 month before screening will be 
collected. 
See below Table 
 
 
Prior medication within 1 month before screening the date of first 
signature of informed consent will be collected.  
Concomitant medications, treatments, and AEs will be collected 
from the date of first signature of informed consent. 
Corrected the 
typo of 
treatment in 
Figure 1 
Figure 1 
Schematic of 
Trial Design 
25 
 
See below Figure 
 
Simplified the 
wording based 
upon the 
description in 
Section 6.6  
Section 5.3.1 
Inclusion 
Criteria 
(Number 5) 
27 
Systolic blood pressure (in supine position) within 100 to 139 
mmHg (inclusive) and diastolic blood pressure (in supine 
position) within 65 to 90 mmHg (inclusive) at Screening, 
during Admission to the Clinical Research Unit (CRU) (12 
hour predose fast) and before each dosing 
Systolic blood pressure (in supine position) within 100 to 139 
mmHg (inclusive) and diastolic blood pressure (in supine position) 
within 65 to 90 mmHg (inclusive) at Screening, during Admission to 
the Clinical Research Unit (CRU) (12 hour predose fast) and before 
each dosing 
The 
information 
was added to 
keep consistent 
with the 
description in 
Section 6.7.5  
Section 5.3.2 
Exclusion 
Criteria 
(Number 23) 
29 
Positive pregnancy test (only for females of child-bearing 
potential) 
Positive pregnancy test (only for females of child-bearing potential), 
or females breast feeding a child 
Updated the 
storage 
condition for 
the 
investigational 
medicinal 
products 
Section 6.1 
Description of 
the 
Investigational 
Medicinal 
Products 
33 
Drug 
Treatme
nt 
Investigation
al Product 
Comparator-
1 
Comparator-2 
Formul
ation: 
Concor AM 
Bisoprolol-A
mlodipine 
5mg/5mg 
Concor 
Bisoprolol 5 
mg tablet 
Norvasc 
Amlodipine 5 
mg tablet 
Drug 
Treatme
nt 
Investigational 
Product 
Comparator-1 
Comparator-2 
Formul
ation: 
Concor AM® 
Concor® 
Bisoprolol 5 mg 
tablet 
Norvasc® 
Amlodipine 5 
mg tablet 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
C O N F I D E N T I A L
I N F O R M A T I O N
88/96
Change
Section
Page
Previous Wording
New Wording
Manufa
cturer:
 
 
Merck 
KGaA., 
Germany
 
 
Storage 
Conditi
on
Do not store 
above 30°C
Do not store 
above 30°C
Store in 
original 
package;
Protected from 
light
Bisoprolol-Am
lodipine 
5mg/5mg
Manufa
cturer:
Merck 
KGaA., 
Germany
 
 
Storage 
Conditi
on
Store 
in 
original 
package;
Do not store 
above 30°C;
Protected 
from light.
Store 
in 
original 
package;
Do 
not 
store 
above 2530°C;
Do not freeze;
Protected from 
light.
Store in 
original 
package;
Do not store 
above 25°C;
Do not freeze;
Protected from 
light.
Updated the 
restriction of 
fluid intake 
Section 6.6
Food 
Restriction and 
Standardizatio
n Diet
36
Fluids
Subjects are not allowed to excessively consume beverages 
containing xanthine (> 5 cups of coffee a day or equivalent) 
and need to stop caffeine consumption from 48 hours prior to 
drug administration until collection of the last PK sample in 
each period. Subjects also need to stop intake of grapefruit, 
orange, cranberry or juices of these 3 fruits, from 14 days 
prior to drug administration until collection of the last PK 
sample in each period. During the hospitalization periods 
(evening of Day -1 to Day 8 of each period), water is allowed 
as desired, except for 2 hours before and until 1 hour after 
drug administrations on Day 1 or Day 15 respectively.
Fluids
Subjects are not allowed to excessively consume beverages 
containing xanthine (> 5 cups of coffee a day or equivalent) and 
need to stop caffeine consumption from 48 hours prior to drug 
administration until collection of the last PK sample in each period. 
Subjects also need to stop intake of grapefruit, orange, cranberry or 
juices of these 23 fruits, from 14 days prior to drug administration 
until collection of the last PK sample in each period. During the 
hospitalization periods (evening of Day -1 to Day 8 of each period), 
water is allowed as desired, except for 2 hours before and until 
1 hour after drug administrations on Day 1 or Day 15 respectively.
Clarification 
that IMP 
Manual will be 
provided 
instead of 
Manual of 
Operation
Section 6.8
Packaging and 
Labelling of 
the 
Investigational 
Medicinal 
Product
38
38-39
The packaging, labeling and documentation of IMP will be 
done according to Annex 13 and GMP requirements, so that it 
shall be possible to retrace the composition and pharmaceutical 
quality.
Detailed instructions for packing and labeling of medications 
will be provided in the manual of operation (MOP).
…..
Instructions for the preparation, handling, and storage of the 
IMPs will be provided. Additional details on the preparation 
and administration of the IMPs will be provided in the MOP.
The packaging, labeling and documentation of IMP will be done 
according to Annex 13 and GMP requirements, so that it shall be 
possible to retrace the composition and pharmaceutical quality.
Detailed instructions for packing and labeling of medications will be 
provided in the manual of operation (MOP).
…..
Instructions for the preparation, handling, and storage of the IMPs 
will be provided. Additional details on the preparation and 
administration of the IMPs will be provided in the MOPIMP 
Manual.
CCI
CCI
CCI
CCI


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
89/96 
 
 
Change 
Section 
Page 
Previous Wording 
New Wording 
Section 6.9 
Preparation, 
Handling and 
Storage of the 
Investigational 
Medicinal 
Product 
….. 
Instruction of destruction of IMP will be provided in the MOP. 
The unused and remained trial medication and the expired 
testing sample has to be destroyed under Sponsor’s greenlight 
and follow the instruction in MOP. 
….. 
Instruction of destruction of IMP will be provided in the MOPIMP 
Manual. The unused and remained trial medication and the expired 
testing sample has to be destroyed under Sponsor’s greenlight and 
follow the instruction in MOPIMP Manual. 
Updated the 
units of 
laboratory tests 
Section 7.1.1 
Screening 
(Day -7 to Day 
-1) 
44-45 
Laboratory Tests 
Hematology assessments 
Parameter 
Dimension/Unit 
 
Erythrocytes 
 
×1012/L 
 
Hemoglobin  
 
g/L 
 
Hematocrit  
 
L/L 
 
Biochemistry assessments 
Parameter 
Dimension/Unit 
Phosphorus 
mmol/L 
α-Amylase 
IU/L 
 
Laboratory Tests 
Hematology assessments 
Parameter 
Dimension/Unit 
 
Erythrocytes 
 
×1012/L 
 
Hemoglobin  
 
g/L 
 
Hematocrit  
 
L/L% 
 
Biochemistry assessments 
Parameter 
Dimension/Unit 
Phosphorus 
mmol/L 
α-Amylase 
IU/L 
 
Updated the 
blood volume 
of PK 
sampling 
Section 7.1.3 
Period 1 
(Day 1 to 
Day 8) 
 
Section 7.1.9 
(Table 4; see 
below table) 
 
48 
 
 
 
 
54 
 
For every subject, during each treatment period, a total of 20 
samples, approximately 5 mL each whole blood, will be 
collected at the following times: at predose (Baseline) and at 
0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 
144, and 168 hours after dosing. One sample will be collected 
at End of Trial (Day 29)/Premature Withdrawal. The PK 
collection time is based on known single-dose PK profiles of 
both drugs and should be frequent and long enough to 
characterize the peak and extent of exposure. Plasma samples 
will be prepared, divided into 2 aliquots and stored at -20 ºC. 
Subjects who complete both treatment periods will have a total 
of 41 samples (5 mL whole blood each sample) collected. 
Total blood volume collection is approximately 205 mL over 
5 weeks. 
For every subject, during each treatment period, a total of 20 
samples, approximately 45 mL each whole blood, will be collected 
at the following times: at predose (Baseline) and at 0.5, 1, 1.5, 2, 3, 
4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144, and 168 hours after 
dosing. One sample will be collected at End of Trial (Day 
29)/Premature Withdrawal. The PK collection time is based on 
known single-dose PK profiles of both drugs and should be frequent 
and long enough to characterize the peak and extent of exposure. 
Plasma samples will be prepared, divided into 2 aliquots and stored 
at -20 ºC. 
Subjects who complete both treatment periods will have a total of 41 
samples (45 mL whole blood each sample) collected. Total blood 
volume collection for PK sampling is approximately 164205 mL 
over 5 weeks. 
Added the 
definition of 
ADR 
Section 7.3.1.1 
Adverse Event 
Definition 
55 
- 
Adverse Drug Reaction 


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
C O N F I D E N T I A L
I N F O R M A T I O N
90/96
Change
Section
Page
Previous Wording
New Wording
In accordance with Good Clinical Practice (GCP), an adverse 
drug reaction (ADR) is defined in this study as any AE 
considered to be related to drug treatment.
Added the 
procedure for 
reporting non-
serious ADRs
related with 
treatment B 
according to 
the 
requirement 
from China 
health 
authority;
Updated the 
wording for 
the process of 
reporting 
SAEs based 
upon the 
changes in real 
operation
Section 7.3.1.4 
Procedure for 
Reporting 
Serious 
Adverse 
Events and 
Non-serious 
Adverse Drug 
Reaction
58
In the event of any SAE occurring during the reporting period, 
the Investigator must immediately (ie, within a maximum 24 
HOURS after becoming aware of the event) inform Global 
Drug Safety by telephone, by fax or by e-mail.
To do so, the Investigator/reporter must complete a Sponsor 
SAE report following specific instructions (SAE report 
Completion Instruction) and using preferably the electronic 
template, and send it directly to the Sponsor’s Global Drug 
Safety department by electronic mail or facsimile, using the 
dedicated e-mail address and facsimile numbers specified 
below.
E-mail:
Facsimile:
In the event of any SAE occurring in Treatment A or B group 
during the reporting period, and in the event of any non-serious 
ADRs related with Treatment B, the Investigator must 
immediately (ieinform Sponsor or its designee in writing, within a 
maximum of 24 HOURS after becoming aware of the event) inform 
Global Drug Safety. All written reports should be transmitted 
using the AE Report Form, which must be completed by 
telephone, by fax or by e mail.the Investigator following specific 
completion instructions. 
To do so, the Investigator/reporter must complete a Sponsor SAE 
report following specific instructions (SAE report Completion 
Instruction) and using preferably the electronic template, and send it 
directly to the Sponsor’s Global Drug Safety departmentdesignee by 
electronic mail or facsimile, using the dedicated e mail. Name,
address, telephone, and facsimilefax numbers specified belowfor 
SAE reporting will be included in the trial specific AE Report 
Form as shown below.
E-mail:
kuntuo.pv@kuntuo.com
Facsimile:
Updated the 
blood volume
of PK 
sampling; and 
updated the 
wording for 
sample 
processing and 
labeling based 
upon the 
changes in real 
operation
Section 7.3.6.1 
Sample 
Processing, 
Labeling and 
Storage
61
At each sampling time point (Section 7.1, Schedule of 
Assessments), the following process will be followed for the 
collection of plasma samples for quantification of bisoprolol 
and amlodipine.
x
Approximately 5 mL venous blood will be taken 
from the subject into a precooled vacutainer.
x
Completely and gently invert the vacutainer 8 to 10 
times and then centrifuge at 1,500 g for 15 min at 
4ºC. This must be conducted within 30 min after 
blood draw. The samples will be kept in an ice bath 
at all times before centrifugation.
x
The separated plasma will be transferred into a spin 
tube and centrifuged again at 2,000 g for a further 15 
min to ensure that no debris is present in the plasma.
At each sampling time point (Section 7.1, Schedule of Assessments), 
the following process will be followed for the collection of plasma 
samples for quantification of bisoprolol and amlodipine.
x
Approximately 54 mL venous blood will be taken from the 
subject into a precooled vacutainer.
x
Completely and gently invert the vacutainer 8 to 10 times 
and then centrifuge at 1,500 to 2,000 g for 15 min at 4ºC. 
This must be conducted within 30 min after blood draw. 
The samples will be kept in an ice bath at all times before 
centrifugation.
x
The separated plasma will be transferred into a spin tube 
and centrifuged again at 2,000 g for a further 15 min to 
ensure that no debris is present in the plasma.
PPD
PPD
PPD
PPD


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
C O N F I D E N T I A L
I N F O R M A T I O N
91/96
Change
Section
Page
Previous Wording
New Wording
x
The resulting plasma will be split into 2 × 2 mL 
transfer vials using a calibrated pipette. The vials 
will be labeled Vial A and Vial B, respectively. Vial 
A should contain a minimum of 1 mL; Vial B will 
be reserved as the back-up sample.
x
These tubes will be labeled containing the following 
information.
o
Test subject ID
o
Drug administered
o
Plasma
o
Test period/time point
o
Sampling date
o
Vial A or Vial B
x
The resulting plasma will be split equally into 2 × 21.8
mL transfer vials using a calibrated pipette. The vials will 
be labeled Vial A and Vial B, respectively. Vial A should 
contain a minimum of 1 mL; Vial B will be reserved as the 
back-up sample.
x
These tubes will be labeled containing the following 
information.
o
Test subject ID
o
Drug administered
o
Plasma
o
Test period/time point
o
Visit Name
o
Sampling date
o
Vial A or Vial B
Clarified the 
randomization
process
Section 8.2.1
65
A total of 32 eligible healthy male and female Chinese subjects 
who meet the eligibility criteria will be randomized (with each 
gender representing no less than 1/3 of the total number) on 
Day 1, in a 1:1 ratio to Period 1 to one of the 2 cohorts (fasting 
or fed). Then each state will be randomized in a 1:1 ratio to one 
of 2 treatment sequences: Sequence A-B or Sequence B-A as 
presented in Table 5.
A total of 32 eligible healthy male and female Chinese subjects (16 in 
fasting cohort and 16 in fed cohort) who meet the eligibility criteria 
will be randomized (with each gender representing no less than 1/3 of 
the total number) on Day 1, in a 1:1 ratio to Period 1 to one of the 2 
cohorts (fasting or fed). Then each state will be randomized in a 1:1 
ratio to one of 2 treatment sequences: Sequence A-B or Sequence B-
A as presented in Table 5.
Specified the 
condition for 
using oral 
contraceptives 
based upon the 
information in 
Section 6.5 
Appendix I 
Contraceptive 
Guidance and 
Woman of 
Childbearing 
Potential
80
Highly Effective Contraceptive Methods That Are User 
Dependent
Failure rate of < 1% per year when used consistently and 
correctly.
x
Combined (estrogen- and progestogen- containing) 
hormonal contraception associated with inhibition of 
ovulationb
x
oral
x
intravaginal
x
transdermal
Highly Effective Contraceptive Methods That Are User 
Dependent
Failure rate of < 1% per year when used consistently and 
correctly.
x
Combined (estrogen- and progestogen- containing) hormonal 
contraception associated with inhibition of ovulationb
x
oral (not allowed for women taking part in the study 
but allowed for female partners of male volunteers)
x
intravaginal
x
transdermal
Administrative 
change on 
clinical team 
lead
Appendix II
84
Name, academic 
degree 
Function / Title:
Institution
Merck Serono (Beijing) Pharmaceutical 
R&D Co., Ltd.
Name, academic 
degree 
Function / Title:
PPD
PPD
PPD
PPD
PPD
PPD


Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
C O N F I D E N T I A L
I N F O R M A T I O N
92/96
Change
Section
Page
Previous Wording
New Wording
Sponsor 
Responsible 
Persons not 
Named on the 
Cover Page
Address
Merck Serono Co., Ltd.
Telephone 
number
Fax number
E-mail address
Institution
Merck Serono (Beijing) Pharmaceutical R&D
Co., Ltd.
Address
Merck Serono Co., Ltd.
Telephone 
number
Fax number
E-mail address
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD








Bisoprolol & Amlodipine 
Bioequivalence Trial of Concor AM® vs Bisoprolol and 
EMR200006-001 
Amlodipine in Chinese Subjects 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
96/96 
 
 
Section 7.1.9 (Estimated Blood Sample Volumes per Subject) with Table 4 
The blood sample volumes of each subject are estimated in Table 4. 
Table 4 
Estimated Blood Sample Volumes per Subject 
Time Points 
Evaluation Indexes 
Total Blood Volume (mL) 
Screening 
Serum virology 
4 
Hematology 
2 
Biochemistry 
4 
Serum Pregnancy Test (if 
applicable) 
4 
Approximate Total 
14 
Period 1 
Hematology 
2 
Biochemistry 
4 
Serum Pregnancy Test (if 
applicable) 
4 
Pharmacokinetics 
45*20 
Approximate Total 
11090 
Period 2 
Hematology 
2*2 
Biochemistry 
4*2 
Serum Pregnancy Test (if 
applicable) 
4 
Pharmacokinetics 
45*20 
Approximate Total 
11696 
End of Trial 
 
Pharmacokinetics 
45 
Approximate Total 
45 
Premature Withdrawal 
Hematology 
2 
Biochemistry 
4 
Serum Pregnancy Test (if 
applicable) 
4 
Pharmacokinetics 
45 
Approximate Total 
1514 
Approximate Total of Each Subject (without premature 
withdrawal) 
245204 
 
 
 

SAP_001.pdf: 
Bisoprolol Amlodipine 5 mg/5 mg Combination Tablets
Two-period Crossover Bioequivalence
EMR200006-001
Final Version 2.2
C O N F I D E N T I A L
I N F O R M A T I O N
1/36
Statistical Analysis Plan
Clinical Trial Protocol 
Identification No.
EMR200006-001
Title:
A Randomized, Two-period Crossover Trial Examining 
Bioequivalence of Bisoprolol-Amlodipine 5 mg/5 mg 
Combination Tablets versus Bisoprolol 5 mg Tablets and 
Amlodipine 5 mg Tablets Given Concomitantly in Healthy 
Subjects in Fasting and Fed State
Trial Phase
Phase I
Investigational Medicinal 
Product(s)
Bisoprolol Amlodipine 5 mg/5 mg Combination Tablets
Clinical Trial Protocol 
Version
28 April 2017 / Version Final 1.0
Statistical Analysis Plan 
Author
 Biostatistician
Biostatistician
Pharmacokineticist
Statistical Analysis Plan
Date and Version
18 Sep 2017/ Final Version 2.2
Statistical Analysis Plan 
Reviewers
Merck-Serono Reviewers:
, Trial Biostatistician, Merck Serono
Reviewers:
 Senior Biostatistician,
, Biostatistician, 
 
, 
Senior 
Research 
Pharmacokineticist, 
 
, 
Senior 
Research 
Pharmacokineticist, 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Bisoprolol Amlodipine 5 mg/5 mg Combination Tablets 
Two-period Crossover Bioequivalence 
EMR200006-001 
 
 
 
 
 
Final Version 2.2 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
2/36 
 
 
 
 
Confidential 
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. 


Bisoprolol Amlodipine 5 mg/5 mg Combination Tablets
Two-period Crossover Bioequivalence
EMR200006-001
Final Version 2.2
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1
Signature Page
Statistical Analysis Plan (18 Sep 2017, Final Version 2.2): EMR200006-001
A Randomized, Two-period Crossover Trial Examining Bioequivalence of Bisoprolol-
Amlodipine 5 mg/5 mg Combination Tablets versus Bisoprolol 5 mg Tablets and Amlodipine 5 
mg Tablets Given Concomitantly in Healthy Subjects in Fasting and Fed State
:
Trial Biostatistician
Merck-Serono (Beijing) Pharmaceutical R&D Co., Ltd.
Signature: ..............................
Date: ..............................
Trial Biostatistician
Signature: ..............................
Date: ..............................
:
Senior Statistical Reviewer
Signature: ..............................
Date: ..............................
CRO Pharmacokineticist
Signature: ..............................
Date: ..............................
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Bisoprolol Amlodipine 5 mg/5 mg Combination Tablets
Two-period Crossover Bioequivalence
EMR200006-001
Final Version 2.2
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I N F O R M A T I O N
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CRO Biostatistician
Signature: ..............................
Date: ..............................
PPD
PPD


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Two-period Crossover Bioequivalence 
EMR200006-001 
 
 
 
 
 
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2 
Table of Contents 
1 
Signature Page ......................................................................................3 
2 
Table of Contents ..................................................................................5 
3 
List of Abbreviations and Definition of Terms ....................................7 
4 
Modification History ............................................................................9 
5 
Purpose of the Statistical Analysis Plan ...............................................9 
6 
Summary of Clinical Trial Features .....................................................9 
7 
Sample Size/Randomization ...............................................................12 
8 
Overview of Planned Analyses ...........................................................14 
9 
Changes to the Planned Analyses in the Clinical Trial Protocol ........14 
10 
Protocol Deviations and Analysis Sets ...............................................14 
10.1 
Definition of Protocol Deviations and Analysis Sets .........................14 
10.2 
Definition of Analysis Sets and Subgroups ........................................15 
11 
General Specifications for Statistical Analyses ..................................16 
12 
Trial Subjects ......................................................................................21 
12.1 
Disposition of Subjects and Discontinuations ....................................21 
12.2 
Protocol Deviations ............................................................................21 
12.2.1 
Important Protocol Deviations ............................................................21 
13 
Demographics and Other Baseline Characteristics .............................22 
13.1 
Demographics .....................................................................................22 
13.2 
Medical History ..................................................................................22 
13.3 
Other Baseline Characteristics ............................................................23 
14 
Previous or Concomitant Medications/Procedures .............................23 
15 
Treatment Compliance and Exposure .................................................23 
16 
Endpoint Evaluation ...........................................................................24 
16.1 
Primary Endpoint Analyses ................................................................24 
16.2 
Secondary Endpoint Analyses ............................................................25 
16.3 
Other Endpoint Analyses ....................................................................25 
16.3.1 
Analysis on PK / Population PK Endpoints .......................................25 
16.3.2 
Estimation of Individual Pharmacokinetic Parameters by 
Noncompartmental Analysis ..............................................................28 
16.3.3 
Analysis PD Endpoints and Biomarker ..............................................30 


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16.3.4 
PK/PD Modelling and Simulation ......................................................30 
16.3.5 
Analysis of Molecular Marker ............................................................30 
17 
Safety Evaluation ................................................................................31 
17.1 
Adverse Events ...................................................................................31 
17.1.1 
All Adverse Events .............................................................................32 
17.1.2 
Adverse Events Leading to Treatment Discontinuation .....................32 
17.1.3 
Deaths .................................................................................................33 
17.1.4 
Serious Adverse Events ......................................................................33 
17.2 
Clinical Laboratory Evaluation ...........................................................33 
17.3 
Vital Signs ..........................................................................................35 
17.4 
Other Safety or Tolerability Evaluations ............................................36 
18 
References ...........................................................................................36 
 


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3 
List of Abbreviations and Definition of Terms 
 
Abbreviation 
Definition 
AE 
Adverse Event 
AUC 
Area under the plasma concentration-time curve 
AUC0-f 
The AUC from time zero (dosing time) extrapolated to infinity 
AUC0-t 
The AUC from time zero (= dosing time) to the last sampling 
time (tlast) at which the concentration is at or above the lower 
limit of quantification 
AUCextra% 
The AUC from time tlast extrapolated to infinity given as 
percentage of AUC0-f 
BE 
Bioequivalence 
CI 
Confidence Interval 
CL/f 
The apparent total body clearance of drug following 
extravascular administration. 
Cmax 
Maximum observed plasma concentration 
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 (%) 
ECG  
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
GCP 
Good Clinical Practice 
GeoCV% 
Geometric Coefficient of Variation 
GeoMean 
Geometric Mean 
HR 
Hazard ratio 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
LLOQ 
Lower Level of Quantification 


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Max 
Maximum 
Mean 
Arithmetic mean 
Min 
Minimum 
MedDRA 
Medical Dictionary For Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
N 
Number of non-missing observations 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Preferred team 
SAE 
Serious Adverse Event 
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 
TEAE 
Treatment-Emergent Adverse Event 
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  
Vz/f 
Apparent volume of distribution during the terminal phase 
following extravascular administration 
λz 
Terminal elimination rate constant 
 


Bisoprolol Amlodipine 5 mg/5 mg Combination Tablets
Two-period Crossover Bioequivalence
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Modification History
Unique
Identifier for
SAP Version
Date of
SAP Version
Author
Changes from the Previous Version
Draft V0.1
02Jun2017
Not Applicable – First Version
Final V1.0
28Jun2017
Update per internal comments
Final V1.1
26Jul2017
Update per sponsor’s comments
Final V1.2
08Aug2017
Update per sponsor’s comments
Final V2.0
01Sep2017
Update per sponsor’s comments
Final V2.1
13Sep2017
Update per sponsor’s comments
Final V2.2
18Sep2017
Update per sponsor’s comments
5
Purpose of the Statistical Analysis Plan
The purpose of this Statistical Analysis Plan (SAP) is to document technical and detailed 
specifications for the final analysis of data collected for protocol EMR200006-001. Results of the 
analyses described in this SAP will be included in the Clinical Study Report (CSR). Additionally, 
the planned analyses identified in this SAP will be included in regulatory submissions or future 
manuscripts. Any post-hoc, or unplanned analyses performed to provide results for inclusion in 
the CSR but not identified in this prospective SAP will be clearly identified in the CSR. 
The SAP is based upon Section 8 (Statistics) of the trial protocol and protocol amendments and is 
prepared in compliance with ICH E9. 
6
Summary of Clinical Trial Features
Trial Objectives
Primary Objectives
x To demonstrate bioequivalence (BE) between the bisoprolol-
amlodipine fixed-dose-combination tablet (investigational 
product) and bisoprolol and amlodipine tablets administered 
concomitantly (comparator) given as a single oral dose in fasting 
and fed state.
Secondary Objectives
x To compare the pharmacokinetic (PK) profiles of bisoprolol and 
amlodipine 
between 
the 
investigational 
product 
and 
comparators.
x To examine the safety and tolerability of bisoprolol and 
amlodipine for the fixed dose combination tablet compared with 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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the 
bisoprolol 
and 
amlodipine 
tablets 
administered 
concomitantly. 
 
x To explore the effect of food intake on the PK of the 2 active 
ingredients. 
 
Trial Endpoints 
Primary Endpoint 
x Primary endpoints will be the PK parameters area under the 
(plasma) concentration-time curve (AUC) from time 0 to time t  
(AUC0-t) and maximum plasma concentration observed (Cmax) 
of bisoprolol and amlodipine. 
Secondary Endpoints 
x Secondary endpoints include time of maximum plasma 
concentration observed (tmax), apparent terminal half-life (t1/2), 
area under the plasma concentration-time curve from time 0 to 
infinity (AUC0-Ğ), the extrapolated part of area under the plasma 
concentration curve (AUCextra%), terminal elimination rate 
constant 
(λz), 
total 
clearance 
following 
extravascular 
administration (CL/f), and apparent volume of distribution (Vz/f) 
for bisoprolol and amlodipine. Safety and tolerability will be 
assessed by AEs, vital signs, biochemistry, hematology, 
urinalysis, 12-lead ECG, and physical examination. 
Safety endpoints: 
x The safety assessments comprise adverse events, laboratory 
tests, vital signs, electrocardiogram (ECG) and concomitant 
medications. 
Trial design  
This is a Phase I, open-label, randomized, 2-period, 2-sequence, 
crossover trial where subjects will be randomized to receive the 
treatment, in each period, either 
x Treatment A: One fixed-dose-combination tablet of 5 mg/5 mg 
bisoprolol-amlodipine (Concor AM), or 
x Treatment B: One tablet of bisoprolol 5 mg (Concor®) co-
administrated with amlodipine 5 mg tablet (Norvasc®). 
x Drug administration will be done with or without food 
depending on cohort allocation to either fasting or fed state. The 
subjects will remain in the same group (fasting or fed) in both 
treatment periods. 


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In each group (fed and fasted), the subjects were randomized to one 
of 2 treatment sequences: A-B or B-A. 
 
Planned number of 
subjects 
A total of 32 healthy male and female Chinese subjects will be enrolled 
in the trial, with each gender representing no less than 1/3 of the total 
number (also evenly allocated to fasting vs. fed group). Sixteen 
subjects each will be enrolled into the fasting group and fed group, 
respectively, and statistically powered to provide adequate sample size 
for BE testing. Each subject will be administered both the 
investigational product and comparators in this 2 × 2 crossover BE trial 
to minimize the effect of the individual difference and periodic 
difference of the testing results. 
Treatment and Trial 
Duration 
The trial has a duration of approximately 5 weeks for the fasting or 
fed group respectively for each subject, including: 
x Screening (assessments to determine eligibility for entry into the 
trial; occurring from Day -7 to Day -1) 
x Admission to the Clinical Research Unit (CRU) on Day -1 
x Period 1 (duration of 8 days; Day 1-8) 
x Washout (duration of 14 days; Day 1-14) 
x Admission to the CRU on Day 14 
x Period 2 (duration of 8 days; Day 15-22) 
x Washout (duration of 14 days; Day 15-28) 
x End of Trial (visit occurring after the second 14-day washout on 
Day 29) or premature withdrawal from the trial. 
Pharmacokinetics 
The plasma concentrations of bisoprolol and amlodipine will be 
determined by a validated analytical method using HPLC with 
MS/MS detection. Pharmacokinetic parameters (primary and 
secondary endpoints) will be calculated according to non-
compartmental analysis methods. The mixed trapezoidal rule will 
be used to calculate the area under the plasma concentration 
curve. 
Randomization and 
Blinding 
As this is an open-label trial, no method of blinding was used. 
Subjects were randomly assigned to one of the 2 treatment 
sequences (A-B, B-A) per group. Randomization occurred 
immediately before dosing on Treatment Period 1/Day 1. 
 




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Historical data showed no food effect on PK for either drugs, bisoprolol and amlodipine 
respectively [1, 2], and the observed variability has been comparable between fasting and fed 
dosing states. By applying statistical powering also to the fed group, assuming the intra-subject 
variability is similar in fed state with standard meal consumption [1, 2]. Based on the sample size 
calculation above, a 16-subject trial (12 subjects with adequate power and 4 subjects to cover 
potential dropout) provides at least 80% power to meet the BE criteria for both parameters and 
both products. 
Sensitivity analysis has been performed to explore impact of potentially different variability on the 
sample size and power calculation. The outcome, as selectively displayed in the tables below, 
suggests that consistently high power (80%+) can be obtained with the proposed sample size. 
Sensitivity Analysis 1: 
Assume 5% variation for all ratios (95% ~ 105%) and 10% all intra-subject CV. 
Sample Size 
Power (%) for Bisoprolol 
Power (%) for Amlodipine 
Joint Power (%) 
Cmax 
AUC0-t 
Cmax 
AUC0-t 
10 
96.83 
96.83 
96.83 
96.83 
87.89 
12 
98.83 
98.83 
98.83 
98.83 
95.42 
14 
99.58 
99.58 
99.58 
99.58 
98.34 
16 
99.85 
99.85 
99.85 
99.85 
99.42 
AUC0-t = area under the (plasma) concentration-time curve from time 0 to time t; CV = coefficient of variation; Cmax = the 
maximum plasma concentration observed 
Sensitivity Analysis 2: 
Assume 5% variation for all ratios (95% ~ 105%) except of Amlodipine AUC0-t (90% ~ 110%), 
and 10% all intra-subject CVs. 
Sample Size 
Power (%) for Bisoprolol 
Power (%) for Amlodipine 
Joint Power (%) 
Cmax 
AUC0-t 
Cmax 
AUC0-t 
10 
96.83 
96.83 
96.83 
77.74 
70.56 
12 
98.83 
98.83 
98.83 
85.17 
82.23 
14 
99.58 
99.58 
99.58 
90.25 
89.13 
16 
99.85 
99.85 
99.85 
93.66 
93.26 
AUC0-t = area under the (plasma) concentration-time curve from time 0 to time t; Cmax = the maximum plasma concentration 
observed 
 
Each eligible subject will be allocated to a treatment sequence according to a computer-
generated randomization schedule. Subjects will be identified only by their assigned subject 
number. The subjects will receive consecutive subject numbers in the order of their enrollment 
into the trial. 
A total of 32 eligible healthy male and female Chinese subjects (16 in fasting group and 16 in fed 
group) who meet the eligibility criteria will be randomized (with each gender representing no less 


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than 1/3 of the total number) on Day 1 in a 1:1 ratio to one of 2 treatment sequences: Sequence A- 
B or Sequence B-A. 
In Sequence A-B, subjects will receive bisoprolol-amlodipine 5 mg/5 mg combination tablets 
(Treatment A) in Period 1 and bisoprolol 5 mg tablets and amlodipine 5 mg tablets given 
concomitantly (Treatment B) in Period 2. In Sequence B-A, subjects will receive bisoprolol 5 mg 
tablets and amlodipine 5 mg tablets given concomitantly (Treatment B) in Period 1 and bisoprolol 
amlodipine 5 mg/5 mg combination tablets (Treatment A) in Period 2. 
The first 4 discontinued subjects of each group will not be replaced. Subjects will only be replaced 
if the number of subjects within a sequence falls below 12. The subject who is replacing a 
discontinued subject will then be allocated to the treatment sequence of the subject who 
discontinued. 
8 
Overview of Planned Analyses 
The methods described in this document will be applied to the preparation of tables, figures and 
listings (TLFs). Statistical analyses will be performed using cleaned electronic clinical report form 
(eCRF) data collected.  
This SAP will cover the final analysis only.  The final analysis will be performed only after the 
last subject has completed the study with all study data in-house and all data queries resolved. The 
SAP will be finalized prior to database lock. 
9 
Changes to the Planned Analyses in the Clinical Trial Protocol 
The Screening Analysis Set has been added to include all subjects who signed informed consent 
in the study. The per-protocol population has been removed. 
The PK parameter, apparent volume of distribution at steady-state after extravascular 
administration (Vss/f) was originally proposed in the CTP (Clinical Trial Protocol).  However, this 
PK parameter cannot be calculated based on the dosing regimen (i.e., single dose) and route of 
administration (i.e., oral).  As such, the apparent volume of distribution during the terminal phase 
following extravascular administration (Vz/f) will be calculated instead to provide an estimate of 
the extent of drug distribution following a single oral dose. 
10 
Protocol Deviations and Analysis Sets 
10.1 
Definition of Protocol Deviations and Analysis Sets 
Protocol deviations describe how closely the study has been conducted according to the protocol 
as expected per GCP.  Some of these deviations may be significant contributors to analysis bias.  
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
subject's rights, safety, or well-being.  


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Examples of clinically important protocol deviations or important events for PK include, but may 
not be limited to, the following: 
x Subjects that are dosed on the study despite not satisfying the inclusion criteria; 
x Subjects that develop withdrawal criteria whilst on the study but are not 
withdrawn; 
x Subjects that receive the wrong treatment or an incorrect dose; 
x Subjects that receive an excluded concomitant medication; 
x Deviation from GCP. 
x Adverse events, vomiting, diarrhea, etc. 
x Vomiting following oral dosing (these instances will be discussed on a case-by 
case basis) 
x Sample processing errors that may lead to inaccurate bioanalytical results 
x Inaccurate dosing or dosing errors 
x Incomplete meal consumption prior to dosing 
x Concomitant medication violations 
The following deviations will be identified and confirmed prior to or at the Data Review Meeting 
at the latest. Important protocol deviations include 
x Deviations from the inclusion and exclusion criteria 
x Deviations post inclusion 
A data review will be held to discuss and update the definition of important protocol deviations so 
as to determine the evaluability of the subjects prior to database lock. 
10.2 
Definition of Analysis Sets and Subgroups 
Screening Analysis Set  
The Screening Analysis Set includes all subjects who have signed the main informed consent (i.e., 
screening failures plus subjects enrolled). 
Safety Analysis Set 
The Safety Analysis Set includes all subjects who received at least 1 dose of trial drug. In general, 
clinical data will be analyzed for the Safety Analysis Set. 
Pharmacokinetic Analysis (PK) Set 
The PK Analysis Set includes all subjects who completed the trial with adequate trial medication 
compliance, without any relevant protocol violations or events with respect to factors likely to 
affect the comparability of PK results, and with sufficient evaluable data to determine primary 
endpoints (AUC0-t and Cmax) for both treatments and analytes.  If subjects receive concomitant 
medication that potentially affects PK for the treatment of an AE, their inclusion in the PK Analysis 
Set will be decided on a case-by-case basis. Emesis occurring within two times of the median tmax 
for a given analyte and the treatment will be considered a relevant event likely to affect the 
comparability of PK results.  Similarly, a predose concentration for a given analyte and treatment 


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period which exceeds 5% of Cmax will be considered a relevant event affecting PK results.  All PK 
analyses will be based on the PK Analysis Set. 
11 
General Specifications for Statistical Analyses 
Unless otherwise indicated all analyses will be presented separately for the two treatment groups 
under different food condition (fed and fasted). 
Listings 
All listings will be reported separately by food condition and sorted by treatment, or treatment 
sequence (A-B or B-A), and/or scheduled timepoint, as appropriate. Data which are only measured 
before administration of trial drug and/or at end of study will be sorted by subject and scheduled 
timepoint (if appropriate). 
All PK concentrations will be reported and analyzed with the same precision as the source data 
provided by the bioanalytical laboratory or clinical laboratory regardless of how many significant 
figures or decimal places the data carry. Pharmacokinetic parameters and actual elapsed sample 
collection times will be rounded for reporting purposes in by-subject listings. Actual elapsed 
sample collection times will be rounded to two decimal places with units of hours. For PK 
parameters, the standard rounding procedure will be as follows: 
x Parameters directly derived from source data (e.g., Cmax) will be reported and analyzed 
with the same precision as the source data. 
x Parameters derived from actual elapsed sample collection times [e.g., time to reach 
maximum observed plasma concentration (tmax)] will be reported to two decimal places 
with units of hours. 
x Values of AUC will be rounded to 3 significant figures. 
x Percentages not derived directly from source data [e.g., percentage of area under the plasma 
concentration-time curve from time zero to infinity (AUC0-∞) obtained by extrapolation 
(AUCextra%)] will be reported to 3 significant figures. 
x Other parameters [e.g., apparent terminal half-life (t1/2), terminal elimination rate constant 
(λZ), apparent total body clearance of drug from plasma following extravascular 
administration (CL/f), apparent volume of distribution during the terminal phase following 
extravascular administration (Vz/f)] will be reported with 3 significant figures. 
Tables and Descriptive Statistics 
All data will be summarized by food condition, treatment, or treatment sequence, and/or scheduled 
time point, as appropriate. Repeated and unscheduled measurements included in the listings will 
not be used for statistical analyses or summaries, unless the repeated measurement was performed 
due to unreliable values/technical reasons, e.g., clotted samples.  


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Bisoprolol and amlodipine concentrations in plasma, and their PK parameters, will be presented 
in tables and descriptively summarized by food condition, treatment, and/or nominal time point, 
as appropriate.   
Presentation of PK Concentration Data 
Pharmacokinetic concentration data will be descriptively summarized using: number of non-
missing observations (N), arithmetic mean (Mean), standard deviation (SD), standard error of the 
mean (SEM), coefficient of variation (CV%), minimum (Min), median (Median) and maximum 
(Max).  
Descriptive statistics of PK concentration data will be calculated using values with the same 
precision as the source data, and rounded for reporting purposes only. The following conventions 
will be applied when reporting descriptive statistics of PK concentration data: 
Mean, Min, Median, Max:  
 
 
 
3 significant digits 
SD: 
 
 
 
 
 
 
4 significant digits 
CV%:  
 
 
 
 
 
1 decimal place 
Derived parameters will be reported using precision similar to the precision of the data from which 
they were derived.   
Descriptive statistics of plasma concentration will additionally show quartiles, and values below 
the lower limit of quantification (LLOQ) will be taken as zero. 
Presentation of PK Parameter Data 
Pharmacokinetic parameter data will be descriptively summarized using: number of non-missing 
observations (N), Mean, SD, CV%, Min, Median, Max, geometric mean (GeoMean), the 
geometric coefficient of variation (GeoCV%), and the 95% confidence interval (CI) for the 
GeoMean (LCI 95% GM, UCI 95% GM).  
Pharmacokinetic parameter Cmax will be reported with the same precision as the source data and 
tmax will be reported to two decimal places. All other PK parameters will be reported to 3 significant 
figures. In export datasets, as well as in the Study Data Tabulation Model (SDTM) PP/XD domain, 
PK parameters will be provided with full precision, and will not be rounded. Descriptive statistics 
of PK parameter data will be calculated using full precision values, and rounded for reporting 
purposes only.  
The following conventions will be applied when reporting descriptive statistics of PK parameter 
data: 
Mean, Min, Median, Max, GeoMean, 95% CI:  
3 significant digits 
SD: 
 
 
 
 
 
 
4 significant digits 


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CV%, GeoCV%:
1 decimal place 
To ensure a reliable estimate of the extent of exposure in pivotal trials (e.g., bioequivalence), 
AUCextra% should be less than or equal to 20.0%. If AUCextra% is greater than 20.0%, all 
parameters derived using λz (i.e., λz, t1/2, AUC0-f AUCextra%, Vz/f, and CL/f) will not be included 
in the calculation of descriptive statistics or statistical analyses.
Software
Pharmacokinetic parameters will be derived using noncompartmental methods with the validated 
computer program Phoenix® WinNonlin® 6.4 or higher (
). Pharmacokinetic figures will be developed using SigmaPlot® 12.5 or higher (
 
), Phoenix® WinNonlin® 6.4 or higher, or SAS® Windows 
Version 9.4 or higher (
).
All other statistical analyses will be performed using SAS® version 9.4 or higher.
Presentation of continuous and qualitative variables:
Continuous variables will be summarized using the following descriptive statistics unless 
otherwise specified, i.e.,
x
number of subjects (N), number of subjects with non-missing values 
x
mean, SD
x
median, 25th Percentile - 75th Percentile (Q1-Q3)
x
minimum and maximum
Qualitative variables will be summarized by counts and percentages.               
Unless otherwise stated the calculation of proportions will be based on the number of subjects of
the analysis set of interest. Therefore, counts of missing observations will be included in the 
denominator and presented as a separate category.
In case the analysis refers only to certain visits, percentages will be based on the number of subjects 
still present in the trial at that visit, unless otherwise specified.
Definition of baseline:
Baseline for assessments is defined as the last non-missing measurement taken prior to or on the 
day of the first trial drug administration.
For vital signs and electrocardiogram (ECG), an assessment performed on dosing date with time 
point marked as “predose” will be considered as baseline. If there is no time point, the last non-
missing assessment prior to dosing will be taken as baseline.
PPD
PPD
PPD


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In the case where the last non-missing measurement and the dosing date/time coincide, that 
measurement will be considered baseline, but AEs and medications commencing on the reference 
start date will be considered post baseline. Such as AE happened on dosing date (even AE before 
dosing, and there is no time to make judgement) it will be treated as a TEAE. 
Definition of duration: 
Duration will be calculated by the difference of start and stop date + 1 if not otherwise specified. 
For example, survival time (days) = date of death - the date of first administration + 1. 
Conversion factors: 
Unless specified, conversion of days to months /years will be defined as:  
1 month = 30.4375 days 
1 year = 365.25 days 
Common calculations:  
For quantitative measurements, change from baseline will be calculated as: 
 
Test Value at Visit X – Baseline Value 
Handling of missing data: 
Unless otherwise specified, missing data will not be replaced.  Handling of missing data for PK 
parameter calculations are discussed under Section 16.3.3. 
In all subject data listings imputed values will be presented. In all listings imputed information 
will be flagged.  
Missing statistics, e.g., when they cannot be calculated, should be presented as “nd”.  For example, 
if n=1, the measure of variability (SD) cannot be computed and should be presented as “nd”. 
For the derivation of new date variables the following rules will apply: 
Partial birth dates will be handled this way: day will be imputed as 15 if it is missing, and month 
imputed as June if missing. If both of day and month are missing, they will be imputed as July 1st. 
If year is missing then the date will not be imputed. 
Any adverse event (AE) with incomplete start and or end dates/times will be handled as described 
below for the classification as treatment-emergent, assignment to treatment periods and calculation 
of duration. 
x Adverse events with unknown start times but known start dates, will be imputed with a 
time of 00:00 hours, unless the start date corresponds to any given dosing date, in which 


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case time of dosing will be used instead. However, if this results in a start time after end 
time of the AE, then the start time will be imputed to 00:00 hours instead. 
x Any adverse event with completely unknown start dates will be imputed with date and time 
of the first administration of a study drug, unless the end date is known and prior to first 
administration. In the latter case, the start date will be imputed as the date of screening and 
a time of 00:00 hours. 
x Adverse events with completely unknown end times, will be imputed with an end time of 
23:59 hours. 
x Adverse events with completely unknown end dates will be imputed with the date of study 
completion (or in case of withdrawal, date of discontinuation).  
Partially known end dates will be treated as follows: 
x If only the day is missing, the last day of the month will be imputed or the date of study 
completion/discontinuation if earlier. 
x If day and month are both missing, then the end date of 31 December will be imputed or 
the date of study completion/discontinuation if earlier. 
Assignment to the different treatment periods will be performed after the imputations have been 
performed. An AE will be assigned to a specific treatment period if it occurs after the IMP 
administration scheduled for that period and before the IMP administration in the next period (or 
study completion for the last period). 
Trial day / treatment day:  
Trial day / Treatment day are defined relative to the date of randomization / the date of first 
administration of trial drug (start of treatment). Trial Day 1 defines the day of randomization, the 
day before is defined as Trial Day –1 (no Trial Day 0 is defined). Treatment day will be calculated 
accordingly: 
Trial day or treatment day =  
x date of event – the date of first administration, if date of event < the date of first 
administration 
x or date of event – the date of first administration + 1 , if date of event ≥ the date of first 
administration 
In the situation where the event date is partial or missing, the date will appear partial or missing in 
the listings, and Trial Day or Treatment Day, and any corresponding durations will be presented 
as missing. Rules of handling missing dates relevant to efficacy will specified in the subsequent 
sections.  


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12 
Trial Subjects 
This section includes specifications for reporting subject disposition and treatment/trial 
discontinuations. Additionally, procedures for reporting protocol deviations are provided. 
12.1 
Disposition of Subjects and Discontinuations 
All subjects who provide informed consent will be accounted for in this study. Subject disposition 
and withdrawals will be presented for the screening analysis set. 
The following summaries will be produced by treatment sequence and overall, for each group: 
x Total number of subjects screened (i.e., subjects who gave informed consent) 
x Number of randomized subjects 
x Number of subjects treated in each period 
x Number of subjects that completed each treatment period 
x Number of subjects who completed the trial 
x Number of subjects who discontinued the study treatment after the first administration, 
grouped by the main reason 
x Number of subjects who discontinued the study, grouped by the main reason 
x Number of subjects included in Safety Analysis Set 
x Number of subjects included in PK Analysis Set 
Corresponding individual listings will be prepared (sorted by group, treatment sequence and 
subject).  
Discontinued subjects will be listed with their reason of withdrawal.  
Additionally, a listing of the screening failures will be produced with the reason of non-inclusion 
in the treatment phase.  
Listings with visit dates will also be carried out by group, treatment sequence and subject. 
12.2 
Protocol Deviations 
12.2.1 
Important Protocol Deviations 
Important protocol deviations will be based upon the Clinical Trial Management System (CTMS) 
data and determined for all subjects by medical review processes. All the important protocol 
deviations will be included in SDTM datasets, if identified by means of medical review. The 
Analysis Data Model (ADaM) datasets will be derived from SDTM and include all important 
protocol deviations. 


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A data review will be held to discuss and update the definition of important protocol deviations so 
as to determine the evaluability of the subjects prior to database lock. 
The following outputs will be provided by treatment sequence and overall, for each group: 
x Summary of important protocol deviations relating to inclusion/exclusion criteria 
x Summary of other important protocol deviations 
 
All protocol deviations will be listed. A listing presenting protocol deviations relating to 
inclusion/exclusion criteria and a listing presenting other deviations will be carried out by group, 
treatment sequence and subject. 
13 
Demographics and Other Baseline Characteristics 
Demographic data and other baseline characteristics will be presented using summary statistics for 
continuous variables and frequency tables for categorical variables. 
13.1 
Demographics 
Demographic characteristics will be summarized overall and by treatment sequence for each group 
using the following information from the Screening/Baseline Visit CRF pages.  
Demographic characteristics:  
x Sex: Male, Female  
x Race: Chinese, Non-Chinese  
x Age (years): summary statistics  
x Weight (kg): summary statistics 
x Height (cm): summary statistics 
x BMI (kg/m2): summary statistics 
Specifications for computation. 
Age [years]:  
x (date of given informed consent - date of birth + 1) / 365.25 
x In case of missing date that according to section 11: day will be imputed as 15 if it is missing, 
and month imputed as June if missing. If both of day and month are missing, they will be 
imputed as July 1st. If year is missing then the date will not be imputed. 
13.2 
Medical History 
The medical history will be summarized from the “Medical History” eCRF page, using MedDRA, 
version 20.0, preferred term as event category and MedDRA system organ class (SOC) body term 
as Body System category. 


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Medical history will be displayed in terms of frequency tables overall and by treatment sequence 
for each group: ordered by primary SOC and PT in alphabetical order. 
13.3 
Other Baseline Characteristics 
The following baseline characteristics will be summarized overall and by treatment sequence for 
each group: 
x Nicotine and Alcohol Consumption 
x Urine  screening of drugs of abuse 
x Breath test of alcohol 
Baseline characteristics with respect to vital signs, physical examinations, ECG recordings, and 
laboratory tests will describe in Section 17 
Results of chest x-ray and serum pregnancy test (for women of childbearing potential) will be 
listed only. 
 
14 
Previous or Concomitant Medications/Procedures 
All previous or concomitant medications will be coded by the most current WHODrug (enhanced) 
01Mar2017.  
Missing or partial dates for medications will not be imputed. In the case where it is not possible to 
define a medication as prior or concomitant, the event will be classified by the worst case; i.e. prior 
and concomitant. 
Previous medications are medications taken prior to screening visit, other than trial medications 
and pre-medications for trial drug, which started and ended before first administration of trial drug. 
Prior medications within 1 month before screening will be collected. 
Concomitant treatments are medications, other than trial medications, which are taken by 
subjects any time on-trial (include medications which started before the first trial drug treatment 
and were ongoing after first trial drug treatment, or started on or after the first day of trial drug 
treatment). 
Previous and concomitant medications/procedures will be summarized overall for both groups as 
well as overall and by treatment sequence for each group, and by PT and ATC 2nd level, 
respectively. The listing of previous and concomitant medications/procedures will be generated. 
15 
Treatment Compliance and Exposure 
Study drug administration will be listed by group, treatment sequence and subject with treatment, 
date and time of administration. 


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16 
Endpoint Evaluation 
16.1 
Primary Endpoint Analyses 
The primary endpoints are the following PK parameters calculated from bisoprolol and 
amlodipine plasma concentrations: 
x AUC0-t of bisoprolol 
x Cmax of bisoprolol 
x AUC0-t of amlodipine 
x Cmax of amlodipine 
The null and alternative hypotheses are as follows: 
25
.1
/
8.0
/
25
.1
/
8.0
/
:
max
0
0
t
d
t
d

C
T
C
T
C
T
C
T
t
or
C
for
or
AUC
for
H
P
P
P
P
P
P
P
P
, for at least 1 primary endpoint 
25
.1
/
8.0
25
.1
/
8.0
:
max
0
1





C
T
C
T
t
C
for
AUC
for
H
P
P
P
P
 , for all 4 primary endpoints and for both fasting and fed 
groups 
where 
 and 
 are the geometric means of the primary endpoints following investigational 
product (Treatment A) and comparators (Treatment B), respectively. 
The analysis of primary endpoints will be based on the PK Population (Section 10.2) 
The primary endpoints, Cmax and AUC0-t in fasting or fed group, will be log-transformed and a 
mixed-effects model will be applied. The model will include fixed effects for sequence, treatment, 
and period and a random effect of subject nested within sequence. Treatment differences on the 
log scale will be estimated for the parameters together with their 90% CIs. The least squares means 
together with their 95% CIs by treatment will also be estimated. Point estimates and CIs will be 
back-transformed to the original scale for presentation, i.e., ratios of geometric means and 
corresponding 90% CIs for Treatment A/Treatment B, geometric means and corresponding 95% 
CIs by treatment, respectively. Intra-subject CV estimated from the model will also be presented. 
The BE will be established if all 4 sets of the 90% CIs for the ratios of geometric means between 
the investigational product and the comparators fall within 80.00% to 125.00%. 
The following example code could be used: 
proc mixed data=pkparam; 
 by food analyte param; 
 class sequence period trt subjid; 
 model lnest = sequence period trt /ddfm=kr; 
 random subjid(sequence); 
 estimate 'A vs B' trt 1 -1 /alpha=0.1 cl; 
 lsmeans trt /alpha=0.05 cl; 
T
P
C
P


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run; 
All primary PK endpoints will be descriptively summarized as described in Section Error! 
Reference source not found.. Graphs of individual values and geometric mean will be presented 
for primary PK parameters versus treatment and food condition. Boxplots will also be created for 
primary PK parameters versus group and treatment. 
16.2 
Secondary Endpoint Analyses 
All secondary PK endpoints will be descriptively summarized as described in Section 11.  The 
secondary PK endpoints are the following parameters in plasma for bisoprolol and amlodipine:  
x tmax, t1/2, λZ, AUC0-∞, AUCextra%, CL/f, Vz/f. 
For tmax, the Hodges-Lehmann estimates for the treatment differences and corresponding 90% CIs 
according to the Tukey method will be calculated. 
The mixed-effects model for treatment comparison as described for the primary endpoints will 
also be applied to AUC0-∞. The ratios of geometric means and corresponding 90% CIs for 
Treatment A/Treatment B will be estimated.  
All secondary endpoints (tmax, t1/2, λZ, AUC0-∞, AUCextra%, CL/f, and Vz/f) will be summarized 
descriptively by group and treatment on the PK analysis set. 
 
16.3 
Other Endpoint Analyses 
16.3.1 
Analysis on PK / Population PK Endpoints 
Pre-dose samples that occur before the first drug administration will be assigned a time of 0 hours, 
as if the sample had been taken simultaneously with the study drug administration. 
Pharmacokinetic concentrations which are erroneous due to a protocol deviation (as defined in the 
protocol), documented handling error or analytical error (as documented in the bioanalytical 
report) may be excluded from the PK analysis if agreed upon prior to performing a statistical 
analysis. In this case the rationale for exclusion must be provided in the Clinical Trial Report 
(CTR). Any other PK concentrations that appear implausible to the Pharmacokineticist/PKPD 
Data Analyst must not be excluded from the analysis. Any implausible data will be documented 
in the CTR. 
Plasma concentration data will be summarized descriptively for bisoprolol and amlodipine as 
described in Section 11. Values below the lower limit of quantification (LLOQ) will be taken as 
zero for descriptive statistics of PK concentrations.  Missing concentrations (e.g., no sample, 
insufficient sample volume for analysis, no result, or result not valid) will be reported and 
displayed generally as “N.R.”.  


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Samples that are collected outside the specified time windows will be included in the PK analysis 
but excluded from the concentration summary.  The PK sampling collection schedule is presented 
in Table 1 below. 
 
 




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Individual plasma bisoprolol and amlodipine concentration versus actual time plots will be 
provided for each treatment by food condition using a linear and semi-logarithmic scale. Plots of 
individual profiles of plasma bisoprolol and amlodipine concentration versus actual time for all 
subjects within each treatment, presented on a single plot (i.e., spaghetti plots), will be provided 
by Fed/Fasting group, separately, using a linear and semi-logarithmic scale.  All statistical analyses 
and descriptive summaries of PK data will be performed on the PK Analysis Set. Pharmacokinetic 
concentrations will be listed for all subjects by treatment and group; concentrations excluded from 
the PK analysis will be flagged within the listing 
A listing of PK blood sample collection times by individual, as well as derived sampling time and 
time deviations, will be provided. 
16.3.2 
Estimation of Individual Pharmacokinetic Parameters by 
Noncompartmental Analysis 
For the PK analysis, predose sample concentrations that are missing will be assigned a numerical 
value of zero for the calculation of AUC. Any anomalous concentration values observed at predose 
will be identified in the CTR, and if the anomalous predose concentration value is greater than 
5.00% of the Cmax in the profile, the profile will be excluded from summaries and inferential 
statistics as appropriate; handling of the data will be documented in the CTR. Pharmacokinetic 
parameters for the affected profile shall be calculated as part of the WinNonlin® run and will be 
listed.  
Pharmacokinetic parameters will be calculated using standard non-compartmental methods. 
Pharmacokinetic parameters will be evaluated and listed for all volunteers who provide sufficient 
concentration-time data. At least 3 valid, postdose concentration points will be required in the PK 
profile to obtain any PK parameter estimate. 
Pharmacokinetic parameters will be calculated using the actual elapsed time since dosing, given 
with a precision of 14 significant digits or the SAS format Best12.  In cases where the actual 
sampling time is missing, calculations will be performed using the scheduled time. Otherwise, 
there will be no further imputation of missing data other than for a missing predose concentration 
as stated above. 
For each subject in the PK Analysis Set the following PK parameters will be calculated for 
bisoprolol and amlodipine, where appropriate: 
 
Symbol 
Definition 
AUC0-t 
The area under the concentration-time curve (AUC) from time zero (= dosing 
time) to the last sampling time (tlast) at which the concentration is at or above the 
LLOQ. Calculated using the mixed log linear trapezoidal rule (linear up, log 
down).  Units: ng*h/mL. 


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Symbol
Definition
AUC0-f
The AUC from time zero (dosing time) extrapolated to infinity, based on the 
predicted value for the concentration at tlast , as estimated using the linear 
regression from λz determination. AUC0-∞=AUC0-t+Clast pred/ λz. Units: ng*h/mL.
AUCextra%
The AUC from time tlast extrapolated to infinity given as percentage of AUC0-
f. AUCextra% = (extrapolated area/AUC0-∞)*100. The predicted AUC0-∞ should 
be used. Units: %.
CL/f
The apparent total body clearance of drug following extravascular 
administration. 
CL/f = Dose p.o. /AUC0-∞. The predicted AUC0-∞ should be used. The dose 
amounts to be used for this calculation are 5 mg for bisoprolol and 5 mg for 
amlodipine.  Units: L/h.
Cmax
Maximum observed concentration,
taken directly from the observed 
concentration-time profile.  Units: ng/mL.
tmax
The time to reach the maximum observed concentration collected during a 
dosing interval (unless otherwise defined, take the first occurrence in case of 
multiple/identical Cmax values).  Units: h.
t1/2
Apparent terminal half-life. t1/2 = ln (2)/λz. Units: h.
Vz/f
The apparent volume of distribution during the terminal phase following 
extravascular administration Vz/f = Dose/(AUC0-∞*λz) following single dose.
Units: L.
Oz
Terminal elimination rate constant. Determined from the terminal slope of the 
log-transformed concentration curve using linear regression on terminal data 
points of the curve.  Units: h-1.


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The following PK parameters will be calculated for diagnostic purposes and listed, but will not be 
summarized: 
x The time interval (h) of the log-linear regression (λz lower, λz upper) to determine λz.  
x Number of data points (Nλ) included in the log-linear regression analysis to determine λz. 
x Goodness-of-fit statistic (Rsq) for calculation of λz.   
The regression analysis should contain data from at least 3 different time points in the terminal 
phase consistent with the assessment of a straight line on the log-transformed scale. Phoenix 
WinNonlin best fit methodology will be used as standard. The last quantifiable concentration 
should always be included in the regression analysis, while the concentration at tmax and any 
concentrations <LLOQ which occur after the last quantifiable data point should not be used.  
The Rsq should be ≥0.800 and the observation period over which the regression line is estimated 
should be at least two-fold the resulting t1/2 itself. If these criteria are not met, then the rate 
constants and all derived parameters (e.g., AUC0-∞, AUCextra%, CL/f, t1/2, and Vz/f.) will be included 
in the parameter outputs and descriptive statistics but will be flagged and discussed appropriately. 
Any flags should be included in the study specific SDTM.  
For both analytes, if more than 20% of AUC0-∞ is extrapolated (AUCextra% >20.0%), then AUC0-∞ 
and λZ estimates and parameters derived from them (e.g., CL/f) will be calculated and included in 
the listing, but flagged as unreliable and set to missing in summaries and in inferential statistical 
analysis. 
The dose amount for investigational medicinal product (IMP) administered is that of the active, 
free drug substance only, and is synonymous with the measured analyte. No adjustment for the 
dose amount value of IMP will be applied when ‘dose’ is used in calculating PK parameters with 
formulas needing a dose value. 
The Phoenix WinNonlin NCA Core Output will be provided in a separate listing. 
16.3.3 
Analysis PD Endpoints and Biomarker 
Not applicable. 
16.3.4 
PK/PD Modelling and Simulation 
Not applicable. 
16.3.5 
Analysis of Molecular Marker 
Not applicable. 


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17 
Safety Evaluation 
Population: Safety Analysis Set 
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical trials such as adverse events, laboratory tests and vital signs.  
 
All safety analyses will be peformed on the Safety Analysis Set. All safety data will be listed in 
individual subject listings by group, treatment sequence and subject.  
 
All data recorded during the trial will be presented in individual data listings performed on the 
safety population. Moreover, all safety variables will be analyzed using descriptive statistics. 
For the evaluation of safety parameters, the continuous variables will be summarized descriptively 
per treatment, period, time point, and overall by N, arithmetic mean, median, SD, and minimum 
and maximum values. Categorical variables will be presented in frequency tables with the counts 
of observations and corresponding percentages. 
Blood pressures, pulse rate measurements and ECG recordings will be individually listed by 
treatment, subject number, period, and time point, and the abnormal values flagged according to 
reference laboratory ranges. All hematology and biochemistry parameters will be listed and 
summarized using descriptive statistics by treatment, period, and time point on observed values. 
Urinalysis will be summarized in frequency tables. 
Safety and tolerability will be assessed by monitoring of assessment of general safety and 
tolerability, adverse events, vital signs, ECG, biochemistry, hematology, urinalysis, and physical 
examination. Results of physical examination will only be listed by treatment, subject, period, time 
point, and body system. 
17.1 
Adverse Events 
After coding of AEs according to the Medical Dictionary for Regulatory Activity classification 
(version 20.0) and assignment to a system organ class and preferred term, all AEs recorded during 
the course of the trial will be listed by treatment and subject number. 
An AE will be considered as 'treatment emergent' if it occurred after the first drug administration 
of each period or if it was present prior to drug administration but exacerbated after the drug 
administration. All other adverse events will be considered ‘pre-treatment’. 
In the case where it is not possible to define an AE as being treatment emergent or not, the AE will 
be classified as treatment emergent as the most conservative approach. 
The AE listings will include the following items: 
x System organ class 
x Preferred term 
x Investigator’s description 


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x Whether the event is treatment-emergent 
x Trial treatment at onset of event 
x Date and time of onset and resolution 
x Duration of the event 
x Date and time of last administration before AE 
x Days under treatment (for TEAEs) or Days in Study (for pre-treatment AEs) 
x Severity/Intensity 
x Causality relationship to investigational product 
x Outcome 
x Action taken to investigational product 
x Other action 
x Seriousness 
17.1.1 
All Adverse Events 
 
A summary table describing all the TEAEs occurring during the trial will be produced overall 
and by group as well as by treatment for each group using frequency of events and number and 
percentage of subjects experiencing these events overall and by SOC and PT. 
 
Group/SOC terms will be sorted by decreasing total frequency. Preferred terms within each 
group/SOC term will likewise be sorted by decreasing total frequency. 
 
In addition, all TEAEs will be tabulated by intensity and relationship to drug in the same manner. 
 
Multiple occurrences of the same TEAE in one subject during the same treatment in the trial will 
be counted as multiple events in the frequency counts for adverse events. If a subject experiences 
more than one occurrence of the same TEAE during the same treatment in the trial, the subject 
will only be counted once for that treatment using the worst severity and the strongest 
relationship. 
In case a subject had events with missing and non-missing severities, the maximum of the non-
missing severities will be displayed. In case all the TEAEs of a subject are all with missing 
severities then Moderate will be used unless there is any evidence that it should be Severe. 
17.1.2 
Adverse Events Leading to Treatment Discontinuation 
 
All adverse events leading to trial or treatment discontinuation will be listed by group, treatment 
sequence and subject including SOC, PT and investigators’ verbatim.  


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17.1.3 
Deaths 
 
AEs leading to deaths will be listed by group, treatment sequence and subject including SOC, PT 
and investigators’ verbatim, if applicable.  
 
17.1.4 
Serious Adverse Events 
 
All serious adverse events (SAEs) will be listed by group, treatment sequence and subject 
including SOC, PT and investigators’ verbatim. 
17.2 
Clinical Laboratory Evaluation 
The following parameters will be measured during the trial as safety evaluation: 
Hematology: 
Biochemistry: 
Serology: 
Urinalysis: 
Erythrocytes 
Alanine 
Aminotransferase 
HBsAg 
Appearance 
Hemoglobin 
Aspartate 
Aminotransferase 
HCV antibody 
Blood 
Hematocrit 
Total Bilirubin 
HIV antibody 
Nitrite 
Mean corpuscular 
volume 
Direct Bilirubin 
TP antibody 
Ketone 
Mean corpuscular 
hemoglobin 
concentration 
Indirect Bilirubin 
 
Protein 
Red blood cell 
distribution width 
Protein total 
 
Glucose 
Platelets 
Albumin 
 
pH 
Mean platelet volume 
Globulin 
 
Leukocytes 
Thrombocytocrit 
A/G 
 
Microscopic 
examination 


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Platelet distribution 
width 
Alkaline Phosphatase 
 
 
White blood cells 
Glutamyl 
Transpeptidase 
 
 
Neutrophils 
Urea Nitrogen 
 
 
Monocytes 
Creatinine 
 
 
Lymphocytes 
Cholesterol 
 
 
 
Triglycerides 
 
 
 
Glucose 
 
 
 
Creatine Kinase 
 
 
 
Creatine 
Phosphokinase MB 
Isoenzyme 
 
 
 
 
Lactate Dehydrogenase 
 
 
 
Calcium 
 
 
 
Phosphorus 
 
 
 
α-Amylase 
 
 
 
Sodium 
 
 
 
Potassium 
 
 
 
Chloride 
 
 
All biochemistry, hematology, and serology parameters will be summarized using descriptive 
statistics overall and by treatment sequence for each group at baseline and at screening to end of 
study visit as raw data and change from baseline. Biochemistry, hematology, and serology will 


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also be described by group, treatment and time point on observed values as raw data and change 
from baseline, ie, change between period 1 Baseline on Screening and period 1 visit on Day 8 to 
evaluate the change during period 1, and change between period 2 Baseline on Day 14 and period 
2 Visit on Day 22 for change during period 2. In additional, frequency tables based on a 
classification of values as low, normal, or high with respect to the reference ranges will be 
summarized. 
Urinalysis based on a classification of values as Normal/-, +-, +, ++, +++, ++++ will be 
summarized in frequency tables y treatment sequence and time point for each group. All abnormal 
laboratory values will be listed.  
In addition, shift tables for laboratory tests (for hematology and biochemistry) based on a 
classification of values as low, normal, or high with respect to the reference ranges will be 
summarized and presented by group, treatment and time point, except for End of study visit which 
will be presented by treatment sequence for each group. 
Baseline is Period 1 Day 1 pre-dose (or Screening if missing at Day 1 pre-dose) for Period 1 and 
end of study visit and Period 2 Day 1 pre-dose for Period 2.  
It is essential that Merck be provided with a list of laboratory normal ranges before shipment of 
trial drug. Any change in laboratory normal ranges during the trial will additionally be forwarded 
to Merck. Subjects without post baseline laboratory samples will be excluded from analyses with 
respect to values after the baseline. 
17.3 
Vital Signs 
The following parameters will be measured during the trial as safety evaluation: 
Blood Pressure 
Pulse rate 
Temperature 
Respiration Rate 
Markedly abnormality of vital signs will be identified in accordance with the criteria as follows: 
Vital Sign Parameter 
Unit 
Low  
High 
 
Systolic blood pressure 
mmHg 
< 85 mmHg  
> 139 mmHg  
 
Diastolic blood pressure 
mmHg 
< 50 mmHg 
> 90 mmHg  
 
Pulse rate 
Beats/min 
< 50 Beats/min  
> 100 Beats/min  
 
Temperature 
ͼC 
< 36 ͼC 
> 37.3 ͼC 
 
Systolic and diastolic blood pressures (mmHg), pulse rate (beats/min) measurements in supine 
position as well as body temperature (°C) and respiration (breaths/min) will be presented by 
descriptive statistics overall and by treatment sequence for each group at screening and end of 
study visit, and by group, treatment and time point for the values obtained during the treatment 
periods as raw data and change from baseline. 


Bisoprolol Amlodipine 5 mg/5 mg Combination Tablets 
Two-period Crossover Bioequivalence 
EMR200006-001 
 
 
 
 
 
Final Version 2.2 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
36/36 
 
 
Baseline is Period 1 Day 1 pre-dose (or Day-1 if missing at Day 1 pre-dose) for Period 1 and End 
of study visit and Period 2 Day 1 pre-dose for Period 2. All data will be listed by group, treatment 
sequence, subject, treatment, visit, and time point.  
All marked abnormal for vital signs values will be listed. Vital signs variables will be summarized 
in frequency tables based on a classification by treatment. 
All data will be listed by group, treatment sequence, subject, treatment, visit, and time point. 
17.4 
Other Safety or Tolerability Evaluations 
ECG 
The following parameters will be measured during the trial as safety evaluation: 
RR-
Interval 
PR-
Interval 
QRS-
Duration 
QT-
Interval 
QTc 
(Bazett) 
QTcF 
(Fridericia) 
Heart 
Rate 
Rhythm 
12-lead ECG parameters (Heart rate (beats/min), PR (ms), QRS (ms), QT (ms), RR (ms), QTcB 
(ms) and QTcF (ms)) will be presented by descriptive statistics overall and by treatment sequence 
for each group at screening and end of study visit, and by group, treatment and time point for the 
values obtained during the treatment periods as raw data and change from baseline. 12-lead ECG 
parameters and result of ECG will be listed in individual subject listing by group, treatment 
sequence, subject, visit, treatment and time point. All marked abnormal for ECG values also will 
be listed. 
Baseline is Period 1 Day-1 (or Screening if missing at Day-1) for Period 1 and End of study visit 
and Period 2 Day-1 for Period 2. 
Physical Examinations, and Chest X-ray  
Full physical examination and chest X-ray examination will be performed, abnormal values will 
be presented in listing only. 
18 
References 
1. Leopold G., Pabst J., Ungethüm W., et al. Basic Pharmacokinetic of Bisoprolol, a New 
Highly Beta1-selective Adrenoceptor Antagonist. Journal of Clinical Pharmacology 1986; 
26: 616-21. 
2. Chung M., Calcagni A., Glue P., et al. Effect of Food on the Bioavailability of Amlodipine 
Besylate/Atorvastatin Calcium Combination Tablet. Journal of Clinical Pharmacology 
2006; 46: 1212-6.