Clinical trial NCT03026088
Conditions: Heart Failure
Keywords: Chronic Heart Failure Bisoprolol Heart rate control
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2017-03-21; Completion date: 2018-12-26
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-arm, open label, interventional, multi-center, phase 4 pilot study.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Bisoprolol
Intervention descriptions: intervention 1: Participants received Bisoprolol orally, once daily at a dose of 1.25 milligram (mg) up to Weeks 3, and then it was up-titrated to 2.5 mg up to Week 6, 3.75 mg up to Week 10, 5 mg up to Week 14, 7.5 mg up to Week 18 and 10 mg up to Week 26.

Protocol documents:
Prot_SAP_000.pdf: 
A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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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 © 2016 by Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights 
reserved. 
 
 
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A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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I agree to conduct the clinical trial in accordance with this clinical trial protocol and in compliance 
with Good Clinical Practice and all applicable regulatory requirements. 
 
_____________________________________ 
____________________________ 
Signature 
Date of Signature 
Tel: 
 
Fax: 
 
E-mail:  
 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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I, the undersigned, am responsible for the conduct of the trial at this site and affirm that: 
x I understand and will conduct the trial according to the clinical trial protocol, any approved 
protocol amendments, ICH Good Clinical Practice (ICH Topic E6 GCP) and all applicable 
Health Authority requirements and national laws. 
x I will not deviate from the clinical trial protocol without prior written permission from the 
Sponsor and prior review and written approval from the Institutional Review Board or 
Independent Ethics Committee, except where necessary to prevent immediate danger to the 
subject. 
 
_____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
 
 
 
 
Tel: 
 
Fax: 
E-mail:  


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A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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Signature Page 
2
Protocol Table of Contents ..................................................................................................5
Table of In-Text Tables .......................................................................................................9
Table of In-Text Figures ......................................................................................................9
List of Abbreviations .........................................................................................................10
1
Synopsis ..............................................................................................12
2
Sponsor, Investigators and Trial Administrative Structure ................19
3
Background information .....................................................................20
3.1
Background .........................................................................................20
3.1.1                       Chronic Heart Failure .........................................................................20
3.1.2                       Elevated Heart Rate and CHF .............................................................20
3.2
Risk-benefit assessment ......................................................................22
4
Trial Objectives ..................................................................................23
4.1
Primary Objectives .............................................................................23
4.2
Secondary Objectives .........................................................................23
4.3

5
Investigational Plan ............................................................................24
5.1
Overall Trial Design and Plan ............................................................24
5.1.1
Major aspects of the trial ....................................................................24
5.1.2
Schematic diagram of the study plan ..................................................25
5.2
Discussion of Trial Design .................................................................25
5.2.1
Inclusion of Special Populations ........................................................26
5.3
Selection of Trial Population ..............................................................26
5.3.1
Inclusion Criteria ................................................................................26
5.3.2
Exclusion Criteria ...............................................................................26
5.4
Criteria for Initiation of Trial Treatment ............................................28
5.5
Criteria for Subject Withdrawal ..........................................................28
5.5.1
Withdrawal from Trial Therapy ..........................................................28
5.6
Premature Termination of the Trial ....................................................29
5.7
Definition of End of Trial ...................................................................30
CCI


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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6 
Investigational Medicinal Product and Other Drugs Used in the 
Trial .....................................................................................................30 
6.1 
Description of the Investigational Medicinal Product ........................30 
6.2 
Dosage and Administration ................................................................30 
6.3 
Assignment to Treatment Groups .......................................................31 
6.4 
Non-investigational Medicinal Products to be Used ..........................31 
6.5 
Concomitant Medications and Therapies ...........................................31 
6.5.1 
Permitted Medicines ...........................................................................31 
6.5.2 
Prohibited Medicines ..........................................................................32 
6.5.3 
Other Interventions .............................................................................32 
6.5.4 
Special Precautions .............................................................................32 
6.6 
Packaging and Labeling of the Investigational Medicinal Product ....33 
6.7 
Preparation, Handling, and Storage of the Investigational 
Medicinal Product ...............................................................................33 
6.8 
Investigational Medicinal Product Accountability .............................33 
6.9 
Assessment of Investigational Medicinal Product Compliance .........34 
6.10 
Blinding ..............................................................................................34 
6.11 
Emergency Unblinding .......................................................................34 
6.12 
Treatment of Overdose .......................................................................34 
6.13 
Medical Care of Subjects after End of Trial .......................................35 
7 
Trial Procedures and Assessments ......................................................35 
7.1 
Schedule of Assessments ....................................................................35 
7.2 
Demographic and Other Baseline Characteristics ..............................39 
7.2.1 
Medical history ...................................................................................39 
7.2.2 
Vital signs and physical examination .................................................39 
7.2.3 
Lab test items ......................................................................................40 
7.3 
Efficacy Assessments .........................................................................41 
7.4 
Assessment of Safety ..........................................................................42 
7.4.1 
Adverse Events ...................................................................................42 
7.4.2 
Pregnancy and In Utero Drug Exposure .............................................47 
7.4.3 
Clinical Laboratory Assessments .......................................................48 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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7.4.4
Vital Signs, Physical Examinations, and Other Assessments .............48
7.5
Pharmacokinetics ................................................................................48
7.6
Biomarkers ..........................................................................................48
7.7
Other Assessments ..............................................................................48
8
Statistics ..............................................................................................48
8.1
Sample Size ........................................................................................48
8.2
Randomization ....................................................................................49
8.3
Endpoints ............................................................................................49
8.3.1
Primary Endpoints ..............................................................................49
8.3.2
Secondary Endpoints ..........................................................................49
8.3.4                       Safety Endpoints .................................................................................49
8.3.5

8.4
Analysis Sets .......................................................................................50
8.5
Description of Statistical Analyses .....................................................51
8.5.1
General Considerations .......................................................................51
8.5.2
Analysis of Primary Endpoints ...........................................................51
8.5.3
Analysis of Secondary Endpoints .......................................................51
8.5.4
Analysis of Safety and Other Endpoints .............................................52
8.6
Interim and Additional Planned Analyses ..........................................52
9
Ethical and Regulatory Aspects ..........................................................52
9.1
Responsibilities of the Investigator ....................................................52
9.2
Subject Information and Informed Consent .......................................53
9.3
Subject Identification and Privacy ......................................................53
9.4
Emergency Medical Support and Subject Card ..................................54
9.5
Clinical Trial Insurance and Compensation to Subjects .....................54
9.6
Independent Ethics Committee or Institutional Review Board ..........54
9.7
Health Authorities ...............................................................................55
10
Trial Management ...............................................................................55
10.1
Case Report Form Handling ...............................................................55
10.2
Source Data and Subject Files ............................................................55
10.3
Investigator Site File and Archiving ...................................................56
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A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................57
10.5
Changes to the Clinical Trial Protocol ................................................57
10.6
Clinical Trial Report and Publication Policy ......................................57
10.6.1
Clinical Trial Report ...........................................................................57
11
Publication ..........................................................................................57
12
References Cited in the Text ...............................................................58
Appendix I   MINNESOTA LIVING WITH HEART FAILURE QUESTIONNAIRE    61
Appendix II  SF-36 QUESTIONNAIRE                                                                           65                                     
Appendix III   Schedule of Assessment                                                                            74          


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ACS 
AE 
Acute coronary syndrome  
Adverse Event 
ALT 
AST 
Bpm 
CRF 
CHF 
Alanine Aminotransferase  
Aspartate Aminotransferase 
beat per minute  
Case Report Form 
Chronic Heart Failure 
DBP 
ECG 
Diastolic Blood Pressure  
Electrocardiogram 
GCP 
Good Clinical Practice 
GFR 
HbA1c 
HIV 
IB 
Glomerular filtration rate  
hemoglobin A1c  
Human Immunodeficiency Virus  
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intention To Treat 
IVRS 
Interactive Voice Response System 
IVST 
LVEF 
LVEDD 
LVESD 
MLHFQ 
NDHP-
CCBs 
NTPro-BNP 
interventricular septal thickness  
Left ventricular ejection fraction  
left ventricle end-diastolic dimension  
left ventricular end-systolic dimension  
Minnesota Living with Heart Failure Questionnaire 
Non-dihydropyridine calcium channel blockers Pharmacodynamics 
 
N-terminal Pro-B-type Natriuretic Peptide 
NYHA 
New York Heart Association  


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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PGx 
Pharmacogenetics/Pharmacogenomics 
PK 
Pharmacokinetics 
SAE 
SBP 
Serious Adverse Event 
Systolic Blood Pressure 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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Merck Serono Co.,Ltd 
25F, Nuo Center Office, No.A2, Jiangtai Road, 
Chaoyang District, Beijing 100016, P.R.China 
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Dec, 2016 – Oct, 2018  
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www.clinicaltrials.gov (in process) 
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   To explore the heart rate control under different doses of Bisoprolol in Chinese Heart Failure 
patients with NYHA class II- IV 
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To explore other efficacy parameters and safety profile of Bisoprolol treatment in Chinese 
Heart Failure patients 
0HWKRGRORJ\A single-arm, interventional, multi-center pilot study to evaluate the efficacy 
of different dose of oral Bisoprolol on heart rate reduction in Chinese Chronic Heart Failure 
(CHF) patients with New York Heart Association (NYHA) class II – IV. 236 eligible CHF 
patients will be enrolled and given oral Bisoprolol up-titration treatment from 1.25mg to 2.5mg, 
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A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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3.75mg, 5mg, 7.5mg and 10mg during 26 weeks treatment period. For all the patients, 6-mins 
walk test and Questionnaires will be tested at both screening period and end of treatment. Other 
laboratory parameters will be collected at Screening, 6 weeks, 14 weeks and 26 weeks of 
treatment. There will be 8 visits from the beginning to the end of the study. 
3ODQQHGQXPEHURIVXEMHFWV236 
3ULPDU\HQGSRLQWVResting heart rate under 2.5mg ( 6±2weeks), 5mg (14±2weeks) and 10mg 
( 26±2weeks) of Bisoprolol vs at baseline 
6HFRQGDU\HQGSRLQWV
x Resting heart rate at 1.25mg (3±1weeks), 3.75mg (10±2weeks), and 7.5mg (18±2weeks) vs 
at baseline 
x Heart function detected by ultrasound cardiogram (UCG): including LVEF,left ventricular 
end-systolic dimension (LVESD) and left ventricle end-diastolic dimension (LVEDD), 
interventricular septal thickness (IVST) and E/A ration at baseline, 5mg (14±2weeks) and 
10mg (26±2weeks). 
x Systolic and diastolic blood pressure, symptoms and NYHA classification at all visits. 
x Proportion of patient number whose Resting heart rate ˘ 70 and ˚55 bpm at all visits 
x  Quality of life [based on the MOS item short from health survey (SF-36) and Minnesota 
Living with Heart Failure (MLHFQ)] at baseline and end of treatment.  
x 6-minute walk test and N-terminal Pro-B-type Natriuretic Peptide (NT Pro-BNP) at baseline 
and end of treatment. 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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x Average 24 hour heart rate, average daytime heart rate, average night time heart rate, 
proportion of arrhythmia, proportion of 24hour heart rate >70bpm, proportion of 24hour 
heart rate <55bpm at Baseline, 2.5mg (6±2weeks), 5mg(14±2weeks) and end of treatment 
(Based on 24 hour Holter); 
x Patient Compliance at the end of study; 
x All cause mortality, cardiac death, re-admission rate due to heart failure at the end of study 
x All AEs and SAEs  
3KDUPDFRNLQHWLFVNot Applicable
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A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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Inclusion criteria 

18-80 y, male or female 

Chronic Heart failure patients with medical history of cardiac disease or other related 
cardiovascular disease 

Left ventricular ejection fraction (LVEF) 40% 

NYHA class of II - IV  
      NYHA II˖Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in undue breathlessness, fatigue or palpitation. 
      NYHA III˖Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes undue breathlessness, fatigue or palpitation. 
      NYHA IV˖Unable to carry on any physical activity without discomfort. Symptoms 
at rest can be present.  If any physical activity is undertaken, discomfort increased. 

Signed Informed Consent Form (ICF) 
Exclusion criteria 

Acute coronary syndrome (ACS) within 3 months 

Under beta-blocker treatment for the last 2 weeks 

Under other medicine treatment which may affect heart rate, like Non-dihydropyridine 
calcium channel blockers (NDHP-CCBs) or ivabradine for the last 2 weeks; Under  
Digoxin treatment (>0.125mg) 

Uncontrolled Diabetes [hemoglobin A1c, (HbA1c) >7.5%]  

Severe or uncontrolled hypertension [resting Systolic Blood Pressure (SBP) >180 
mmHg, or resting Diastolic Blood Pressure (DBP) >110mmHg at screening period]   

Severe hypotension (resting SBP<90mmHgˈor resting DBP<50mmHg) 

Resting heart rate <60 beat per minute (bpm) 
x Any contradiction to Bisoprolol according to label, including:

acute heart failure or during episodes of heart failure decompensation requiring i.v. 
inotropic therapy 

cardiogenic shock 

AV block of second or third degree (without a pacemaker) 

sick sinus syndrome 

sinoatrial block 

slowed heart rate, causing symptoms (symptomatic bradycardia), 

decreased blood pressure, causing symptoms (symptomatic hypotension), 

severe bronchial asthma or severe chronic obstructive pulmonary disease 

sever forms of  peripheral arterial occlusive disease and Raynaud's syndrome 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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
untreated phaeochromocytoma 

metabolic acidosis 

hypersensitivity to bisoprololor to any of the excipients 

Severe Arrhythmia including atrial fibrillation, atrial flutter, ventricular fibrillation, 
ventricular flutter or ventricular tachycardia 

Significant valvular heart disease, congenital heart disease, pulmonary heart disease or 
perinatal heart disease 

Acute pulmonary edema 

Severe hepatic  dysfunction, defined as: 
-    Serum Alanine Aminotransferase (ALT) > triple the upper limit of the normal range; 
and/or 
- 
Serum Aspartate Aminotransferase (AST) > triple the upper limit of the normal 
value range and/or 

Severe renal dysfunction, defined as: 
- 
Serum creatinine > twice the upper limit of the normal range 
-     Chronic Kidney Disease (CKD) [glomerular filtration rate (GFR)<45 ml/min] 

hyperthyroidism or hypothyroidism

Severe infectious disease, eg. Human Immunodeficiency Virus (HIV) positive or active 
tuberculosis

Severe autoimmune disease, e.g. lupus erythematosus, multiple sclerosis 

Severe respiratory, digestive, hematological disease (including Anemia of Hb ˘
100g/L) or tumor  

Known to be hypersensitivity to Bisoprolol, or any of the excipient 

Substance or alcohol abuse 

Received heart transplantation or pacemaker implantation; revascularization treatment 
within 3 months; or plan to receive above treatment in 6months 

Currently undertaking other treatment that may affect the safety and/or efficacy 
evaluation, e.g. beta receptors agonists, etc. 

No legal ability or legal ability is limited 

Patients unlikely to cooperate in the study or with inability or unwillingness to give 
informed consent


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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
Child-bearing period women without effective contraceptive measures, pregnancy and 
lactation

Participation in another clinical trial within the past 90 days 

Other significant disease that in the Investigator’s opinion would exclude the subject 
from the trial
,QYHVWLJDWLRQDO0HGLFLQDO3URGXFWGRVHPRGHRIDGPLQLVWUDWLRQGRVLQJVFKHGXOH
Bisoprolol (Concor® Tablets 5.0mg/ Concor® Tablets 2.5mg) / Oral /once daily , 26 weeks  
Patients receive oral Bisoprolol, starting from 1.25mg (3±1weeks), up-titration to 2.5mg 
(6±2weeks), 3.75mg (10±2weeks), 5mg (14±2weeks), 7.5mg (18±2weeks) with an interval of 
2-4 weeks, then up-titration to 10mg after 8 weeks (26±2weeks).  
5HIHUHQFHWKHUDS\GRVHPRGHRIDGPLQLVWUDWLRQGRVLQJVFKHGXOH 
Standardized therapy recommended by &KLQD+HDUW)DLOXUH*XLGHOLQH 
3ODQQHGWULDODQGWUHDWPHQWGXUDWLRQSHUVXEMHFW 26 weeks 
6WDWLVWLFDOPHWKRGV
Ь It is supposed that the mean change from baseline of heart rate is -3.8bpm at week 6 
and -7.4bpm at week 14. The Standard Deviation is assumed to be 10bpm across time. 
Ь Based on assumption above about treatment effect and up-titration status at different 
visit, assuming 236 subjects under 15% dropout rate, distance from mean to limit of the 
95% confidence interval of the change from baseline of mean heart rate is 1.54 at week 
6 and 2.12 at week 14. Due the limit evidence at week 26, there is no robust 
extrapolation.  
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A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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Ь Linear regression will be applied with change from baseline of HR as dependent 
variable and baseline HR and age as covariates at week 6, 14 and 26, respectively. 
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Ь Same approach will be used for secondary continuous endpoints 
Descriptive statistics will be generated for all primary and secondary endpoints.  
 
 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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This clinical trial will be sponsored by: 
Merck Serono Co., Ltd.  
Address: 25F, Nuo Center Office, No.A2, Jiangtai Road, Chaoyang District, Beijing 100016, 
P.R.China  
Tel.: +86˄10˅59072473   Fax: +86˄10˅59072699 
The trial will be conducted at 10 sites in China. 
The Coordinating Investigator 
, CAMS and PUMC, represents 
all Investigators for decisions and discussions regarding this trial, consistent with the International 
Conference on Harmonisation (ICH) Topic E6 Good Clinical Practice (GCP; hereafter referred to 
as ICH GCP). The Coordinating Investigator will provide expert medical input and advice relating 
to trial design and execution and is responsible for the review and signoff of the clinical trial report.   
Signature pages for the Protocol Lead and the Coordinating Investigator as well as a list of Sponsor 
responsible persons are in Appendix. 
The trial will appear in the following clinical trial registries:  
Specify: 
x www.clinicaltrials.gov 
x Any special committees or boards, such as a Safety or Data Monitoring Committee, Endpoint 
Adjudication Committee, or Steering Committee (Tasks and memberships may be included 
here or cross referenced to relevant sections below. Full details may be provided in separate 
charter or appendix). Consult the appropriate contract or Alliance Manual to ensure that the 
correct terminology is used for applicable trials.  
x If a Safety Monitoring Committee is used, appropriate Merck Group SOPs or Working 
Instructions must be consulted to ensure compliance.  It is recommended that Global Drug 
Safety review the scientific content. 
x Responsibilities for drug supply and distribution, for example, the use of regional distribution 
centers 
To be determined (TBD) 
x Drug Safety responsibilities 
 Merck Serono,
 
x Role of the Sponsor 
x Any further important trial administrative information. 
PPD
PPD
PPD


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Details of structures and associated procedures will be defined in a separate Manual of Operations, 
which will be prepared under the supervision of the Clinical Trial Leader. 

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Heart failure (HF) is a clinical syndrome characterized by typical symptoms (e.g. breathlessness, 
ankle swelling and fatigue) that may be accompanied by signs (e.g. elevated jugular venous 
pressure, pulmonary crackles and peripheral oedema) caused by a structural and/or functional 
cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at 
rest or during stress [1]. CHF is the end stage and main death cause of most cardiovascular disease. 
Recent European data (ESC-HF pilot study) demonstrate that 12-month all-cause mortality rates 
for hospitalized and stable/ambulatory HF patients were 17% and 7%, respectively, and the 12-
month hospitalization rates were 44% and 32%, respectively [2]. The Cardiovascular Health Study, 
a US longitudinal cohort of community-dwelling older adults, reported 1-, 5-, and 10-year 
mortality rates of 19%, 56%, and 83%, respectively, after the onset of HF [3]. 
 
The prevalence of CHF is approximately 1–2% of the adult population in developed countries, 
rising to 10% among people˚70 years of age [4-6]. In China, CHF was reported to 0.9 %, 0.7% 
and 1.0% for the general population, the males and females, respectively. Also, prevalence of CHF 
increased substantially with aging, which is 0.4%, 1.0%, 1.3 % and 1.3 % in 35 -44, 45 -54, 55-
64, 65 -74 years of age groups, respectively [7] . 
The large societal burden of CHF presents a substantial financial challenge to the health care 
system, with estimated annual direct costs of $2.8 billion in Canada [8]. In the United States, 
estimated yearly expenditures of $30.7 billion are expected to rise to $69 billion/y by 2030 [9], with 
proportional increases forecast in China over this time frame as well. 
 
(OHYDWHG+HDUW5DWHDQG&+)
Increased resting HR has been shown to be a negative prognostic indicator in failure [10].The 
BEAUTIFUL study found that patients with coronary artery disease (CAD), left ventricular 
systolic dysfunction, and a heart rate (HR) >70 bpm had increased cardiovascular mortality, 
increased HF hospitalization, myocardial infarction, and need for coronary revascularization[11]. 
ȕ-blockers work in chronic HF by antagonizing the effects of the sympathetic nervous system. 
This results in decreased heart rate, increased diastolic filling times, and decreased peripheral 
vascular resistance. They have been used in the treatment of CHF for decades but their benefits 
were only confirmed through randomized controlled trials in the late 1990s and early 2000s. The 
most important trials were the CIBIS II (bisoprolol) [12], COPERNICUS (carvedilol) [13], and 
MERIT-HF (metoprolol CR/XL) [14] trials. When looked at in combination, more than 9000 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
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patients were studied. Results showed a relative risk reduction (RRR) in mortality versus placebo 
of approximately 34 % and a RRR in heart failure hospitalization of 28–36% [15]. 
A recent meta-analysis of 23 trials looking at the use of ȕ-blockers in the treatment of heart failure 
found that the magnitude of heart rate reduction is significantly associated with survival benefit, 
independent of the actual dosage used. Every HR reduction of 5 bpm resulted in an 18 % reduction 
in mortality [16]. Beta blockers could reduce heart rate and this is consistently reflected in current 
guidelines for CHF. It was recommended to control the heart rate to 55-60 bpm for these patients 
in most clinical guidelines, LQFOXGLQJ &KLQHVH+HDUW)DLOXUH*XLGHOLQH [17]. 
3.1.3 Bisoprolol titration in CHF 
Bisoprolol is a beta-1 selective blocker with the highest selectivity for this receptor, in doses less 
than 10 mg it has very little or no effect on beta-2 receptors. Bisoprolol was first tested in CHF in 
the CIBIS I trial which enrolled 641 patients and showed improvement in functional class, less 
hospitalizations for heart failure and a trend to improved survival. The much larger randomized 
CIBIS II assigned 2647 patients with class III or IV HF and an LVEF <40% to Bisoprolol or 
placebo; the patients also received standard therapy with diuretics and ACE inhibitors. After an 
average follow-up of 1.4 years, the trial was prematurely stopped when the benefits were observed 
in the active treatment group: significant reduction in total all-cause mortality (11.8 versus 17.3 
percent] that was independent of the severity or cause of HF. This benefit was primarily due to a 
reduction in SCD (3.6 versus 6.3%, 3< 0.001], with a non-significant trend toward fewer deaths 
from HF; significant 15% reduction in hospital admissions for any cause and a 30% reduction in 
admissions for HF (3< 0.0001). CIBIS II showed that both baseline heart rate and its change over 
time are prognostic markers, with lower baseline heart rate and greater reductions being better [12]. 
Not only did Bisoprolol increase survival and reduce hospital admissions in CIBIS II, it also cut 
the cost of care in so doing [18]. 
A recent study reported an attempt to Bisoprolol up-titrate toward guideline-recommended dosages 
offers additional benefit in terms of restoration of LV systolic function and remodeling for HF 
patients with systolic dysfunction [19]. 
Although clinical trials have consistently shown overall high beta-blocker tolerability, many 
patients even in the trial setting were unable to achieve target beta-blocker doses. For example, the 
mean dose of carvedilol in the Carvedilol Prospective Randomized Cumulative Survival 
(COPERNICUS) trial [13] was 37 mg compared with the target dose of 50 mg/d and, in the 
Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF) [14], metoprolol 
succinate dose on average was 159 mg as compared with the target dose of 200 mg. Only about 
two thirds of the patients in both these trials reached target doses. These results not only suggest 
that heart rate may be a major determinant of the ability to titrate beta-blocker dose and their 
tolerability, but that it may also serve as a therapeutic target for beta-blocker therapy. 
It has been shown that beneficial effects of beta-blockers are related to the magnitude of heart rate 
reduction [20], which favors the selective beta1-adrenoceptor-blocker bisoprolol [21].In CIBIS-ELD 
trial [22], indicates the heart rate after up-titration, predicted all-cause mortality risk in elderly 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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patients with chronic heart failure. Achieved resting heart rate between 55 and 64 bpm bisoprolol 
up-titration was associated with lower long-term mortality risk and the lowest frequency of adverse 
events. For every 10 bpm. increase in heart rate, a corresponding 19% increase was seen in all-
cause mortality after adjusting for age, sex, beta-blocker pre-treatment, ventricular function, heart 
rate, and NYHA class at baseline. This finding is consistent with results from a large prospective 
observational survey, where 26% of the patients were uptitrated to the target dose [23]. 
However, up-titration is frequently associated with challenging, dose-related side effects such as 
hypotension, bradycardia, dizziness, and sometimes worsening of concomitant COPD, 
predominantly with non-selective beta-blockers [24-26]. As a consequence, recommended target 
doses can rarely be reached. A recent analysis demonstrates that among other dose-related effects, 
heart rate reduction was the major factor limiting beta-blocker up-titration to recommended doses 
[27]. 
To sum up, data from various clinical studies have demonstrated elevated resting heart rate is 
associated with increased morbidity and mortality in patients with chronic systolic heart failure 
(CHF). It has also been shown that titration of doses of BBs improves outcomes of morbidity and 
mortality in CHF patients with reduced ejection fraction. However, there is only few studies to 
investigate the heart rate reduction during Bisoprolol up-titration in Chinese CHF. It remains 
unclear about the magnitude of heart rate reduction during Bisoprolol up-titration in Chinese CHF 
and this study serves as the first one to explore. This study will mainly investigate the heart control 
efficacy of oral Bisoprolol during the up-titration, as well as other efficacy, safety and compliance 
in treatment of Chinese CHF patients. 

5LVNEHQHILWDVVHVVPHQW
a. The pre-clinical, clinical-pharmacological and clinical results together form a rational basis for 
the planned clinical trial. 
b. The risk-benefit relationship has been carefully considered in the planning of the trial. Based 
on the pre-clinical and clinical data available to date, the conduct of the trial is considered 
justifiable using the dose(s) and dosage regimen(s) of the Investigational Medicinal Product 
(IMP) as specified in this clinical trial protocol. The trial shall be discontinued in the event of 
any new findings that indicate a relevant deterioration of the risk-benefit relationship and 
would render continuation of the trial unjustifiable. 
c. Based on the pre-clinical and clinical data available to date, the conduct of the trial is regarded 
as justifiable at the planned dose ranges. 
d.  Besides the study drug Bisoprolol, all subjects need to undergo ECG, UCG and Holter test both 
at baseline and end of treatment. These tests are common used in clinical practice and have 
been proven to be safe and well tolerant. For subjects suffer from CHF with all current standard 
therapies, the free test of cardiac function may allow both health care givers and subjects 
themselves know better with current condition and guide their treatment; 


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
7ULDO2EMHFWLYHV

3ULPDU\2EMHFWLYHV
To explore the heart rate control (the change of heart rate) under different doses of Bisoprolol in 
Chinese Heart Failure patients with NYHA class II- IV. 

6HFRQGDU\2EMHFWLYHV
To explore other efficacy parameters and safety profile of Bisoprolol treatment in Chinese Heart 
Failure patients. Secondary endpoints include˖ 
x Resting heart rate at 1.25mg (3±1weeks), 3.75mg (10±2weeks), and 7.5mg (18±2weeks) vs at 
baseline 
x Heart function detected by UCG: including LVEF, left ventricular end-systolic dimension 
(LVESD) and left ventricle end-diastolic dimension (LVEDD), interventricular septal thickness 
(IVST) and E/a ration at baseline, 5mg (14±2weeks) and 10mg (26±2weeks). 
x Systolic and diastolic blood pressure, symptoms and NYHA classification at all visits. 
x Proportion of patient number whose Resting heart rate ˘ 70 and ˚55 bpm at all visits 
x  Quality of life [based on the MOS item short from health survey (SF-36) and Minnesota Living 
with Heart Failure (MLHFQ)] at baseline and end of treatment.  
x 6-minute walk test and N-terminal Pro-B-type Natriuretic Peptide (NT Pro-BNP) at baseline 
and end of treatment. 
x Average 24 hour heart rate, average daytime heart rate, average night time heart rate, proportion 
of arrhythmia, proportion of 24hour heart rate >70bpm, proportion of 24hour heart rate 
<55bpm at Baseline, 2.5mg (6±2weeks), 5mg(14±2weeks) and end of treatment (Based on 24 
hour Holter); 
x Patient compliance at the end of study; 
x All cause mortality, cardiac death, re-admission rate due to heart failure at the end of study 
x All AEs and SAEs 

2WKHU2EMHFWLYHV
Not applicable. 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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
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This is a single-arm, non-randomized, open label, interventional, multi-center, phase IV pilot study 
5.1.1
Major aspects of the trial 
There will be a 2-week screening period when baseline lab tests, electrocardiogram (ECG), 
ultrasound cardiogram (UCG), Holter and Questionnaires will be conducted in this period. Patients 
who met all the inclusion criteria but none of the exclusion criteria will be enrolled. Totally 236 
patients will be enrolled in the study. The anticipated period of the whole study is approximately 
21 months including a 14-month recruitment period and a 26-week treatment period. 
All enrolled patients will start to take oral Bisoprolol 1.25mg, once daily. All other cardiovascular 
medicines must be stabilized at least one month before screening period and could be continued. 
There will be 8 visits in total. Oral Bisoprolol needs to be started from 1.25mg (3±1weeks), up-
titrated to 2.5mg (6±2weeks), 3.75mg (10±2weeks), 5mg (14±2weeks), 7.5mg (18±2weeks) with 
an interval of 3-4 weeks, then up-titrated to 10 mg after 8 weeks (26±2weeks). Symptoms, ECG 
and safety endpoints will be assessed at all visits. Lab tests will be assessed at 2.5mg (6±2weeks), 
5mg (14±2weeks) and 10mg (26±2weeks). Please refer to Figure 1 for a detailed study diagram. 
The Up-titration should be judged by the investigator and patients must well tolerate the previous 
dose. Intolerance may be defined as:  
(1)Resting heart rate ˘55bpm; 
(2) Blood pressure ˘ 90/50 millimetre(s) of mercury(mmHg); 
(3)Adverse Event (AE) lead to intolerance as judged by the investigator; 
The primary endpoint is: 
Resting heart rate under 2.5mg (6±2weeks), 5mg (14±2weeks) and 10mg (26±2weeks) of 
Bisoprolol vs at baseline 
The secondary endpoints include: 
z Resting heart rate at 1.25mg (3±1weeks), 3.75mg (10±2weeks), and 7.5mg (18±2weeks) vs at 
baseline 
z Heart function detected by UCG: including LVEF, left ventricular end-systolic dimension 
(LVESD) and left ventricle end-diastolic dimension (LVEDD), interventricular septal 
thickness (IVST) and E/a ration at baseline, 5mg (14±2weeks) and 10mg (26±2weeks). 
z Systolic and diastolic blood pressure, symptoms and NYHA classification at all visits. 


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z Proportion of patient number whose Resting heart rate ˘ 70 and ˚55 bpm at all visits 
z  Quality of life [based on the MOS item short from health survey (SF-36) and Minnesota Living 
with Heart Failure (MLHFQ)]   at baseline and end of treatment.  
z 6-minute walk test and N-terminal Pro-B-type Natriuretic Peptide (NT Pro-BNP) at baseline 
and end of treatment. 
z Average 24 hour heart rate, average daytime heart rate, average night time heart rate, 
proportion of arrhythmia, proportion of 24hour heart rate  >70bpm, proportion of 24hour heart 
rate  <55bpm at Baseline, 2.5mg (6±2weeks), 5mg(14±2weeks) and end of treatment (Based 
on 24 hour Holter); 
z Patient Compliance at the end of study; 
z All cause mortality, cardiac death, re-admission rate due to heart failure at the end of study 
z All AEs and SAEs. 
Medical history, physical examination, lab tests, ECG and UCG should be conducted in a 2-week 
screening period (Visit 1). If patients have conducted lab tests, ECG or Echocardiogram in this 
period, but not specifically for this trial, the result could also be used for the screening. Totally 236 
patients who meet all the inclusion criteria but none of the exclusion criteria will be enrolled in the 
study.  
5.1.2
Schematic diagram of the study plan 
See Appendix III. 

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This is a single-arm, non-randomized, open label, interventional, multi-center, phase IV study. 
Beta blockers are one of the cornerstones of heart failure pharmacotherapy since they were proven 
to reduce morbidity and mortality and consequently recommended by clinical guidelines. 
Therefore it will violate the basic ethical benefits when a placebo control group was set in this 
trial. Because the main purpose of this trial is to explore the heart rate control under different doses 
of Bisoprolol, but not head-to-head comparison of heart rate control level, no other active control 
drug group was set. Due to good efficacy of Bisoprolol and aim of this trial, open label and non-
randomized design was adopted. Resting heart rate is chosen for the assessment of primary 
endpoints because it is an easy and applicable standard to guide clinical practice recommended by 
all guidelines for CHF treatment. Bisoprolol is proven to improve prognosis for chronic heart 
failure patients with good efficacy on heart rate control. However, there are few clinical evidences 
to show Bisoprolol’s effect on resting heart rate control data during up-titration in CHF patients in 
China before. In order to investigate Bisoprolol’s effect on heart rate control during dose up-


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
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titration, and to collect more information and parameters for further studies, this interventional, 
pilot study is designed.   

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Not applicable 

6HOHFWLRQRI7ULDO3RSXODWLRQ
Only patients meeting all inclusion criteria and none of the exclusion criteria may be enrolled into 
the trial as subjects. Prior to performing any trial assessment that is not part of the subject’s routine 
medical care, the Investigator will ensure that the subject or the subject’s legal representative has 
provided written informed consent following the procedure described in Section 9.2. 

,QFOXVLRQ&ULWHULD
For inclusion in the trial, all of the following inclusion criteria must be fulfilled: 

18-80 y, male or female 

Chronic Heart failure patients with medical history of cardiac disease or other related 
cardiovascular disease 

Left ventricular ejection fraction (LVEF) 40% 

NYHA class of II - IV  
      NYHA II˖Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in undue breathlessness, fatigue or palpitation. 
      NYHA III˖Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes undue breathlessness, fatigue or palpitation. 
      NYHA IV˖Unable to carry on any physical activity without discomfort. Symptoms at 
rest can be present.  If any physical activity is undertaken, discomfort increased. 

Signed Informed Consent Form (ICF) 

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Subjects are not eligible for this trial if they fulfill any of the following exclusion criteria: 

Acute coronary syndrome (ACS) within 3 months 

Under beta-blocker treatment for the last 2 weeks 

Under other medicine treatment which may affect heart rate, like Non-dihydropyridine 
calcium channel blockers (NDHP-CCBs) or ivabradine for the last 2 weeks; Under  
Digoxin treatment (>0.125mg) 

Uncontrolled Diabetes [hemoglobin A1c, (HbA1c) >7.5%]  


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
Severe or uncontrolled hypertension [resting Systolic Blood Pressure (SBP) >180 mmHg, 
or resting Diastolic Blood Pressure (DBP) >110mmHg at screening period]   

Severe hypotension (resting SBP<90mmHgˈor resting DBP<50mmHg) 

Resting heart rate <60 beat per minute (bpm) 
x Any contradiction to Bisoprolol according to label, including:

acute heart failure or during episodes of heart failure decompensation requiring i.v. 
inotropic therapy 

cardiogenic shock 

AV block of second or third degree (without a pacemaker) 

sick sinus syndrome 

sinoatrial block 

slowed heart rate, causing symptoms (symptomatic bradycardia), 

decreased blood pressure, causing symptoms (symptomatic hypotension), 

severe bronchial asthma or severe chronic obstructive pulmonary disease 

sever forms of  peripheral arterial occlusive disease and Raynaud's syndrome 

untreated phaeochromocytoma 

metabolic acidosis 

hypersensitivity to bisoprololor to any of the excipients 

Severe Arrhythmia including atrial fibrillation, atrial flutter, ventricular fibrillation, 
ventricular flutter or ventricular tachycardia 

Significant valvular heart disease, congenital heart disease, pulmonary heart disease or 
perinatal heart disease 

Acute pulmonary edema 

Severe hepatic  dysfunction, defined as: 
-    Serum Alanine Aminotransferase (ALT) > triple the upper limit of the normal range; 
and/or 
- 
Serum Aspartate Aminotransferase (AST) > triple the upper limit of the normal value 
range and/or 

Severe renal dysfunction, defined as: 
- 
Serum creatinine > twice the upper limit of the normal range 
-     Chronic Kidney Disease (CKD) [glomerular filtration rate (GFR)<45 ml/min] 

hyperthyroidism or hypothyroidism 

Severe infectious disease, eg Human Immunodeficiency Virus (HIV) positive or active 
tuberculosis 

Severe autoimmune disease, e.g. lupus erythematosus, multiple sclerosis 

Severe respiratory, digestive, hematological disease (including Anemia of Hb ˘100g/L) 
or tumor  


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
Known to be hypersensitivity to Bisoprolol, or any of the excipient 

Substance or alcohol abuse 

Received heart transplantation or pacemaker implantation; revascularization treatment 
within 3 months; or plan to receive above treatment in 6months 

Currently undertaking other treatment that may affect the safety and/or efficacy evaluation, 
e.g. beta receptors agonists, etc. 

No legal ability or legal ability is limited 

Patients unlikely to cooperate in the study or with inability or unwillingness to give 
informed consent 

Child-bearing period women without effective contraceptive measures, pregnancy and 
lactation 

Participation in another clinical trial within the past 90 days 

Other significant condition that in the Investigator’s opinion would exclude the subject 
from the trial 

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All subjects can initiate trial treatment as long as the enrollment is confirmed. 

&ULWHULDIRU6XEMHFW:LWKGUDZDO
Subjects are free to discontinue the trial at any time without giving their reasons. A subject must 
be withdrawn in any of the following event: 
z Withdrawal of the subject’s consent. 
z    Participation in any other interventional trial during the duration of this trial 
z Withdrawal of the Investigational Medicinal Product 
If a subject has failed to attend scheduled trial visits, the reasons must be collected and recorded 
in CRF by investigator as completely and accurately as possible. 
In any case, the appropriate Case Report Form (CRF) section must be completed. 

:LWKGUDZDOIURP7ULDO7KHUDS\
A subject must be withdrawn from trial therapy if any of the following occurs:  
x Occurrence of an exclusion criterion which is clinically relevant and affects the subject’s safety, 
if discontinuation is considered necessary by the Investigator and/or Sponsor. 
x Therapeutic failure requiring urgent additional drug, or dose adjustment of other drugs that 
investigator believes would affect the elevation of the safety and/or efficacy, including but not 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
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limited to ACEI, ARB, Statins, ȕ-blockers, CCB, ivabradine, and trimetazidine, also other long-
term Chinese traditional medicines for the treatment of CHF. 
x Occurrence of adverse events, if discontinuation of trial drug is desired or considered necessary 
by the Investigator and/or the subject. 
x Occurrence of pregnancy. 
x Use of a non-permitted concomitant drug, as defined in Section 6.5.2, where the predefined 
consequence is withdrawal from the IMP. 
x Non-compliance. 
x Subject withdrew consent 
x Subject lost to follow up 
x Participation in another clinical trial   
x Any events that unacceptably endanger the safety of the subject. 

3UHPDWXUH7HUPLQDWLRQRIWKH7ULDO
The whole trial may be discontinued prematurely in the event of any of the following: 
x New information leading to unfavorable risk-benefit judgment of the IMP, e.g. due to: 
x Evidence of inefficacy of the IMP, 
x Occurrence of significant previously unknown adverse reactions or unexpectedly high 
intensity or incidence of known adverse reactions, or 
x Other unfavorable safety findings. 
1RWHHYLGHQFHRILQHIILFDF\PD\DULVHIURPWKLVWULDORUIURPRWKHUWULDOVXQIDYRUDEOHVDIHW\
ILQGLQJVPD\DULVHIURPFOLQLFDORUQRQFOLQLFDOH[DPLQDWLRQVHJWR[LFRORJ\
x Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical reasons. 
x Poor enrollment of subjects making completion of the trial within an acceptable time frame 
unlikely. 
x Discontinuation of development of the Sponsor’s IMP. 
x Withdrawal of the IMP from the market for safety reasons. 
Ethics Committee and Institutional Review Boards (IRBs) will be informed about the 
discontinuation of the trial in accordance with applicable regulations. 
The whole trial may be terminated or suspended upon request of Health Authorities. 
The clinical trial may be terminated prematurely or suspended at the request of Health Authorities 
or if new safety or efficacy information leads to an unfavorable risk benefit judgment for any IMP. 
The Sponsor may discontinue the trial if it becomes unjustifiable for medical or ethical reasons, 


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for poor enrollment, or because of discontinuation of clinical development of an IMP or 
withdrawal of an IMP or comparator from the market for safety reasons. 
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) 
will be informed about the discontinuation of the trial in accordance with applicable regulations. 

'HILQLWLRQRI(QGRI7ULDO
A clinical trial protocol may not be considered closed as long as: 
x Any subject is still receiving any IMP, 
x Visits specified by the protocol are still taking place, 
x Procedures or interventions according to the protocol are still being undertaken in any subject,  
x The post-treatment follow up period, defined in the clinical trial protocol as being part of the 
trial, has not yet been completed for any subject. 
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,QYHVWLJDWLRQDO0HGLFLQDO3URGXFWDQG2WKHU'UXJV8VHGLQ
WKH7ULDO
The term “Investigational Medicinal Product” refers to an active substance or a placebo being 
tested or used as a reference therapy in a clinical trial, including products that have a marketing 
authorization but are formulated, packaged, or administered differently from the authorized form, 
used for an unauthorized indication, or used to gain further information about the authorized form.   

'HVFULSWLRQRIWKH,QYHVWLJDWLRQDO0HGLFLQDO3URGXFW
Bisoprolol (Concor® Tablets, 2.5mg), film-coated tablets are white and heart-shaped with a break-
line on both sides; Bisoprolol (Concor® Tablets, 5mg), film-coated tablets are yellowish-white 
and heart-shaped with a break-line on both sides; manufactured by Merck Serono Co. Ltd. 
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'RVDJHDQG$GPLQLVWUDWLRQ
During the whole study duration, enrolled subjects would take Concor® orally, Once daily. The 
whole tablet is to be swallowed with water, not chewed. 
Patients receive oral Bisoprolol, starting from 1.25mg (3±1weeks), up-titration to 2.5mg 
(6±2weeks), 3.75mg (10±2weeks), 5mg (14±2weeks), 7.5mg (18±2weeks) with an interval of 2-4 
weeks, then up-titration to 10mg after 8 weeks (26±2weeks). 



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Not Applicable. 

1RQLQYHVWLJDWLRQDO0HGLFLQDO3URGXFWVWREH8VHG
No other drugs are mandatory in this trial.  
The standard treatment for CHF should include ACEI/ARB, ȕ-blockers, aldosterone antagonists 
and diuretic if condition permits.  

&RQFRPLWDQW0HGLFDWLRQVDQG7KHUDSLHV
All concomitant medications taken by the subject during the trial, from the date of signature of 
informed consent are to be recorded in the appropriate section of the CRF, noting the name, dose, 
duration and indication of each drug. Nondrug interventions and any changes to a concomitant 
medication or other intervention should also be recorded in the CRF. 

3HUPLWWHG0HGLFLQHV
Any medications (other than those excluded by the clinical trial protocol) that are considered 
necessary for the subjects’ welfare and will not interfere with the trial medication may be given at 
the Investigator’s discretion. Rescue medications may be administered to address ineffective 
treatment, anticipated adverse reactions or anticipated emergency situations. 
Patients should take all the current standard therapy for CHF. It should include ACEI/ARB, ȕ-
blockers, aldosterone antagonists and diuretics if permits. Other medicines for CHF treatment are 
also permitted, such as trimetazidine, and other Chinese traditional medicines, such as Tong Xin 
Luo capsule.  


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The Investigator will record all concomitant medications taken by the subject during the trial, from 
the date of signature of informed consent, in the appropriate section of the CRF. 
Any additional concomitant therapy that becomes necessary during the trial and any change to 
concomitant drugs must be recorded in the corresponding section of the CRF, noting the name, 
dose, duration and indication of each drug. 

3URKLELWHG0HGLFLQHV
NDHP-CCBs, ivabradine, beta receptors agonists and Digoxin (>0.125mg) treatment which may 
influence the heart control level of Bisoprolol. 
Any other additional concomitant therapy that becomes necessary during the trial and any change 
to concomitant drugs must be recorded in the corresponding section of the CRF, noting the name, 
dose, duration and indication of each drug. 
If the administration of a non-permitted concomitant drug becomes necessary during the trial, e.g., 
because of AEs, the subject should withdraw from the study, the data should only be used for 
safety. 
The product label should be consulted with regards to combinations not recommended and 
combinations to be used with caution. 
 

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If the subjects undergone PCI, CABG, pacemaker implantation or heart transplantation during the 
study, they should withdraw from the trial. If patients need to perform other surgeries that need 
hospitalization, they should withdraw from the trial.  

6SHFLDO3UHFDXWLRQV
(1)For drugs that are dispensed in a press-through package (PTP), instruct the patient to remove 
the drug from the package prior to use (It has been reported that, if the PTP sheet is accidentally 
swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, resulting in 
perforation, and possible severe complications such as mediastinitis); 
(2)Instruct the patient to avoid moisture and to keep the medicine in a cool place; 
(3)Keep out of children; 
(4)Expired drug should not be used. 


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
3DFNDJLQJ DQG /DEHOLQJ RI WKH ,QYHVWLJDWLRQDO 0HGLFLQDO
3URGXFW
All IMPs will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines. 
Packaging: 2.5/5mg tablets, boxes of 10 tablets in PTP.  
Labeling: “use only for clinical study MS200006-0039” will be labelled on the box by an idpendent 
Company. 
Packaging and labeling will be in accordance with applicable local regulatory requirements and 
applicable GMP Guidelines. 
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3UHSDUDWLRQ +DQGOLQJ DQG 6WRUDJH RI WKH ,QYHVWLJDWLRQDO
0HGLFLQDO3URGXFW
Bisoprolol should be stored in room temperature and avoid moisture. 

,QYHVWLJDWLRQDO0HGLFLQDO3URGXFW$FFRXQWDELOLW\
The Storage Manager at the trial site who was assigned by the Head of the trial site is responsible 
for ensuring IMP accountability, including reconciliation of drugs and maintenance of records.  
After the conclusion of the trial contract with the trial site, the Sponsor (or designee) may deliver 
the IMP to the Storage Manager at the trial site. 
x Upon receipt of IMP, the responsible person will check for accurate delivery and acknowledge 
receipt by signing or initialing and dating the appropriate documentation provided by Sponsor 
and returning it to the Sponsor. A copy will be archived for the Investigator Site File. 
x IMP dispensing will be carefully recorded by the Storage Manager on the appropriate drug 
accountability forms provided by sponsor so that accurate records will be available for 
verification by the Sponsor Monitor at each monitoring visit. 
x IMP accountability records will include the following: 
x Confirmation of IMP receipt, in good condition and in the defined temperature range. 
x The inventory of IMP provided for the clinical trial and prepared at the site. 
x IMP accountability forms (provided by the Sponsor and completed at the site). 
x The use of each dose by each subject. 
x The disposition (including return, if applicable) of any unused IMP. 
x Dates, quantities, batch numbers, vial numbers, expiry dates, formulation (for IMP prepared 
at the site), and the individual subject trial numbers. 


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The Storage Manager should maintain records that adequately document the following: 
x The subjects received the doses specified by the clinical trial protocol/amendment(s); and 
x All IMP provided by the Sponsor were fully reconciled. 
The Investigator site should maintain records, which adequately document that subjects were 
provided the doses specified in this protocol, and all IMPs provided were fully reconciled. 
Unused IMP must not be discarded or used for any purpose other than the present trial. No IMP 
that is dispensed to a subject may be re-dispensed to a different subject. 
The Sponsor Monitor will periodically collect the IMP accountability forms and will check all the 
IMPs to be returned or discarded before arrangements for returns (both unused and used 
containers) are made at the trial site or their destruction by the trial site is authorized. 

$VVHVVPHQWRI,QYHVWLJDWLRQDO0HGLFLQDO3URGXFW&RPSOLDQFH
Subjects should be instructed to bring with them to each visit both opened and unopened IMP 
packages, in order to allow the assessment of compliance with trial treatment. IMP administration 
must be recorded in the CRF, as applicable. 
Medication possession ratio (MPR) is used to assess the medicine compliance. MPR is defined as 
the actual drug number taken by the patients divided by the drug number should be taken by the 
patients according to the protocol. MPR between 80%-100% is defined as good compliance. 
Medication rate of <80% or >100% is defined as insufficient compliance. 

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Not Applicable. 

(PHUJHQF\8QEOLQGLQJ
Not applicable. 

7UHDWPHQWRI2YHUGRVH
An overdose is defined as any dose greater than the highest daily dose included in a clinical trial 
protocol or planned for an individual subject enrolled in the trial. Even if it does not meet other 
criteria for an SAE, any overdose must be recorded in the trial medication section of the CRF and 
reported to Drug Safety in an expedited manner using the SAE Report Form, and following the 
procedure in Section 7.4.  
For monitoring purposes, any case of overdose – whether or not associated with an adverse event 
(serious or non-serious) – must be reported to the Sponsor’s Global Drug Safety department in an 
expedited manner using the appropriate reporting form (see Section 7.4.1.4). 


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In a clinical trial conducted in European CAD patients, the dose of Bisoprolol was 20mg daily, 
and patients showed good tolerance of the medicine and less coronary events at 1 year follow-
up[28].While the maximum recommended dose is 10 mg once daily in China.

0HGLFDO&DUHRI6XEMHFWVDIWHU(QGRI7ULDO
After a subject has completed the trial or has withdrawn early, usual treatment will be 
administered, if required, in accordance with the trial site’s standard of care and generally accepted 
medical practice and depending on the subject’s individual medical needs. 
The Sponsor will not provide any additional care to subjects after they leave the trial because such 
care should not differ from what is normally expected for patients with [the medical condition].  

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
6FKHGXOHRI$VVHVVPHQWV
Day 0 is defined as the first day of enrollment and oral Bisoprolol administration in subject. 
The trial procedures and assessment contents are as follow: 
1. Screening Visit/Visit 1: Day-14 to Day 0: this visit entails the following: 
Before any procedures that are related to the trial is undertaken, informed consent of the patient 
should be obtained. Thereafter, basic information of the patient will be obtained and patients are 
screened for eligibility based on the inclusion and exclusion criteria. 
a) Record birth date, gender, height, weight, BMI, waist circumference, current medical 
condition and past medical history, including concomitant therapies 
b) Perform physical examinations, including vital signs (systolic and diastolic blood pressure, 
resting heart rate) 
c) NYHA classification and clinical symptoms 
d) ECG: heart rate; sinus rhythm/arrhythmia, specify; cardiac hypertrophy(yes/no); 
abnormal ST-T change(yes/no),if yes, specify; 
e) Echocardiography: LVEFˈLVESD, LVEDD, IVST and E/A ratio 
f)
Routine blood tests: full blood count (white blood cells, neutrophils, red blood cells, 
hemoglobin and platelets),   liver function (ALT, AST), renal function (Bun, Cr), fasting 
blood glucose and blood lipids (TC, TG, LDL-C and HDL-C), electrolyte (K, Na) , NT 
Pro-BNP(data within -28 days of liver function, renal function, fasting blood glucose and 
blood lipids are accepted)  


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g) Routine urine test(PH, Specific gravity, Protein, Glucose, Ketone, Nitrite, Leukocytes, 
Hemoglobin, Red blood cells, Bilirubin)ˈurine pregnancy test 
h) Questionnaires: SF-36 and MLHFQ 
i)
6-minute walk test 
j)
Holter: heart rate (24 hour, day time, night time); sinus rhythm/arrhythmia, specify; 
proportion of  24 hour heart rate ˚70bpm, proportion of  24hour heart rate ˘55 bpm; 
proportion of arrhythmia 
k) Record adverse events, concomitant drugs/procedure; 
l)
Signed the informed consent form 
2. Visit 2 (Baseline) Day 0: this visit entails the following: 
a) Perform physical examinations, including vital signs (systolic and diastolic blood pressure, 
resting heart rate); Weight 
b) NYHA classification and clinical symptoms; 
c) ECG: heart rate; sinus rhythm/arrhythmia, specify; cardiac hypertrophy(yes/no); 
abnormal ST-T change(yes/no),if yes, specify; 
d) Record adverse events, concomitant drugs/procedure and use of study drug; 
3. Visit 3 (1.25mg measurement) 3±1week: This visit entails the following: 
a) Perform physical examinations, including vital signs (systolic and diastolic blood 
pressure, resting heart rate); Weight 
b) NYHA classification and clinical symptoms; 
c) ECG: heart rate; sinus rhythm/arrhythmia, specify; cardiac hypertrophy(yes/no); 
abnormal ST-T change(yes/no),if yes, specify; 
d) Record adverse events, concomitant drugs/procedure and use of study drug; 
4. Visit 4 (2.5mg measurement) 6±2week: This visit entails the following: 
a) Perform physical examinations, including vital signs (systolic and diastolic blood 
pressure, resting heart rate); Weight 
b) NYHA classification and clinical symptoms; 


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c) ECG: heart rate; sinus rhythm/arrhythmia, specify; cardiac hypertrophy(yes/no); 
abnormal ST-T change(yes/no),if yes, specify; 
d) Routine blood tests: full blood count (white blood cells, neutrophils, red blood 
cells, hemoglobin and platelets)  
e) Routine urine test(PH, Specific gravity, Protein, Glucose, Ketone, Nitrite, 
Leukocytes, Hemoglobin, Red blood cells, Bilirubin) 
f)
Holter: heart rate (24 hour, day time, night time); sinus rhythm/arrhythmia, 
specify; proportion of  24 hour heart rate ˚70bpm, proportion of  24hour heart 
rate ˘55 bpm; proportion of arrhythmia 
g) Record adverse events, concomitant drugs/procedure and use of study drug; 
5. Visit 5 (3.75mg measurement) 10±2weeks: This visit entails the following: 
a) Perform physical examinations, including vital signs (systolic and diastolic blood pressure, 
resting heart rate); Weight 
b) NYHA classification and clinical symptoms; 
c) ECG: heart rate; sinus rhythm/arrhythmia, specify; cardiac hypertrophy(yes/no); 
abnormal ST-T change(yes/no),if yes, specify; 
d) Record adverse events, concomitant drugs/procedure and use of study drug; 
6. Visit 6 (5mg measurement) 14±2weeks: This visit entails the following: 
a) Perform physical examinations, including vital signs (systolic and diastolic blood 
pressure, resting heart rate); Weight 
b) NYHA classification and clinical symptoms; 
c) ECG: heart rate; sinus rhythm/arrhythmia, specify; cardiac hypertrophy(yes/no); 
abnormal ST-T change(yes/no),if yes, specify; 
d) Routine blood tests: full blood count (white blood cells, neutrophils, red blood 
cells, hemoglobin and platelets)  
e) Routine urine test (PH, Specific gravity, Protein, Glucose, Ketone, Nitrite, 
Leukocytes, Hemoglobin, Red blood cells, Bilirubin) 
f)
Echocardiography: LVEFˈLVESD, LVEDD, IVST and E/A ratio 


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g) Holter: heart rate (24 hour, day time, night time); sinus rhythm/arrhythmia, 
specify; proportion of  24 hour heart rate ˚70bpm, proportion of  24hour heart 
rate ˘55 bpm; proportion of arrhythmia 
h) Record adverse events, concomitant drugs/procedure and use of study drug; 
7. Visit 7 (7.5mg measurement) 18±2weeks: This visit entails the following: 
a) Perform physical examinations, including vital signs (systolic and diastolic blood pressure, 
resting heart rate); Weight 
b) NYHA classification and clinical symptoms; 
c) ECG: heart rate; sinus rhythm/arrhythmia, specify; cardiac hypertrophy(yes/no); 
abnormal ST-T change(yes/no),if yes, specify; 
d) Record adverse events, concomitant drugs/procedure and use of study drug; 
8. Visit 8 (10mg measurement) 26±2weeks: This visit entails the following: 
a) Perform physical examinations, including vital signs (systolic and diastolic blood 
pressure, resting heart rate); Weight, BMI, waist circumference 
b) NYHA classification and clinical symptoms 
c) ECG: heart rate; sinus rhythm/arrhythmia, specify; cardiac hypertrophy(yes/no); 
abnormal ST-T change(yes/no),if yes, specify; 
d) Echocardiography: LVEF, LVESD, LVEDD, IVST and E/A ratio 
e) Routine blood tests: full blood count (white blood cells, neutrophils, red blood cells, 
hemoglobin and platelets),   liver function (ALT, AST), renal function (Bun, Cr), 
fasting blood glucose and blood lipids (TC, TG, LDL-C and HDL-C), electrolyte (K, 
Na) , NT Pro-BNP  
f)
Routine urine test (PH, Specific gravity, Protein, Glucose, Ketone, Nitrite, 
Leukocytes, Hemoglobin, Red blood cells, Bilirubin) 
g) Questionnaires: SF-36 and MLHFQ 
h) 6-minute walk test 
i)
Holter: heart rate (24 hour, day time, night time); sinus rhythm/arrhythmia, specify; 
proportion of  24 hour heart rate ˚70bpm, proportion of  24hour heart rate ˘55 bpm; 
proportion of arrhythmia 


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j)
Record adverse events, concomitant drugs/procedure and use of study drug; 
k) Patient Compliance 
Prior to performing any trial assessments not part of the subject’s routine medical care, the 
Investigator will ensure that the subject or the subjects legal representative has provided written 
informed consent according to the procedure described in Section 9.2. 

'HPRJUDSKLFDQG2WKHU%DVHOLQH&KDUDFWHULVWLFV
At screening, the following demographic data will be collected: date of birth, sex (gender), race, 
ethnicity. 
Major demographic information is as follows:  
1.  Birth date  
2. Gender  
3. Race  
7.2.1
Medical history 
The following information will be collected for the medical history of the subjects: 
  Chronic Heart Failure 
1. Basic information: Initial cardiovascular disease (start date, stop date/ongoing); start date of 
heart failure; frequency of heart failure acceleration in recent 6 month ( how many times/ 
6months) and how many times result to hospitalization when applicable; previous treatment 
procedures (PCI or CABG), time of the procedure; history of MI or not, if yes, the time need 
to be recorded; 
2. Current medicine treatment at screening period of the study: name, dose, initiation date 
(month/year) 
7.2.1.1
  Other medical history 
1. History of hypertension/ heart failure/ diabetes; the severity of these diseases; the current 
medicine therapy at the screening period of the study; 
2. Other medical histories and concomitant medicines. 
7.2.2
Vital signs and physical examination 
Vital signs and physical examination should at least include the following items: 


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1. General status: 
Heart rate (resting heart rate) measurement: sit rest for 5 minutes, no smoking, no excitatory food 
and beverage such as tea and coffee for 30 minutes, measurements are taken at sitting position for 
a continuous record of 3 minutes. Heartbeats in each minute are calculated and averaged to obtain 
the resting heart rate. 
Blood pressure measurement: sit rest for 5 minutes, no smoking, no excitatory food and beverage 
such as tea and coffee for 30 minutes, measurements are taken at sitting position, with the elbow 
at the same level with the heart. Diastolic blood pressure is recorded at the fifth Korotkoff sound, 
repeated after 2 minutes and averaged. If the difference in diastolic blood pressure readings is > 
5mmHg, measurement is repeated again after 2 minutes, and the 3 readings are averaged. 
2. Physical examination of the respiratory system 
3. Physical examination of the cardiovascular system 
4. Physical examination of other systems 
5. Body mass index: body weight (Kg)/Height 2(m2) 
6. Measurement of waist circumstance: At screening visit, under fasting, standing, calm breathing 
conditions, feet apart 25-30cm, waist circumstance is measured at horizontal position at the 
midpoint of iliac spine and the 12th rib, with measuring tape close to but not press the skin, accurate 
to 0.1cm. 
7.2.3
Lab test items 
Lab examination should include at least the following items: hematological examination, and 
echocardiography need to be done at the screening visit and last visit; ECG need to be done at 
every visit. 
1. Hematology tests (all these lab test need to be done by fast in the morning): 
a) Full blood count: red blood cell count, neutrophils, hemoglobin, white blood cell count and 
platelet count 
b) Liver function (ALT, AST) 
c) Kidney function (BUN, Cr) 
d) Fasting blood glucose 
e) Blood lipid levels (TC, TG, HDL-C, LDL-C) 
f) NT Pro-BNP 


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g) Electrolyte (K, Na) 
2. Routine urine test(PH, Specific gravity, Protein, Glucose, Ketone, Nitrite, Leukocytes, 
Hemoglobin, Red blood cells, Bilirubin), urine pregnancy test 
2. ECG: heart rate; sinus rhythm/arrhythmia, depict what kind of arrhythmia; cardiac hypertrophy 
(yes/no); abnormal ST-T change (yes/no); 
3. Echocardiography: to measure LVEFˈLVESD,LVEDD, IVST and E/A ratio 
4. 6-min walk test: is a practical simple test that requires a 100-ft hallway but no exercise 
equipment or advanced training for technicians. Walking is an activity performed daily by all but 
the most severely impaired patients. This test measures the distance that a patient can quickly walk 
on a flat, hard surface in a period of 6 minutes.  
5. SF-36 and MLHFQ˖ the detailed description of questionnaire test will be described in 
Appendix II and II. 
6. Holter: Average 24 hour heart rate, average daytime heart rate, average night time heart rate, 
proportion of arrhythmia, proportion of 24hour heart rate  >70bpm, proportion of 24hour heart rate  
<55bpm. 

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7.3.1 Resting heart rate 
Resting heart rate obtained from the method described above. 
7.3.2 Echocardiography 
LVEFˈLVESD, LVEDD,  IVST and E/A ratio. 
7.3.3 SF-36 questionnaire 
The SF-36 assesses 8 health status domains (ie, physical functioning, role physical functioning, 
role emotional functioning, mental health, vitality, social functioning, bodily pain, and general 
health). Scale scores are obtained by summing the items together within a domain, dividing this 
outcome by the range of scores and then transforming the raw scores to a scale from 0 to 100 (See 
appendix II). 
7.3.4 The Minnesota Living with Heart Failure Questionnaire (MLHF)  
The questionnaire has 21 items. Questions assess the impact of frequent physical symptoms of 
heart failure - shortness of breath, fatigue, swollen ankles and difficulty sleeping. Other items ask 
about the effects of heart failure on physical and social functions including walking and climbing 
stairs, household work, need to rest, working to earn a living, going places away from home, doing 


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things with family or friends, recreational activities, sports or hobbies, sexual activities, eating 
foods he patient likes and mental and emotional functions of concentration and memory, worry, 
loss of self control, and being a burden to others. Since treatments might have direct effects on a 
patient’s life in addition to their effects on symptoms and functional limitations of heart failure, 
questions about side effects of medications, hospital stays and costs of care were included to help 
measure the overall impact of treatments for heart failure on patients’ quality of life. 
Scoring: Simple summation of responses. Total score (min = 0, max = 105), physical dimension 
(min= 0, max = 40) emotional dimension (min = 0, max = 25); the higher the summed score, the 
worse is the impact of heart failure on a patient’s quality of life (See Appendix I).  

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The safety profile of the IMP will be assessed through the recording, reporting and analysis of 
baseline medical conditions, adverse events (AEs), physical examination findings including vital 
signs and laboratory tests. 
Comprehensive assessment of any apparent toxicity experienced by each subject will be performed 
from the time of giving informed consent and throughout the trial. The investigator will report any 
AEs, whether observed by the Investigator or reported by the subject (see Section 7.4.1.2).  
The reporting period for AEs is described in Section (UURU5HIHUHQFHVRXUFHQRWIRXQG. 
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An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product, regardless of 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.  
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself. 
The Investigator is required to grade the severity or toxicity of each AE. 
Investigators will reference the National Cancer Institute - Common Terminology Criteria for AEs 
(CTCAE), version 4.0 (publication date: 28 May 2009), a descriptive terminology that can be used 
for AE reporting.  
A general grading (severity/intensity; hereafter referred to as severity) scale is provided at the 
beginning of the above referenced document, and specific event grades are also provided. 


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If a particular AE’s severity is not specifically graded by the guidance document, the Investigator 
is to use the general NCI-CTCAE definitions of Grade 1 through Grade 5 following his or her best 
medical judgment. 
The 5 general grades are: 
x Grade 1 or Mild 
x Grade 2 or Moderate 
x Grade 3 or Severe  
x Grade 4 or Life-threatening   
x Grade 5 or Death  
According to Sponsor convention, any clinical AE with severity of Grade 4 or 5 must also be 
reported as an SAE. However, a laboratory abnormality of Grade 4, such as anemia or neutropenia, 
is considered serious only if the condition meets one of the serious criteria described above. 
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event. Only, if no cause of death can be reported (for example, sudden 
death, unexplained death), the death per se might then be reported as an SAE. 
Investigators must also systematically assess the causal relationship of AEs to IMP using the 
following definitions.  
8QUHODWHG Not 
reasonably 
related 
to 
the 
IMP. 
AE 
could 
not 
medically 
(pharmacologically/clinically) be attributed to the IMP under study in this clinical 
trial protocol. A reasonable alternative explanation must be available. 
5HODWHG 
Reasonably related to the IMP. AE could medically (pharmacologically/clinically) 
be attributed to the IMP under study in this clinical trial protocol.  
$EQRUPDO/DERUDWRU\)LQGLQJVDQG2WKHU$EQRUPDO,QYHVWLJDWLRQDO)LQGLQJV
Abnormal laboratory findings and other abnormal investigational findings (for example, 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 a laboratory abnormality fulfills these criteria, the identified medical condition 
(for example, anemia, increased ALT) must be reported as the AE rather than the abnormal value 
itself. 
x
$GYHUVH5HDFWLRQ$'5 


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In accordance with GCP, adverse drug reaction is an adverse event considered related to drug 
treatment. 
6HULRXV$GYHUVH(YHQW
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
x Results in death. 
x Is life-threatening. 
NOTE: The term “life-threatening” refers to an event in which the subject is at risk of death at the 
time of the event; not an event that hypothetically might have caused death if it was more severe. 
x Requires inpatient hospitalization or prolongation of existing hospitalization. 
x Results in persistent or significant disability/incapacity. 
x Is a congenital anomaly/birth defect. 
x Is otherwise considered as medically important. 
Note: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered as SAEs when, based upon appropriate medical judgment, they 
may jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is also 
considered a SAE as described in Section 7.4.1.4. 
(YHQWVWKDW'R1RW0HHWWKH'HILQLWLRQRIDQ6$(
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (for 
example, an overnight stay to facilitate chemotherapy and related hydration therapy application) 
are not considered as SAEs. However, all events leading to unplanned hospitalizations or 
unplanned prolongation of an elective hospitalization (for example, undesirable effects of any 
administered treatment) must be documented and reported as SAEs. 
(YHQWV1RWWR%H&RQVLGHUHGDV$(V6$(V 
Medical conditions present at the initial trial visit that do not worsen in severity or frequency during 
the trial are defined as Baseline Medical Conditions, and are NOT to be considered AEs. 
However, if adverse signs or symptoms occur in association with disease progression then these 
should be recorded as AEs.  


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Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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
0HWKRGVRI5HFRUGLQJDQG$VVHVVLQJ$GYHUVH(YHQWV
At each trial visit, the subject will be queried on changes in his/her 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.  
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the CRF. 
Among these AEs, all SAEs or non-serious ADRs must be additionally documented and reported 
using an Adverse Event Safety Report Form as described in Section 7.4.1.4. 
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates [and times, when it is important to assess the time of AE onset relative to the 
recorded treatment administration time]), its severity, its causal relationship with the trial 
treatment, any other potential causal factors, any treatment given or other action taken (including 
dose modification or discontinuation of the IMP) and its outcome. In addition, serious cases should 
be identified and the appropriate seriousness criteria documented. If an AE constitutes a DLT this 
has to be documented accordingly 
Specific guidance can be found in the CRF Completion and Monitoring Conventions provided by 
the Sponsor. 

'HILQLWLRQRIWKH$GYHUVH(YHQW5HSRUWLQJ3HULRG
The adverse event reporting period for safety surveillance begins when the subject is included in 
the trial (date of first signature of informed consent) and continues until the 30-Day Post-Treatment 
Safety Follow-up. 
Any SAE assessed as related to IMP must be reported whenever it occurs, irrespective of the time 
elapsed since the last administration of IMP. 

3URFHGXUH IRU 5HSRUWLQJ 6HULRXV $GYHUVH (YHQWV DQG 1RQ
VHULRXV$GYHUVH'UXJ5HDFWLRQV
In the event of any new SAE or new non-serious ADR occurring during the reporting period, the 
Investigator must immediately (within a maximum 24 HOURS after becoming aware of the 
event) report to Merck Serono Global Drug Safety Department by telephone, by fax or by 
emails.  
Names, addresses, telephone and fax numbers for AE reporting as follows: 
0HUFN6HURQR*OREDO'UXJ6DIHW\'HSDUWPHQW
$GGUHVV0HUFN.*D$)UDQNIXUWHU6WUDH''DUPVWDGW*HUPDQ\
(PDLO*OREDO'UXJ6DIHW\#PHUFNJURXSFRP

)D[


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7HOHSKRQH
 
When an SAE or its follow-up information is reported by telephone, a written report must be sent 
immediately thereafter by fax or e-mail. Names, addresses, and telephone and fax numbers for 
SAE reporting will be included in the trial-specific SAE Report Form. 
Reporting procedures and timelines are the same for any new information on a previously reported 
SAE (= follow-up). 
All written reports should be transmitted with the Adverse Event Safety Report Form (Clinical 
Trials), which must be completed by the Investigator following specific completion instructions. 
The AE section of the CRF must be completed, and a copy of the information must be transmitted 
along with the Adverse Event Safety Report Form (Clinical Trials). Relevant pages from the CRF 
may be provided in parallel (for example, medical history, concomitant drugs). Additional 
documents may be provided by the Investigator, if available (for example, laboratory results, 
hospital report, autopsy report). In all cases, the information provided on the SAE Report Form 
must be consistent with the data about the event recorded in the CRF. 
The Investigator/reporter must respond to any request for follow-up information (for example, 
additional information, outcome, final evaluation, other records where needed) or to any question 
the Sponsor may have on the AE within the same timelines as those noted above for initial reports. 
This is necessary to ensure that the Sponsor promptly assesses the event and, where applicable, 
meets the strict regulatory timelines with expedited safety reporting. 
Requests for follow-up will usually be made via the responsible Monitor. Although in exceptional 
circumstances the Global Drug Safety department may contact the Investigator directly for further 
information or to discuss the event. 

6DIHW\ 5HSRUWLQJ WR +HDOWK $XWKRULWLHV ,QGHSHQGHQW (WKLFV
&RPPLWWHHVDQG,QYHVWLJDWRUV
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations. 
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving trial subjects to the IEC/IRB that approved the 
trial. 
In accordance with the ICH GCP guidelines, the Sponsor will inform Investigator of “findings that 
could adversely affect the safety of subjects, impact the conduct of the trial or alter the IEC’s 
approval/favorable opinion to continue the trial.” In particular and in line with respective 
applicable 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 the safety reports 
PPD


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in the Investigator Site File. National regulations with regard to Safety Report notifications to 
Investigators will be taken into account. 
When specifically required by regulations and guidelines, the Sponsor will provide appropriate 
Safety Reports directly to the concerned lead EC/IRB and will maintain records of these 
notifications. When direct reporting is not clearly defined by national or site-specific regulations, 
the Investigator will be responsible for promptly notifying the concerned IEC/IRB of any Safety 
Reports provided by the Sponsor and of filing copies of all related correspondence in the 
Investigator Site File. 

0RQLWRULQJRI6XEMHFWVZLWK$GYHUVH(YHQWV
AEs are recorded and assessed continuously throughout the trial (see Section (UURU5HIHUHQFH
VRXUFHQRWIRXQG) and are assessed for final outcome at the 30-Day Follow-up Safety Visit. All 
SAEs ongoing at the 30-Day Follow-up Safety Visit (note any other type or category of AE to be 
followed up) must be monitored and followed up by the Investigator until stabilization or 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 also the responsibility of the 
Investigator to ensure that any necessary additional therapeutic measures and follow-up procedures 
are performed.  

3UHJQDQF\DQG,Q8WHUR'UXJ([SRVXUH
Pregnancies are not considered per se to be adverse events. However, all pregnancies with an 
estimated conception date during the period defined in Section 7.4.1.3 must be recorded by 
convention in the AE page/section of the CRF. The same rule applies to pregnancies in female 
subjects and to pregnancies in female partners of male subjects. The Investigator must notify the 
Sponsor 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 7.4.1.4.  
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 of these outcomes using the Pregnancy Report Form, and 
if an abnormal outcome occurs, the SAE Report Form 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 7.4.1.4, 
while normal outcomes must be reported within 45 days from 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 must be notified without delay 
and the subject must be followed as mentioned above. 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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
&OLQLFDO/DERUDWRU\$VVHVVPHQWV
All clinical laboratory assessments have been detailed listed in Section 7.1 and Section 7.2.

9LWDO6LJQV3K\VLFDO([DPLQDWLRQVDQG2WKHU$VVHVVPHQWV
All vital signs, physical examinations, and other assessments have been detailed listed in Section 7.1 
and Section 7.2. 

3KDUPDFRNLQHWLFV
Not applicable.  

%LRPDUNHUV
Not applicable.  

2WKHU$VVHVVPHQWV
Not Applicable. 

6WDWLVWLFV

6DPSOH6L]H
A single-arm, interventional, multi-center pilot study to evaluate the efficacy of different dose of 
oral Bisoprolol on heart rate reduction in Chinese Chronic Heart Failure (CHF) patients with New 
York Heart Association (NYHA) class II – IV.  
Suppose the difference of Mean change from baseline follows normal distribution, and the 
following assumptions are made to determine the sample size: 
Ь It is supposed that the mean change from baseline of heart rate is -3.8bpm at week 6 and -
7.4bpm at week 14. The Standard Deviation is assumed to be 10bpm across time. 
Ь Based on assumption above about treatment effect and up-titration status at different visit, 
assuming 236 subjects under 15% dropout rate, distance from mean to limit of the 95% 
confidence interval of the change from baseline of mean heart rate is 1.54 at week 6 and 
2.12 at week 14. Due the limit evidence at week 26, there is no robust extrapolation.  


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
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
5DQGRPL]DWLRQ
Not Applicable. 

(QGSRLQWV

3ULPDU\(QGSRLQWV
Resting heart rate under 2.5mg (6±2weeks), 5mg (14±2weeks) and 10mg (26±2weeks) of 
Bisoprolol vs at baseline. 

6HFRQGDU\(QGSRLQWV
z Resting heart rate at 1.25mg (3±1weeks), 3.75mg (10±2weeks), and 7.5mg (18±2weeks) vs at 
baseline 
z Heart function detected by UCG: including LVEF, left ventricular end-systolic dimension 
(LVESD) and left ventricle end-diastolic dimension (LVEDD), interventricular septal 
thickness (IVST) and E/a ration at baseline, 5mg (14±2weeks) and 10mg (26±2weeks). 
z Systolic and diastolic blood pressure, symptoms and NYHA classification at all visits. 
z Proportion of patient number whose Resting heart rate ˘ 70 and ˚55 bpm at all visits 
z Quality of life [based on the MOS item short from health survey (SF-36) and Minnesota Living 
with Heart Failure (MLHFQ)]   at baseline and end of treatment.  
z 6-minute walk test and N-terminal Pro-B-type Natriuretic Peptide (NT Pro-BNP) at baseline 
and end of treatment. 
z Average 24 hour heart rate, average daytime heart rate, average night time heart rate, 
proportion of arrhythmia, proportion of 24hour heart rate  >70bpm, proportion of 24hour heart 
rate  <55bpm at Baseline, 2.5mg (6±2weeks), 5mg(14±2weeks) and end of treatment (Based 
on 24 hour Holter); 
z Patient Compliance at the end of study; 
z All cause mortality, cardiac death, re-admission rate due to heart failure at the end of study 
6DIHW\(QGSRLQWV
Assessment of safety endpoints will include: 
y
All AEs and SAEs  


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
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y
All deaths. 
y
All AEs and SAEs occurred during treatment period. 
y
Vital signs (heart rate, and blood pressure). 
y
Clinical laboratory assessments from hematology and biochemistry samples. 
y
Drug exposure. 

)XUWKHU(QGSRLQWVRI,QWHUHVW
No further endpoints of interest. 

$QDO\VLV6HWV
y
6FUHHQ3RSXODWLRQ
The screening population will include all subjects who provide written informed consent and who 
undergo screening assessments, regardless of treatment status in the trial. 
y
)XOO$QDO\VLV6HW)$6
x Enrolled 
x Presence of measurement at baseline and time point of interest 
y
3HU3URWRFRO33
The per protocol set of subjects is defined as a subset of the FAS analysis set who are compliant 
with the clinical trial protocol, and is characterized by criteria such as: 
x The completion of a certain minimal exposure to the trial drug. 
x The absence of any major clinical trial protocol violations.    
Major protocol violation will be defined in the Statistical Analysis Plan (SAP). 
The PP population will be identified before database lock and will be used to test the primary 
endpoint as sensitivity analysis..
y
6DIHW\
The safety population will include all subjects who received at least one dose of trial treatment.  


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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
'HVFULSWLRQRI6WDWLVWLFDO$QDO\VHV

*HQHUDO&RQVLGHUDWLRQV
Statistical analysis will be performed using CRF data obtained until database lock. The FAS 
population will be used primarily to present baseline characteristics and analyze efficacy data. 
Selected efficacy analyses will be repeated for the PP population.  
If confidence intervals are to be calculated, 2-sided with significance level 0.05 is used, unless 
otherwise specified. 
Continuous variables will be summarized using descriptive statistics, i.e., number of subject (N), 
mean, median, standard deviation (S.D.), 25th and 75th percentile (Q1-Q3), minimum and 
maximum. Counts of missing observation will be included in the denominator and presented as a 
separate category. 
For all variables, the baseline value will be defined as the last measurement taken prior to the 
first administration of treatment drug. 
The dropouts and missing data will not be imputed. 
 

$QDO\VLVRI3ULPDU\(QGSRLQWV
Liner regression will be applied with change from baseline of HR as dependent variable and 
baseline HR and age as covariates at week 6, 14 and 26, respectively. 
Furthermore, the mean value, standard deviation and 95% confidence interval (CI) will be 
calculated for the difference between HR at baseline and after week 6, 14 and 26 weeks treatment. 
This analysis will be done both in FAS population and PP population. 

$QDO\VLVRI6HFRQGDU\(QGSRLQWV
Same approach will be used for secondary continuous endpoints. For secondary endpoints such as 
SBP, DBP, NT-Pro BNP, left ventricular ejection fraction (EF%), left ventricular end-systolic 
dimension (LVESD), left ventricular wall thickness, E/A ratio,6min walk test, questionnaires 
score, paired t test will be used to compare the difference of these parameters between baseline 
and after 26 week treatment directly, furthermore, 95% confidence interval will also be calculated. 
The SF-36 assesses 8 health status domains (ie, physical functioning, role physical functioning, 
role emotional functioning, mental health, vitality, social functioning, bodily pain, and general 
health). Scale scores are obtained by summing the items together within a domain, dividing this 
outcome by the range of scores and then transforming the raw scores to a scale from 0 to 100 [29-
31]. 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
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The questionnaire of Minnesota Living with Heart Failure Questionnaire (MLHF) has 21 items. 
Questions assess the impact of frequent physical symptoms of heart failure - shortness of breath, 
fatigue, swollen ankles and difficulty sleeping. Other items ask about the effects of heart failure 
on physical and social functions including walking and climbing stairs, household work, need to 
rest, working to earn a living, going places away from home, doing things with family or friends, 
recreational activities, sports or hobbies, sexual activities, eating foods the patient likes and mental 
and emotional functions of concentration and memory, worry, loss of self control, and being a 
burden to others. Since treatments might have direct effects on a patient’s life in addition to their 
effects on symptoms and functional limitations of heart failure, questions about side effects of 
medications, hospital stays and costs of care were included to help measure the overall impact of 
treatments for heart failure on patients’ quality of life. 
Scoring: Simple summation of responses. Total score (min = 0, max = 105), physical dimension 
(min= 0, max = 40) emotional dimension (min = 0, max = 25); the higher the summed score, the 
worse is the impact of heart failure on a patient’s quality of life [32-34]. 

$QDO\VLVRI6DIHW\DQG2WKHU(QGSRLQWV
All safety analyses will be performed on the safety population. AEs will be classified by Primary 
System Organ Class (SOC) and Preferred Term (PT) according to the Medical Dictionary for 
Regulatory Activities (MedDRA). 
The incidence of treatment-emergent adverse events will be tabulated. In addition, the incidence 
of treatment-emergent AEs considered related to study medication (i.e., those AEs judged by the 
investigator to be either certainly, probably or possibly related to study medication and those with 
missing casual relationship) as well as the incidence of treatment-emergent AEs with severe or 
very severe intensity will also be reported. 
All SAEs and those AEs leading to permanent discontinuation of study medication will be reported. 
Summary statistics will be provided for body weight, vital signs, ECG parameters and safety-
related laboratory analyses. Summaries will consist of the number of patients assessed, sample 
mean value observed together with its associated standard error, sample mean change versus 
baseline together with its associated standard error and 95% confidence interval. 

,QWHULPDQG$GGLWLRQDO3ODQQHG$QDO\VHV
No formal interim analysis is planned. 

(WKLFDODQG5HJXODWRU\$VSHFWV

5HVSRQVLELOLWLHVRIWKH,QYHVWLJDWRU
The Investigator is responsible for the conduct of the trial at the site and will ensure that the trial 
is performed in accordance with this protocol, the ethical principles outlined in the Declaration of 
Helsinki, ICH GCP, and any other applicable regulations. The Investigator must ensure that only 
subjects who have given informed consent are included in the trial. 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
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
6XEMHFW,QIRUPDWLRQDQG,QIRUPHG&RQVHQW
An unconditional prerequisite for each subject prior to participation in the trial is written informed 
consent, which 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 subject information sheet must be prepared in the local language in accordance with ICH GCP 
and 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 will inform the subject 
verbally of all pertinent aspects of the trial, using language chosen so that the information can be 
fully and readily understood by laypersons. The subject will be given sufficient time to read the 
information and the opportunity to ask questions and to request additional information and 
clarification. 
After the information is provided by the Investigator, the Informed Consent Form must be signed 
and dated by the subject and the Investigator. This process should be recorded in medical history 
as documentation. 
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived 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 Informed Consent Form 
should be provided to the subject prior to participation. 
Whenever important new information becomes available that may be relevant to informed consent, 
the Investigator will revise the subject information sheet and any other written information to be 
provided to the subjects and submit them to the EC/IRB for review and opinion. Using the 
approved revised subject information sheet and other written information, The Investigator will 
explain the changes to the previous version to each trial subject and obtain new written consent for 
continued participation in the trial. The subject will be given sufficient time to read the information 
and the opportunity to ask questions and to request additional information and clarification about 
the changes. 

6XEMHFW,GHQWLILFDWLRQDQG3ULYDF\
A unique number will be assigned to each subject, immediately after informed consent has been 
obtained. This number will serve as the subject’s identifier in the trial as well as in the clinical trial 
database. All subject data collected in the trial will be stored under the appropriate subject number. 
Only the Investigator will be able to link trial data to an individual subject via an identification list 
kept at the site. For each subject, original medical data will be accessible for the purposes of source 
data verification by the Monitor, audits and regulatory inspections, but patient confidentiality will 
be strictly maintained. 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
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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. 
For subject registration, the investigator will fill out the subject registration form completely and 
send it to the subject registration center by fax. 
When it is confirmed that the subject meets all inclusion criteria and does not meet any of the 
exclusion criteria, the subject registration center registers the subject and informs the Investigator 
and the Sponsor of the registration number by fax. If the subject is ineligible for the trial and is 
therefore not given a registration number, a subject number is allocated and documented. 

(PHUJHQF\0HGLFDO6XSSRUWDQG6XEMHFW&DUG
Subjects enrolled in this clinical trial will be provided with Emergency Medical Support cards 
supplied by the Sponsor for use during trial participation in order to provide clinical trial subjects 
with a way of identifying themselves as participating in a clinical trial and to give health care 
providers access to any information about this participation that may be needed to determine the 
course of medical treatment for the subject.  
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. If the Investigator is available when an event occurs, they will answer 
any questions. Any subsequent action will follow the standard process established for 
Investigators. 
In cases where the Investigator is not available, Merck Serono provides the appropriate means to 
contact a Sponsor physician. This includes the provision of a 24-hour contact number at a call 
center, whereby the health care providers will be given access to the appropriate Sponsor physician 
to assist with the medical emergency and to provide support for the subject concerned. 

&OLQLFDO7ULDO,QVXUDQFHDQG&RPSHQVDWLRQWR6XEMHFWV
Insurance coverage will be provided for each country participating in the trial. Insurance conditions 
will meet good local standards, as applicable. 

,QGHSHQGHQW(WKLFV&RPPLWWHHRU,QVWLWXWLRQDO5HYLHZ%RDUG
Prior to commencement of the trial at a given site, this clinical trial protocol will be submitted 
together with its associated documents (Informed Consent Form) to the responsible EC/IRB for its 
favorable opinion or approval, which will be filed in the Investigator Site File. A copy will be filed 
in the Sponsor Trial Master File at Sponsor. 
The EC/IRB will be asked to document the date of the meeting at which the favorable opinion or 
approval was given and the members and voting members present. Written evidence of favorable 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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opinion or approval that clearly identifies the trial, the clinical trial protocol version and the Subject 
Information and Informed Consent Form version reviewed should be provided. Where possible, 
copies of the meeting minutes should be obtained. 
Amendments to this clinical trial protocol will also be submitted to the concerned EC/IRB, before 
implementation of substantial changes (see Section 10.5). Relevant safety information will be 
submitted to the EC/IRB during the course of the trial in accordance with national regulations and 
requirements. 
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As a China local post-market study, the health authorities do not release the clinical trial approval 
letter, the clinical trial protocol and any applicable documentation (for example, Investigational 
Medicinal Product Dossier, Subject Information and Informed Consent Form). 
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The main purpose of the eCRF is to obtain data required by the clinical trial protocol in a complete, 
accurate, legible and timely fashion. The data in the eCRF should be consistent with the relevant 
source documents. 
The Investigator or designee is responsible for ensuring that the data collected in the course of this 
trial is accurate and documented appropriately on all applicable forms. They will then be 
processed, evaluated, and stored in anonymous form in accordance with applicable data protection 
regulations. The Investigator must ensure that the eCRFs and any other associated documents 
forwarded to Sponsor or its designated organization contain no mention of any subject names. 
The Investigator or designee will be responsible for entering trial data in the electronic CRF 
(eCRF) provided by the Sponsor. 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. Makrocare will be responsible for data 
processing, in accordance with the Sponsor’s data management procedures. Database lock will 
occur once quality control procedure, and quality assurance procedures (if applicable) have been 
completed. PDF files of the eCRFs will be provided to the Investigators at the completion of the 
trial. 
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The Investigator must keep a file (medical file, original medical records) on paper or electronically 
for every subject in the trial. It must be possible to identify each subject by using this subject file. 
This file will contain the available demographic and medical information for the subject, and 
following data should be available in this file.  


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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x Subject’s full name, date of birth, sex, height, weight 
x Medical history and concomitant diseases 
x Prior and concomitant therapies (including changes during the trial) 
x Trial identification MS200006-0039 , and subject number 
x Dates for entry into the trial (informed consent) and visits to the site 
x Any medical examinations and clinical findings predefined in this clinical trial protocol 
x All AEs 
x Date that the subject left the trial including any reason for early withdrawal from the trial or 
IMP (if applicable). 
All documents containing source data must be filed, including, but not limited to 
Echocardiography scan images, ECG recordings, and laboratory results. Such documents must 
bear the subject number and the date of the procedure. If possible, this information should be 
printed by the instrument used to perform the assessment or measurement. As necessary, medical 
evaluation of such records should be performed; all evaluations should be documented, signed, 
and dated by the Investigator. 
For data that may be recorded directly in the CRF such as a questionnaire or diary, there will be 
no record in the original subject file and therefore the data entered in the CRF will be considered 
source data. The clinical trial protocol or the Manual of Operations should clearly and completely 
specify all subject data in the CRF to be considered source data.  
Electronic subject files 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. 
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Upon initiation of the trial, the Investigator will be provided with an Investigator Site File 
containing all necessary trial documents, which will be completed throughout the trial and updated 
as necessary. The file must be available for review by the Monitor, during Sponsor audits and for 
inspection by Health Authorities during and after the trial, and must be safely archived for at least 
15 years (or longer, per local requirements or as otherwise notified by the Sponsor) after the end 
of the trial. The documents to be archived include the Subject Identification List and the signed 
subject Informed Consent Forms. If archiving of the Investigator Site File is no longer possible at 
the site, the Investigator must notify the Sponsor/designee. 
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. 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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This trial will be monitored in accordance with the ICH Note for Guidance on Good Clinical 
Practice (ICH Topic E6, 1996), and any other applicable regulations. The site Monitor will perform 
visits to the trial site at regular intervals. 
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance activities. 
Audits may be conducted at any time during or after the trial to ensure the validity and integrity of 
the trial data. Representatives of the Quality Assurance unit from the Sponsor or a designated 
organization, as well as Health Authorities, must be permitted to access all trial documents and 
other materials at the site, including the Investigator Site File, the completed CRFs, all IMP and 
IMP accountability records, and the original medical records or files for each subject. 

&KDQJHVWRWKH&OLQLFDO7ULDO3URWRFRO
Changes to the clinical trial protocol will be documented in writing. Substantive amendments will 
usually require submission to EC and to the relevant IRB for approval or favorable opinion. In 
such cases, the amendment will be implemented only after approval or favorable opinion has been 
obtained. 
Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant EC/IRB. Any amendment that 
could affect the subject’s agreement to participate in the trial requires additional informed consent 
prior to implementation following the process as described in Section 9.2. 
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
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After completion of the trial, a clinical trial report will be written by the Sponsor in consultation 
with the Coordinating Investigator following the guidance in ICH Topic E3.  

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The first publication will include the results of the analysis of the primary endpoint and will include 
data from all trial sites. 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 review by the Sponsor before submission. The Sponsor will not 
suppress publication, but maintains the right to delay publication in order to protect intellectual 
property rights. 
 
 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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
5HIHUHQFHV&LWHGLQWKH7H[W
1. Ponikowski P, Voors AA, Anker SD, et al. Eur J Heart Fail. 2016 Aug;18(8):891-975. 
2. Maggioni AP, Dahlström U, Filippatos G, et al. EURObservational Research Programme: 
regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF 
Pilot). Eur J Heart Fail. 2013 Jul;15(7):808-17. 
3. K. Murad, D.C. Goff Jr., T.M. Morgan, et al. Burden of comorbidities and functional and 
cognitive impairments in elderly patients at the initial diagnosis of heart failure and their impact 
on total mortality: the Cardiovascular Health Study JACC Heart Fail, 3 (2015), pp. 542–5. 
4. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 2007;93: 1137–1146. 
5. Redfield MM, Jacobsen SJ, Burnett JC, et al. Burden of systolic and diastolic ventricular 
dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA 
2003;289:194–202. 
6. Bleumink GS, Knetsch AM, Sturkenboom MCJM, et al. Quantifying the heart failure epidemic: 
prevalence, incidence rate, lifetime risk and prognosis of heart failure The Rotterdam Study. 
Eur Heart J England; 2004;25:1614–1619. 
7. GU Df, HUANG Gy, HE J, et al. Investigation of prevalence and distributing feature of chronic 
heart failure in Chinese adult population Chin J Cardiol, January 2003 , Vol.31 No 1. 
8. Heart & Stroke foundation. 2016 REPORT ON THE HEALTH OF CANADIANS 
9. P.A. Heidenreich, N.M. Albert, L.A. Allen, et al. Forecasting the impact of heart failure in the 
United States: A policy statement from the American Heart Association Circ Heart Fail, 6 
(2013), pp. 606–619. 
10.Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure 
(SHIFT): 
a 
randomised 
placebo-controlled 
study. 
Lancet 
(London, 
England). 
2010;376(9744):875–85. 
11.Ferrari R, Ford I, Fox K, Steg PG, Tendera M. The BEAUTIFUL study: randomized trial of 
ivabradine in patients with stable coronary artery disease and left ventricular systolic 
dysfunction—baseline characteristics of the study population. Cardiology. 2008;110(4):271–
82. 
12.The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet (London, 
England). 1999;353(9146):9–13. 
13.Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with 
severe chronic heart failure: results of the carvedilol prospective randomized cumulative 
survival (COPERNICUS) study. Circulation. 2002;106(17):2194–9. 
14.Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised 
Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet (London, England). 
1999;353(9169):2001–7. 
15.McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment 
of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of 
Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in 
collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 
2012;14(8):803–69. 
16.McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: beta-


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med. 
2009;150(11):784–94. 
17.Zhonghua Xin Xue Guan Bing Za Zhi. Chinese guidelines for the diagnosis and treatment of 
heart failure 2014. Chin J Cardiol,014 Feb;42(2):98-122. 
18.Reduced costs with bisoprolol treatment for heart failure: an economic analysis of the second 
Cardiac Insufficiency Bisoprolol Study (CIBIS-II). Eur Heart J. 2001 Jun;22(12):1021-31. 
19.Han SW1, Choi SW1, Ryu KH Beneficial Effect on Surrogate Markers of Heart Failure with 
Bisoprolol Up-Titration to Recommended Targets in Korean Patients with Heart Failure and 
Left Ventricular Systolic Dysfunction. Cardiovasc Ther. 2016 Jun;34(3):172-9. 
20.F.A. McAlister, N. Wiebe, J.A. Ezekowitz, A.A. Leung, P.W. Armstrong Meta-analysis: beta-
blocker dose, heart rate reduction, and death in patients with heart failure Ann Intern Med, 150 
(2009), pp. 784–794. 
21.H.D. Düngen, S. Apostoloviü, S. Inkrot, et al. Titration to target dose of bisoprolol versus 
carvedilol in elderly patients with heart failure: the CIBIS-ELD trial Eur J Heart Fail, 13 (6) 
(2011), pp. 670–680. 
22.H.D. Düngen, S. Apostoloviü, S. Inkrot, et al. Bisoprolol vs. carvedilol in elderly patients with 
heart failure: rationale and design of the CIBIS-ELD trial Clin Res Cardiol, 97 (2008), pp. 
578–586. 
23.M. Lainscak, C. Moullet, N. Schön, et al. Treatment of chronic heart failure with carvedilol in 
daily practice: the SATELLITE survey experience Int J Cardiol, 122 (2007), pp. 149–155. 
24.Komajda M, Follath F, Swedberg K, et al. The EuroHeart Failure Survey programme—a 
survey on the quality of care among patients with heart failure in Europe. Part 2: treatment. 
Eur Heart J 2003;24:464–474. 
25.Ko DT, Hebert PR, Coffey CS, et al. Adverse effects of beta-blocker therapy for patients with 
heart failure: a quantitative overview of randomized trials. Arch Intern Med 2004;164:1389–
1394 
26.Zugck C, Franke J, Gelbrich G, Frankenstein L, et al. Implementation of pharmacotherapy 
guidelines in heart failure: experience from the German Competence Network Heart Failure. 
Clin Res Cardiol 2012;101:263–272. 
27.Gelbrich G, Edelmann F, Inkrot S, et al. Cibis-Eld investigators Is target dose the treatment 
target? Uptitrating beta-blockers for heart failure in the elderly. Int J Cardiol 2012;155:160–
166. 
28.Von Arnim T. Prognostic significance of transient ischemic episodes: response to treatment 
shows improved prognosis. Results of the Total Ischemic Burden Bisoprolol Study (TIBBs) 
follow-up. J Am Coll Cardiol. 1996 Jul;28(1)_20-4 
29.McHorney CA, Ware JE, Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-
36): II. Psychometric and clinical tests of validity in measuring physical and mental health 
constructs. Med Care. 1993;31:247–263.  
30.Ware JE, Jr, Sherbourne CD. The MOS 36-item Short-Form health survey (SF-36). I. 
Conceptual framework and item selection. Med Care. 1992;30:473–483. 
31.McHorney, C. A., Ware, J. E., Lu, J. F. R., & Sherbourne, C. D. (1994). The MOS 36-item 
short form health survey (SF-36): III. Tests of data quality, scaling assumptions, and reliability 
across diverse patient groups. 0HGLFDO&DUH , 40–66. 
32.Fayers PM et al. Incomplete quality of life data in randomized trails: missing items. Statistics 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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in Medicine 1998;17:679-696. 
33.Schaffer JL and Graham JW. Missing data: our view of the state of the art. Psychological 
Methods 2002;7:147-177. 
34.Raghunathan TE, et al. A multivariate technique for multiply imputing missing values using a 
sequence of regression models. Survey Methodology 2001;27:85-95


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
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The following questions ask how much your heart failure (heart condition) affected your 
life during the past month (4 weeks).  After each question, circle the 0, 1, 2, 3, 4 or 5 to show 
how much your life was affected.  If a question does not apply to you, circle the 0 after that 
question.  
©1986 Regents of the University of Minnesota, All rights reserved.  Do not copy or 
reproduce without permission. LIVING WITH HEART FAILURE® is a registered trademark of 
the Regents of the University of Minnesota. 
  Instructions for Data Collection and Scoring˖ 
1.             Patients should respond to the questionnaire prior to other assessments and 
interactions that may bias their responses. You might tell the patient that you would like to get 
his or her opinion before doing your medical assessment.  
2.            Ample, uninterrupted time should be provided for the patient to complete the 
questionnaire. We recommend that the patient answer the questions without being influenced by 
others such as their spouse or family members. Studies show that patient proxies often have 
different perspectives.     
3.             We recommend that you use the first question to give the respondent more 
detailed instructions as follows.  
a. Read the introductory paragraph at the top of the questionnaire. 
b. Read the first question with the respondent – “Did your heart failure prevent you living as 
you wanted during  the last month (4 weeks) by causing swelling in your ankles or legs?”  Then 
tell the respondent - 
If you did not have any ankle or leg swelling during the past month (4 weeks) you should 
circle the zero (0) after this question.   
If you did have swelling that was caused by a sprained ankle or some other cause that you 
are sure was not related to heart failure, you should circle the zero (0) after this question.   
If you had swelling that might be related to your heart condition, then rate how much the 
swelling prevented you from doing things you wanted to do or feeling the way you would like to 
feel.  In other words, how much did the swelling affect your life? Circle either the 0, 1, 2, 3, 4 or 
5 to indicate how much the swelling affected your life during the past month – zero (0) means 
not at all, one (1) means very little and five (5) very much. 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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Ask the patient read and respond to all 21 questions. The entire questionnaire may be read 
directly to the patient if one is careful not to influence responses by verbal or physical cues. 
Check to make sure the patient has responded to each question. If a question does not apply 
to the patient they should circle the zero (0). Make sure there is only one answer clearly marked 
for each question. 
Score the questionnaire by summating the responses to all 21 questions. In addition, a 
physical dimension score (items 2, 3, 4, 5, 6, 7, 12, 13 on the version sent with these instructions) 
and emotional dimension score (items 17, 18, 19, 20, 21) have been identified by factor analysis 
and may be scored by simple summation to further characterize the effect of heart failure on a 
patient’s life. 
Partially complete questionnaires do occur despite best efforts to minimize missing data. 
However, missing data can greatly bias the data and complicate analysis. To reiterate, you need 
to make sure the respondents understand to mark zero for any items that do not apply to them, 
rather than leave a blank. Whenever possible review the questionnaire before the respondent 
leaves to make sure there are no unanswered questions or questions with more than one answer.  
Several methods to impute missing data are discussed in the literature, Multiple imputation 
using completed questions and perhaps other study variables to predict missing responses should 
be considered.  If a missing response is not imputed, the item will be eliminated from that 
person’s score (the sum of responses). Since intermittently missing data can greatly affect 
within-person changes in scores, you might want to use the same subset of questions to represent 
a person at all times by omitting questions that have missing data at any point in time. We do not 
have any recommendations about when missing data become too extensive to render the 
information being collected useless. 
 
 
 
 
 
 
 
 
 
 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
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Did your heart failure prevent you from living as you wanted 
during the last month by 
NO 
Very 
Little 
 
  
  
Very 
Much 
1. 
causing swelling in your ankles or legs, etc.? 
0 
1 
2 
3 
4 
5 
2. 
making you sit or lie down to rest during the day?        
0 
1 
2 
3 
4 
5 
3. 
making your walking about or climbing  stairs difficult? 
0 
1 
2 
3 
4 
5 
4. 
making your working around the house or yard difficult?   
0 
1 
2 
3 
4 
5 
5. 
making your going places away from home difficult? 
0 
1 
2 
3 
4 
5 
6. 
making your sleeping well at night difficult?  
0 
1 
2 
3 
4 
5 
7. 
making your relating to or doing things with your friends 
or family difficult? 
0 
1 
2 
3 
4 
5 
8. 
making your working to earn a living difficult?     
0 
1 
2 
3 
4 
5 
9. 
making your recreational pastimes, sports or hobbies 
difficult? 
0 
1 
2 
3 
4 
5 
10. making your sexual activities difficult? 
0 
1 
2 
3 
4 
5 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
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11. making you eat less of the foods you like? 
0 
1 
2 
3 
4 
5 
12. making you short of breath?   
0 
1 
2 
3 
4 
5 
13. making you tired, fatigued, or low on energy? 
0 
1 
2 
3 
4 
5 
14. making you stay in a hospital? 
0 
1 
2 
3 
4 
5 
15. costing you money for medical care? 
0 
1 
2 
3 
4 
5 
16. giving you side effects from treatments? 
0 
1 
2 
3 
4 
5 
17. making you feel you are a burden to your family or 
friends? 
0 
1 
2 
3 
4 
5 
18. making you feel a loss of self-control in your life? 
0 
1 
2 
3 
4 
5 
19. making you worry?        
0 
1 
2 
3 
4 
5 
20. making it difficult for you to concentrate or remember 
things? 
0 
1 
2 
3 
4 
5 
21. making you feel depressed?           
0 
1 
2 
3 
4 
5 


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(2)Somewhat better now than one year ago 
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During the past 4 weeks, have you had any of the following problems with your work or other regular daily activities as a result of 
your physical health? 
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(1)Yes (2)No 
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During the past 4 weeks, have you had any of the following problems with your work or other regular daily activities as a result of any 
emotional problems (such as feeling depressed or anxious)? 
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A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
Version 0.2/01 March 2016 
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(1)Not at all (2)Slightly (3)Moderately (4)Severe (5)Very Severe 
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(1)None (2)Very Mild (3)Mild Moderate (4)Severe (5)Very Severe 
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These questions are about how you feel and how things have been with you during the last 4 weeks. For each question, please give the 
answer that comes closest to the way you have been feeling. 
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(1)All of the time 
(2)Most of the time 
(3)A good Bit of the Time 
(4)Some of the time 
(5)A little bit of the time 
(6)None of the Time 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
Version 0.2/01 March 2016 
69/75 
 
 
69/75 
 
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(1)All of the time 
(2)Most of the time 
(3)A good Bit of the Time 
(4)Some of the time 
(5)A little bit of the time 
(6)None of the Time 
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(1)All of the time 
(2)Most of the time 
(3)A good Bit of the Time 
(4)Some of the time 
(5)A little bit of the time 
(6)None of the Time 
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(1)All of the time 
(2)Most of the time 
(3)A good Bit of the Time 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
Version 0.2/01 March 2016 
70/75 
 
 
70/75 
 
(4)Some of the time 
(5)A little bit of the time 
(6)None of the Time 
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(1)All of the time 
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(1)All of the time 
(2)Most of the time 
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(4)Some of the time 
(5)A little bit of the time 
(6)None of the Time 
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A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
Version 0.2/01 March 2016 
71/75 
 
 
71/75 
 
(1)All of the time 
(2)Most of the time 
(3)A good Bit of the Time 
(4)Some of the time 
(5)A little bit of the time 
(6)None of the Time 
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(1)All of the time 
(2)Most of the time 
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(4)Some of the time 
(5)A little bit of the time 
(6)None of the Time 
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(1)All of the time 
(2)Most of the time 
(3)A good Bit of the Time 
(4)Some of the time 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
Version 0.2/01 March 2016 
72/75 
 
 
72/75 
 
(5)A little bit of the time 
(6)None of the Time 
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(1)Definitely true (2)Mostly true (3)Don't know (4)Mostly false (5)Definitely false 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
Version 0.2/01 March 2016 
73/75 
 
 
73/75 
 
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(1)Definitely true (2)Mostly true (3)Don't know (4)Mostly false (5)Definitely false 
 
The SF-36 assesses 8 health status domains (ie, physical functioning, role physical functioning, role emotional functioning, mental 
health, vitality, social functioning, bodily pain, and general health). Scale scores are obtained by summing the items together within a 
domain, dividing this outcome by the range of scores and then transforming the raw scores to a scale from 0 to 100. 
 
 


A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
Version 0.2/01 March 2016 
74/75 
 
 
74/75 
 
 
Appendix III 
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(10
weeks) 
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weeks) 
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(18
weeks) 
9LVLW
(26
weeks) 
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A single-arm, interventional, multi-center, pilot study to evaluate the efficacy of oral Bisoprolol on heart rate reduction in 
Chinese Chronic Heart Failure patients with NYHA class II – IV (Biso-CHF Study) 
 
 
Version 0.2/01 March 2016 
75/75 
 
 
75/75 
 
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