Temporal Trends of Thrombolysis Treatment in Chinese Acute Ischemic Stroke (AIS) Patients From 2007 2017: Analysis of China National Stroke Registry (CNSR) I, II, and III
Conditions: Stroke
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-124_RD-01 (4.0)
TITLE PAGE
Protocol for non-interventional studies based on existing data
TITLE PAGE
Document Number:
c31688667-01
BI Study Number:
0135-0343
BI Investigational
Product(s):
Actilyse
Title:
Temporal trends of thrombolysis treatment in Chinese acute ischemic
stroke (AIS) patients from 2007-2017: analysis of China National Stroke 
Registry (CNSR) I, II, and III
Protocol version identifier:
1.1
Date of last version of 
protocol:
12 Mar 2020
PASS:
No
EU PAS register number:
EUPAS33970
Active substance:
Alteplase
Medicinal product:
Actilyse
Product reference:
Not applicable
Procedure number:
Not applicable
Joint PASS:
No
Research question and 
objectives:
Primary objectives: 

To investigate the temporal changes in the proportion of 
intravenous recombinant plasminogen activator (IV-rtPA) 
treatment from 2007 to 2017 among intravenous thrombolytics 
(IVT)-eligible patients and overall AIS patients in China;

To investigate the temporal changes in IV-rtPA treatment time 
intervals from 2007 to 2017 among IV-rtPA-treated patients in 
China.
Secondary objectives: 

To describe the demographic and clinical characteristics of the 
IV-rtPA-treated patients, IVT-eligible patients and the overall 
AIS patients from the CNSR I to III.

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Country(-ies) of study:
China
Author:
Marketing authorisation 
holder(s):
MAH contact person:
Not applicable
In case of PASS, add:
<EU-QPPV:>
Not applicable
In case of PASS, add:
<Signature of EU-QPPV:>
Not applicable
Date:
17 Apr 2020
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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Protocol for non-interventional studies based on existing data
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001-MCS-90-124_RD-01 (4.0)
1. TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 7
4.
ABSTRACT........................................................................................................... 8
5.
AMENDMENTS AND UPDATES..................................................................... 14
6.
MILESTONES..................................................................................................... 15
7.
RATIONALE AND BACKGROUND................................................................ 16
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 18
9.
RESEARCH METHODS .................................................................................... 19
9.1
STUDY DESIGN............................................................................................ 19
9.2
SETTING........................................................................................................ 19
9.3
VARIABLES .................................................................................................. 20
9.3.1
Exposures ................................................................................................ 20
9.3.2
Outcomes................................................................................................. 21
9.3.2.1 Primary outcomes ....................................................................................21
9.3.2.2 Secondary outcomes ................................................................................21
9.4
DATA SOURCES........................................................................................... 22
9.5
STUDY SIZE.................................................................................................. 23
9.6
DATA MANAGEMENT................................................................................ 23
9.7
DATA ANALYSIS......................................................................................... 24
9.7.1
Main analysis........................................................................................... 24
9.8
QUALITY CONTROL................................................................................... 25
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 26
9.10
OTHER ASPECTS ......................................................................................... 26
9.11
SUBJECTS...................................................................................................... 26
9.11.1
Cases........................................................................................................ 26
9.11.2
Controls................................................................................................... 26
9.12
BIAS................................................................................................................ 26
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 27

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11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 28
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS............................................................................................................ 29
13.
REFERENCES .................................................................................................... 30
13.1
PUBLISHED REFERENCES......................................................................... 30
13.2
UNPUBLISHED REFERENCES................................................................... 30
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 31
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 32
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 38

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2. LIST OF ABBREVIATIONS
ADRs
Adverse Drug Reactions
AEs
Adverse Events
AIS
Acute Ischemic Stroke
BI
Boehringer Ingelheim
CI
Confidence Interval
CRC
Clinical Research Coordinators
CRF
Case Report Form
CROs
Contract Research Organizations
CNSR
China National Stroke Registry
CT
Computed Tomography
DSMB
Data Safety and Management Board
DTN
Door to Needle
ECASS
European Cooperative Acute Stroke Study
EDC
Electronic Data Capture
ESOC
European Stroke Organization Conference
GPP
Good Pharmacoepidemiology Practices
H
Hours
ICFs
Informed Consent Forms
ICH
Intracranial Hemorrhage
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IS
Ischemic Stroke 
IV-rtPA
Intravenous Recombinant Plasminogen Activator
IVT
Intravenous Thrombolytics
Min
Minutes
MOH
Ministry of Health
MRA
Magnetic Resonance Angiography
MRI
Magnetic Resonance Imaging
NCRC-ND
National Clinical Research Center for Neurological Diseases
NIHSS
National Institutes of Health Stroke Scale
PRF
Paper-based Registry Forms

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SAH
SubArachnoid Hemorrhage
SAP
Statistical Analysis Plan
SD
Standard Deviation
SOPs
Standard Operation Procedures
TIA
Transient Ischemic Attack

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3. RESPONSIBLE PARTIES
BI Contact Person:
Address:
Contact details:
Principal Investigator:
Address:
 
Contact details:

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4. ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Actilyse
Name of active ingredient:
Alteplase
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
17 Apr 2020
0135-0343
1.1
12 Mar 2020
Title of study:
Temporal trends of thrombolysis treatment in Chinese acute ischemic 
stroke patients (AIS) from 2007-2017: analysis of China National 
Stroke Registry (CNSR) I, II, and III 
Rationale and 
background:
Based on the conclusion from the European Cooperative Acute Stroke 
Study (ECASS) III study, the Chinese treatment guideline for AIS was 
updated in 2010, with intravenous recombinant plasminogen activator
(IV-rtPA) treatment recommendation time window extended from 
within 3h of symptom onset to 4.5h. In addition, efforts have been 
taken by the government and academic societies to develop stroke 
centers and stroke care quality control networks. In order to understand 
the impact of these efforts on the clinical practices for AIS treatment in 
China, we plan to evaluate the 10-year temporal changes from 
2007-2017, in the IV-rtPA treatment proportion and treatment time 
intervals of AIS patients by using the CNSR I, II, and III. In addition, 
the demographic and clinical characteristics of the AIS patients will be 
described.
Research question 
and objectives:
Primary objectives: 

To investigate the temporal changes in the proportion of 
intravenous recombinant plasminogen activator (IV-rtPA) 
treatment from 2007 to 2017 among intravenous thrombolytics 
(IVT)-eligible patients and overall AIS patients in China;

To investigate the temporal changes in IV-rtPA treatment time 
intervals from 2007 to 2017 among IV-rtPA-treated patients in 
China.
Secondary objectives: 

To describe the demographic and clinical characteristics of the 
IV-rtPA-treated patients, IVT-eligible patients and the overall 
AIS patients from the CNSR I to III.
Study design:
This is a non-interventional study based on existing data from the 
CNSR.

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Protocol for non-interventional studies based on existing data
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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Actilyse
Name of active ingredient:
Alteplase
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
17 Apr 2020
0135-0343
1.1
12 Mar 2020
Population:
All eligible patients from the CNSR I to III will be included. Patient 
groups include the overall AIS patients (patient group A), IVT-eligible 
patients (patient groups B and B’), and IV-rtPA-treated patients 
(patient groups C and C’).
The in- and exclusion criteria for the reporting groups are listed below:
1) All AIS patients (patient group A)
1.Inclusion criteria:
(1) Aged 18-80 years
(2) Diagnosed with AIS on admission
2.Exclusion criteria:
(1) Missing baseline data including age and gender
(2) Diagnosed with intracranial intracranial hemorrhage (ICH), 
Transient Ischemic Attack (TIA), subarachnoid hemorrhage 
(SAH), or unspecific stroke
(3) Arrived at hospital after 7 days of symptom onset
2) IVT-eligible patients (patient groups B and B’)
1.
Inclusion criteria:
(1) Met the in- and exclusion criteria of “all AIS patients”
(2) Arrived at hospital within 2h (patient group B) or 3.5h 
(patient group B’) of symptom onset
2.
Exclusion criteria:
(1) Missing key data including 
i.
symptom onset time (or last known well time);
ii.
hospital arrival time;
iii.
whether received IVT treatment or not;
iv.
the time of IVT treatment.
(2) Documented IVT absolute contraindications, according to 
the case report form (CRF) for each wave of CNSR (please 
refer to ANNEX 3 for details)
3) IV-rtPA-treated patients (patient groups C and C’)

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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Actilyse
Name of active ingredient:
Alteplase
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
17 Apr 2020
0135-0343
1.1
12 Mar 2020
1.
Inclusion criteria:
(1) Met the in- and exclusion criteria of “IVT-eligible patients”
(2) Treated with IV-rtPA within 3h (patient group C) or 4.5h 
(patient group C’) of symptom onset
2.
Exclusion criteria:
(1) Not received IVT
(2) Received IVT other than rtPA
(3) Treated with IV-rtPA after 3h (patient group C) or 4.5h
(patient group C’) of symptom onset 
(4) Received additional treatments with intra-arterial 
reperfusion or experimental therapies
Variables and 
co-variables:
Primary outcomes:
For all the three waves of CNSR, the following primary outcomes will 
be assessed:

Proportion of patients who received IV-rtPA treatment within 
3h of symptom onset (patient group C) among 2hr IVT-eligible 
patients (patient group B);

Proportion of patients who received IV-rtPA treatment within 
4.5h of symptom onset (patient group C’) among 3.5h 
IVT-eligible patients (patient group B’).
Secondary outcomes: the analysis will be performed for each wave 
of CNSR
Among all AIS patients (patient group A), the following secondary 
outcomes will be assessed:

Proportion of patients who arrived at hospital within 2h of 
symptom onset and who received IV-rtPA treatment within 3h 
of symptom onset (patient group C);

Proportion of patients who arrived at hospital within 3.5h of 
symptom onset and who received IV-rtPA treatment within 4.5h 
of symptom onset (patient group C’);
Among 3h IV-rtPA-treated patients (patient group C), the following 
secondary outcomes will be assessed:

The door-to-needle (DTN) time (time between arrival at 
hospital and the administration of IV-rtPA treatment);

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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Actilyse
Name of active ingredient:
Alteplase
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
17 Apr 2020
0135-0343
1.1
12 Mar 2020

Proportion of patients DTN time ≤60 minutes (min);

Time between symptom onset and arrival at hospital;

Time between symptom onset and the administration of IV-rtPA 
treatment.
Among 4.5h IV-rtPA-treated patients (patient group C’), the following 
secondary outcomes will be assessed:

The DTN time;

Proportion of patients DTN time ≤60 min;

Time between symptom onset and arrival at hospital;

Time between symptom onset and the administration of IV-rtPA 
treatment.
 
 
 
 
 
 
 
 
 
 
 

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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Actilyse
Name of active ingredient:
Alteplase
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
17 Apr 2020
0135-0343
1.1
12 Mar 2020
 
 

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Protocol for non-interventional studies based on existing data
BI Study Number 0135-0343
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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Actilyse
Name of active ingredient:
Alteplase
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
17 Apr 2020
0135-0343
1.1
12 Mar 2020
Data sources:
CNSR I, II, and III
Study size:
It was estimated that in CNSR I, II, and III, the number of total AIS 
patients is 14704, 19604, and 15204, respectively. 
Assuming the IV-rtPA-treated among IVT-eligible patients in CNSR I, 
II, and III are 4%, 5%, and 28% with the 95% confidence interval (CI)
for each wave as below, then which can be distinguished with current 
study size.
CNSR
Wave I
Wave II
Wave III
Assumed 
IV-rtPA 
proportion
among eligible 
patients % 
(95% CI)
4%
(3.7-4.3%)
5%
(4.7-5.3%)
28%
(27.3-28.7%)
Data analysis:
The study is descriptive in nature. For continuous data, descriptive 
statistics (number of patients, mean, standard deviation [SD], 
minimum, median, interquartile range, and maximum) will be 
presented. Categorical data will be presented as frequency and 
proportion with 95% CI as appropriate.
 
Milestones:
Feasibility assessment: Jun 2019
Protocol finalization: Dec 2019
Statistical and epidemiological analysis plan: Mar 2020
Start of data collection: NA
End of data collection: NA
Statistical and epidemiological analysis report finalization: Mar 2020
Final results: Apr 2020
Clinical study report finalization: Apr 2020
Final report of the study result: Apr 2020

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5. AMENDMENTS AND UPDATES
None

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6. MILESTONES
Milestone
Planned Date
Feasibility assessment
Jun 2019
Protocol finalization
Dec 2019
Statistical and 
epidemiological analysis 
plan
Mar 2020
Start of data collection
DD Month YYYY
End of data collection
DD Month YYYY
Statistical and 
epidemiological analysis 
report
Mar 2020
Final results
Apr 2020
Clinical study report
Apr 2020
Final report of study results:
Apr 2020

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7. RATIONALE AND BACKGROUND
Stroke is the leading cause of mortality in China, resulting in about 1.9 million deaths in 
2013[P20-03289]. Intravenous recombinant plasminogen activator (IV-rtPA) has been 
demonstrated to be essential to decrease disability among acute ischemic stroke (AIS)
patients. However, currently a large number of stoke patients who have arrived hospitals on 
time and with no documented absolute contraindications for IV-rtPA are not receiving the 
thrombolysis treatment in China0 [P14-16838]. Since 2015, Chinese government and professional 
societies have put a lot of efforts in improving the quality of stroke care, including supporting 
hospitals to build stroke centers/units, encouraging stroke centers to submit thrombolysis 
treatment data, and issuing stroke care quality reports.
The China National Stroke Registry (CNSR), sponsored by the China Ministry of Health
(MOH), is a nationwide hospital-based, prospective stroke registry for patients presented to 
hospitals with acute cerebrovascular events. The primary objectives of CNSR are to evaluate 
the quality of care during the acute hospitalization phase for cerebrovascular patients. The 
objectives are evaluated based on the performance indicators for stroke care delivery, and 
factors associated with the performance indicators are identified. The secondary objectives of 
CNSR include measuring longitudinal trends in clinical/functional outcomes of 
cerebrovascular patients at 3 months, 6 months, and 12 months after disease onset, the
relationship between the clinical/functional outcomes of the patients with the quality of care 
during acute hospitalization, and adherence of the patients to secondary stroke prevention 
medication [P11-07866]. Patients had been continually enrolled for 8-12 months every five years
since 2007. Data collected for each patient included demographics, medical history, initial,
National Institutes of Health Stroke Scale (NIHSS) score, time intervals related to symptom 
onset, hospital arrival, and IV-rtPA treatment during the acute hospitalization phase. 
Till 2017, three waves of CNSR were completed: 2007-2008 (CNSR I), 2012-2013 
(CNSR II), and 2015-2017 (CNSR III). The number of hospitals participating each of CNSR
were 132, 219, and 201, respectively. When compared to CNSR I, data from CNSR II 
showed a 1.17-fold increase in the adjusted odds of delivering evidence-based performance 
metrics for ischemic stroke (IS) care. Nevertheless, no statistically significant difference in 
the proportion of patient who received intravenous thrombolytics (IVT) treatment within 
3 hours (h) of symptom onset was observed between the two CNSR [P20-03289]. 
In China, IV-rtPA was approved for the treatment of AIS patients within 3h of symptom 
onset without absolute contraindications. However, in 2008, the European Cooperative Acute 
Stroke Study (ECASS) III study concluded that AIS patients could still benefit from IV-rtPA 
treatment when given between 3h and 4.5 [P08-12177]the Chinese treatment guideline for AIS 
was updated in 2010, for which a recommendation of IV-rtPA treatment within 3h to 4.5h of 
symptom onset was added [P20-03291]. 
The current study aims at evaluating differences, if any, in clinical practice of IV-rtPA 
treatment among AIS patients from 2007 to 2017. In addition, the study will also provide 
information on the demographic and clinical characteristics of AIS patients receiving IV-rtPA 
in China. Taken together, the study will help us to better understand the trend of clinical 
practices for AIS treatment in China during the last decade, especially after the update of the 

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national AIS treatment guideline and the continuous efforts made by academic society and 
MOH in the field of stroke care.

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8. RESEARCH QUESTION AND OBJECTIVES
The present study is to be conducted based on the AIS patient data collected from CNSR I, II,
and III.
The primary objectives are:
To investigate the temporal changes in the proportion of IV-rtPA treatment from 2007 
to 2017 among IVT-eligible patients (patient groups B and B’) and overall AIS 
patients (patient group A) in China;
To investigate the temporal changes in IV-rtPA treatment time intervals from 2007 to 
2017 among IV-rtPA-treated patients (patient groups C and C’) in China.
The secondary objectives are:
To describe the demographic and clinical characteristics of the IV-rtPA-treated 
patients (patient groups C and C’), IVT-eligible patients (patient groups B and B’) and 
the overall AIS patients (patient group A) from 2007 to 2017 from the CNSR I to III.

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9. RESEARCH METHODS
9.1
STUDY DESIGN
This is a non-interventional study based on existing data. We will analyze data from three 
cross-sectional surveys of AIS patients in China: CNSR I (2007-2008), II (2012-2013), and 
III (2015-2017).
9.2
SETTING
In this study, AIS patient data from CNSR I to III will be used. The study will analyze data 
for the following patient groups: 
(1) All AIS patients (patient group A): the overall AIS patients aged 18-80 years who 
arrived at hospital within 7 days of symptom onset; 
(2) IVT-eligible patients (patient groups B and B’): AIS patients who arrived at hospital 
within 2h (patient group B) and 3.5h (patient group B’) of symptom onset and with no 
documented absolute contraindications to IVT treatment; 
(3) IV-rtPA-treated patients (patient groups C and C’): IVT-eligible patients who arrived 
at hospital within 2h of symptom onset and received IV-rtPA within 3h of symptom 
onset (patient group C) and those who arrived at hospital within 3.5h of symptom 
onset and received IV-rtPA within 4.5h of symptom onset (patient group C’).
The flow of data selection for each of the three reporting patient groups is depicted in Figure
1 below.
Figure 1
Patient groups selected for the time-trend study
(a) Patient groups A, B, and C
(b) Patient groups A, B’, and C’

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The in- and exclusion criteria for each of the reporting groups are listed below:
1) All AIS patients (patient group A)
1. Inclusion criteria:
(1) Aged 18-80 years
(2) Diagnosed with AIS on admission
2. Exclusion criteria:
(1) Missing baseline data including age and gender
(2) Diagnosed with intracranial hemorrhage (ICH), Transient Ischemic 
Attack (TIA), subarachnoid hemorrhage (SAH), or unspecific 
stroke
(3) Arrived at hospital after 7 days of symptom onset
2) IVT-eligible patients (patient groups B and B’)
1. Inclusion criteria:
(1) Met the in- and exclusion criteria of “all AIS patients”
(2) Arrived at hospital within 2h (patient group B) or 3.5h (patient
group B’) of symptom onset
2. Exclusion criteria:
(1) Missing key data including 
i.
symptom onset time (or last known well time);
ii.
hospital arrival time;
iii.
whether received IVT treatment or not;
iv.
the time of IVT treatment
(2) Documented IVT absolute contraindications, according to the case 
report form (CRF) for each wave of CNSR (please refer to 
ANNEX 3 for details)
3) IV-rtPA-treated patients (patient groups C and C’)
1. Inclusion criteria:
(1) Met the in- and exclusion criteria of “IVT-eligible patients”
(2) Treated with IV-rtPA within 3h (patient group C) or 4.5h (patient
group C’) of symptom onset
2. Exclusion criteria:
(1) Not received IVT
(2) Received IVT other than rtPA
(3) Treated with IV-rtPA after 3h (patient group C) or 4.5h (patient 
group C’) of symptom onset 
(4) Received additional treatments with intra-arterial reperfusion or 
experimental therapies
9.3
VARIABLES
9.3.1
Exposures
The study is descriptive in nature. It will not assess the association between any exposure and 
outcomes.

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9.3.2
Outcomes
9.3.2.1 Primary outcomes
For all the three waves of CNSR, the following primary outcomes will be assessed:

Proportion of patients who received IV-rtPA treatment within 3h of symptom 
onset (patient group C, please refer to Figure 1 for details on patient groups) 
among 2h IVT-eligible patients (patient group B);

Proportion of patients who received IV-rtPA treatment within 4.5h of symptom 
onset (patient group C’) among 3.5h IVT-eligible patients (patient group B’).
9.3.2.2 Secondary outcomes: the analysis will be performed for each wave of CNSR
Among all AIS patients (patient group A), the following secondary outcomes will be 
assessed:

Proportion of patients who arrived at hospital within 2h of symptom onset and 
who received IV-rtPA treatment within 3h of symptom onset (patient group C);

Proportion of patients who arrived at hospital within 3.5h of symptom onset and 
who received IV-rtPA treatment within 4.5h of symptom onset (patient group C’);
Among 3h IV-rtPA-treated patients (patient group C), the following secondary outcomes will 
be assessed 

The door-to-needle (DTN) time (time between arrival at hospital and the 
administration of IV-rtPA treatment);

Proportion of patients DTN time ≤60 minutes (min);

Time between symptom onset and arrival at hospital;

Time between symptom onset and the administration of IV-rtPA treatment.
Among 4.5h IV-rtPA-treated patients (patient group C’), the following secondary outcomes 
will be assessed 

The DTN time;

Proportion of patients DTN time ≤60 min;

Time between symptom onset and arrival at hospital;

Time between symptom onset and the administration of IV-rtPA treatment.

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9.4
DATA SOURCES
The current study will be conducted based on data collected from the three waves of CNSR.
CNSR I (2007-2008) used IS patient data from 132 hospitals in China, including 100 tertiary 
and 32 urban hospitals. Ischemic stroke patients aged 18 years and older within 14 days of 
symptom onset were included for the study. Paper-based registry forms (PRF) developed by 
the expert advisory panel were used for data collection. Patient information including 
demographics (age, gender, etc.), NIHSS, medical history (diabetes mellitus, hypertension, 
coronary heart disease/previous myocardial infarction, atrial fibrillation, previous stroke, 
TIA, dyslipidemia), symptom onset-to-door time, health insurance schemes (urban basic 
medical insurance schemes for urban and governmental employees and urban residents, new 
rural cooperative medical schemes for rural residents, commercial insurance, and 
self-payment [P20-03289]), vascular risk factors, imaging [mainly magnetic resonance imaging 
(MRI) or magnetic resonance angiography (MRA)], blood sampling, time-related variables
[symptom onset time, hospital arrival time, CT time, IV-rtPA treatment time, etc.],
implementation of performance measures for acute stroke care, final diagnosis, length of stay, 
in-hospital death, and follow-up information for 3-month, 6-month, and 12-month was
collected. Hospital-level information including geographic region (e.g., east, central, or west,
according to the annual report on health statistics of China [R20-1011])), teaching status, hospital 
bed size, and annual stoke volume was collected0.
CNSR II (2012-2013) used IS patient data from 219 hospitals in China. IS patients aged 
18 years and older within 7 days of symptom onset were included for the study. Web-based 
case report forms (CRF) were used for data collection. Patient information including 

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demographics, NIHSS, medical history, symptom onset-to-door time, health insurance 
schemes, vascular risk factors, imaging, blood sampling, time-related variables, 
implementation of performance measures for acute stroke care, final diagnosis, length of stay, 
modified Rankin scale at discharge, and in-hospital death was collected. Follow-up 
information for 3-month, 6-month, and 12-month was collected by phone interview.
Hospital-level information including geographic region, teaching status, hospital bed size, 
and annual stoke volume was collected [P20-03289].
CNSR III (2015-2017) used AIS or TIA patient data from 201 hospitals in China. AIS or TIA 
patients aged 18 years and older within 7 days of symptom onset were included for the study. 
An electronic data collection (EDC) system was used through an electronic software or the 
internet. Patient information including demographics, NIHSS, medical history, symptom 
onset-to-door time, health insurance schemes, vascular risk factors, imaging, blood sampling,
time-related variables, implementation of performance measures for acute stroke care, final 
diagnosis, length of stay, modified Rankin scale at discharge, and in-hospital death was
collected. Follow-up information for 3-month, 6-month, and 12-month was collected by 
phone interview. Hospital-level information including geographic region, teaching status, 
hospital bed size, and annual stoke volume was collected.
9.5
STUDY SIZE
It was estimated that in CNSR I, II, and III, the number of total AIS patients is 14704, 19604, 
and 15204, respectively. 
Assuming the IV-rtPA-treated among IVT-eligible patients in CNSR I, II, and III are 4%, 
5%, and 28% with the 95% confidence interval (CI) for each wave as below, then which can 
be distinguished with current study size.
CNSR
I
II
III
Assumed IV-rtPA 
proportion among 
eligible patients % 
(95% CI)
4% (3.7-4.3%)
5% (4.7-5.3%)
28% (27.3-28.7%)
No formal sample size calculation is performed due to the nature of this study. All eligible 
AIS patients within the existing database from the three waves of CNSR will be included in 
this study.
9.6
DATA MANAGEMENT
For the CNSR, all hospitals participating in the CNSR were selected by a Steering Committee 
using a convenient sampling method from the China National Network of Stroke Research 
developed by the National Center of Quality Management in Stroke Care. In total, 
491 hospitals were included based on their geographic region, teaching status, hospital beds, 
and annual stroke discharges. The internal data validity of CNSR I, II, and III were ensured 
by introducing trained clinical research coordinators (CRCs) to these studies to guarantee the 
quality of data entry. The CRCs examined all medical records of stroke or TIA patients to 
identify eligible cases for the registries. The operating books were printed and sent to each 

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researcher and coordinator for guidance. Independent contract research organizations (CROs)
were invited to monitor the study procedures and to ensure the quality of data entry. All data 
elements collected by PRF, web-based CRF, or EDC system were manually or mechanically 
checked for completeness, coding correctness, and appropriateness of the diagnostic 
algorithm conducted by a research specialist from independent CROs throughout the study 
period. A professional data processing company was responsible for the computer or PAD 
data entry. The Data Management Group of the National Clinical Research Center for 
Neurological Diseases (NCRC-ND) served as the data analysis department and analyzed the 
aggregated de-identified data for research purposes.
For the current study, the data will be managed by NCRC-ND. Data management, tabulations, 
and graphics will be carried out with SAS version 9.3 software (SAS institute). Source code 
of data management and data analyses will be kept for inspection for at least five years after 
publication of the results.
9.7
DATA ANALYSIS
9.7.1
Main analysis
For continuous data, descriptive statistics (number of patients, mean, standard deviation (SD), 
minimum, median, interquartile range, and maximum) will be presented. Categorical data 
will be presented as frequency and proportion with 95% CI. Unless otherwise stated, the 
calculation will be based on the available data. No data imputation will be performed for the 
missing data. Details for all analyses will be provided in the statistical analysis plan (SAP). 
 
 
.

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9.8
QUALITY CONTROL
For the CNSR, safety and risk control was assessed by the Data Safety and Monitoring Board 
(DSMB) before the study. Clinical research associates conducted data verification on site 
during the study. Data management team of NCRC-ND performed remote real time data 
supervision for all the data cleaning, integration, analysis, and other processing.
For the current study, the standard operation procedures (SOPs) of Boehringer Ingelheim (BI), 
such as NISed SOP, will be strictly followed. In addition, key elements of the International 
Society for Pharmacoepidemiology Good Pharmacoepidemiology Practices (GPP) will be 
followed [R16-5416]. The statistical analysis method will be reviewed and repeated by a second 
analyst. All the data cleaning, integration, analysis, and other processing will be conducted 

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under the guidance and supervision of data management team of NCRC-ND. The study 
report will be reviewed, approved, and archived per SOPs of BI.
9.9
LIMITATIONS OF THE RESEARCH METHODS
The quality of a study based on existing data relies on accuracy of recorded data. Important
data may not be available. The hospitals participating in the CNSR, although spread 
throughout China and covered all geographic areas, were mainly selected by convenience in 
nature. These hospitals possess more resources and expertise in ischemic stroke when 
compared to other hospitals in China, especially those at a country-level or lower ranks.
Therefore, results from the current study will have to be interpreted with caution as it is not 
known what proportion of stroke patients in China have access to hospital cares at a level 
similar to those participated in the CNSR. Due to the nature of explore existing data, the 
interpretation is based on non-missing data.
9.10
OTHER ASPECTS
CNSR I, II, and III data collection were initiated after receiving approval from the central
institutional review board at 
. The 
informed consent forms (ICFs) were provided by patients or their legal representatives. 
For the current study, the study protocol will be submitted to 
 
Institutional Review Board (IRB)/Independent Ethics Committee
(IEC) for review. The IRB/IEC approval will be obtained before the study initiation. A 
waiver for the ICF will be applied since the study will use existing data.
9.11
SUBJECTS
9.11.1 Cases
Not applicable.
9.11.2 Controls
Not applicable.
9.12
BIAS
Refer to Section 9.9.

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10.
PROTECTION OF HUMAN SUBJECTS
The section is not applicable since the current study is a time-trend analysis of the data 
collected from the CNSR I to III.
The procedures set out in this study protocol are designed to ensure that the sponsor and 
investigator abide by the principles of the GPP guidelines [R16-5416]. The study also will be 
carried out in keeping with local legal requirements.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
The current study is a time-trend analysis of the existing data collected from the CNSR I
to III. Boehringer Ingelheim or third party acting on behalf of BI will not have access to 
individual patient data during the study. Data will be provided to BI in aggregated manner.
Thus, collection and reporting of adverse events (AEs)/adverse drug reactions (ADRs) is not 
applicable.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS
The final report of the study report is planned in March 2020. Results of this 
non-interventional study will be disclosed on encepp.eu and clinicaltrials.gov.
A conference abstract and at least one manuscript will be generated from the study.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
[P08-12177] Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrue V, 
Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, 
Toni D; ECASS investigators. Thrombolysis with alteplase 3 to 4.5 hours after 
acute ischemic stroke, N Engl J Med. 2008; 359(13):1317-1329.
[P11-07866] Wang Y, Cui L, Ji X, Dong Q, Zeng J, Wang Y, Zhou Y, Zhao X, Wang C, Liu 
L, Nguyen-Huynh MN, Claiborne Johnston S, Wong L, Li H; China national 
stroke registry investigators. The China national stroke registry for patients with 
acute cerebrovascular events: design, rationale, and baseline patient 
characteristics, Int J Stroke. 2011; 6(4):355-361.
[P14-16838] Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, Brott T, 
Cohen G, Davis S, Donnan G, Grotta J, Howard G, Kaste M, Koga M, von 
Kummer R, Lansberg M, Lindley RI, Murray G, Olivot JM, Parsons M, Tilley 
B, Toni D, Toyoda K, Wahlgren N, Wardlaw J, Whiteley W, del Zoppo GJ, 
Baigent C, Sandercock P, Hacke W; Stroke thrombolysis trialists' collaborative 
group. Effect of treatment delay, age, and stroke severity on the effects of 
intravenous thrombolysis with alteplase for acute ischaemic stroke: a 
meta-analysis of individual patient data from randomised trials, Lancet. 2014; 
384(9958):1929-1935.
[P20-03289] Li Z, Wang C, Zhao X, Liu L, Wang C, Li H, Shen H, Liang L, Bettger J, Yang 
Q, Wang D, Wang A, Pan Y, Jiang Y, Yang X, Zhang C, Fonarow GC, 
Schwamm LH, Hu B, Peterson ED, Xian Y, Wang Y, Wang Y; China national 
stroke registries. Substantial progress yet significant opportunity for 
improvement in stroke care in China, Stroke. 2016; 47(11):2843-2849.
[P20-03291] Acute Ischemic Stroke Treatment Guideline Writing, Cerebrovascular Group, 
Neurology Sub association, Chinese Medical Association. Chinese Acute 
Ischemic Stroke Treatment Guideline 2010, Chin J Neurol. 2010;
43(2):146-153.
[R16-5416]  International Society for Pharmacoepidemiology (ISPE). Guidelines for good 
pharmacoepidemiology practices (GPP), Pharmacoepidemiol Drug Saf. 2015;
25(1): 2-10.
13.2
UNPUBLISHED REFERENCES
[R20-1011]  2013 China Health Statistical Yearbook
http://www.nhc.gov.cn/htmlfiles/zwgkzt/ptjnj/year2013/index2013.html

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
None

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Study title: Temporal trends of thrombolysis treatment in Chinese acute ischemic stroke (AIS) 
patients from 2007-2017: analysis of China National Stroke Registry (CNSR) I, II, 
and III
EU PAS Register® number: Not applicable
Study reference number (if applicable):
Section 1: Milestones
Yes
No
N/A
Section 
Number
1.1
Does the protocol specify timelines for 
1.1.1 Start of data collection1
1.1.2 End of data collection2
1.1.3 Progress report(s)
1.1.4 Interim report(s)
1.1.5 Registration in the EU PAS Register®
1.1.6 Final report of study results.
Comments:
Section 2: Research question
Yes
No
N/A
Section 
Number
2.1
Does the formulation of the research question and 
objectives clearly explain: 
2.1.1 Why the study is conducted? (e.g. to address an 
important public health concern, a risk identified in the 
risk management plan, an emerging safety issue)
2.1.2 The objective(s) of the study?
2.1.3 The target population? (i.e. population or subgroup to 
whom the study results are intended to be generalised)
2.1.4 Which hypothesis(-es) is (are) to be tested?
2.1.5 If applicable, that there is no a priori hypothesis?
Comments:
Section 3: Study design
Yes
No
N/A
Section 
Number
3.1
Is the study design described? (e.g. cohort, case-control, 
cross-sectional, other design) 
                                                
1 Date from which information on the first study is first recorded in the study dataset or, in the case of secondary use of data, the date from 
which data extraction starts.
2 Date from which the analytical dataset is completely available.

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Section 3: Study design
Yes
No
N/A
Section 
Number
3.2
Does the protocol specify whether the study is based on 
primary, secondary or combined data collection?
3.3
Does the protocol specify measures of occurrence? 
(e.g., rate, risk, prevalence)
3.4
Does the protocol specify measure(s) of association? 
(e.g. risk, odds ratio, excess risk, rate ratio, hazard ratio, 
risk/rate difference, number needed to harm (NNH))
3.5
Does the protocol describe the approach for the 
collection and reporting of adverse events/adverse 
reactions? (e.g. adverse events that will not be collected 
in case of primary data collection)
Comments:
Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.1
Is the source population described?
4.2
Is the planned study population defined in terms of:
4.2.1 Study time period
4.2.2 Age and sex
4.2.3 Country of origin
4.2.4 Disease/indication
4.2.5 Duration of follow-up
4.3
Does the protocol define how the study population will 
be sampled from the source population? (e.g. event or 
inclusion/exclusion criteria)
Comments:
Section 5: Exposure definition and measurement
Yes
No
N/A
Section 
Number
5.1
Does the protocol describe how the study exposure is 
defined and measured? (e.g. operational details for 
defining and categorising exposure, measurement of 
dose and duration of drug exposure)
5.2
Does the protocol address the validity of the exposure 
measurement? (e.g. precision, accuracy, use of 
validation sub-study)
5.3
Is exposure categorised according to time windows? 
5.4
Is intensity of exposure addressed? (e.g. dose, duration)
5.5
Is exposure categorised based on biological mechanism 
of action and taking into account the pharmacokinetics 
and pharmacodynamics of the drug?
5.6
Is (are) (an) appropriate comparator(s) identified?

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Comments:
Section 6: Outcome definition and measurement
Yes
No
N/A
Section 
Number
6.1
Does the protocol specify the primary and secondary (if 
applicable) outcome(s) to be investigated?
6.2
Does the protocol describe how the outcomes are 
defined and measured? 
6.3
Does the protocol address the validity of outcome 
measurement? (e.g. precision, accuracy, sensitivity, 
specificity, positive predictive value, use of validation 
sub-study)
6.4
Does the protocol describe specific outcomes relevant 
for Health Technology Assessment? (e.g. HRQoL, 
QALYs, DALYS, health care services utilisation, burden 
of disease or treatment, compliance, disease 
management)
Comments:
Section 7: Bias
Yes
No
N/A
Section 
Number
7.1
Does the protocol address ways to measure 
confounding? (e.g. confounding by indication)
7.2
Does the protocol address selection bias? (e.g. healthy 
user/adherer bias)
7.3
Does the protocol address information bias? 
(e.g. misclassification of exposure and outcomes, time-
related bias)
Comments:
Section 8: Effect measure modification
Yes
No
N/A
Section 
Number
8.1
Does the protocol address effect modifiers? 
(e.g. collection of data on known effect modifiers, sub-
group analyses, anticipated direction of effect)
Comments:
Section 9: Data sources
Yes
No
N/A
Section 
Number

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Section 9: Data sources
Yes
No
N/A
Section 
Number
9.1
Does the protocol describe the data source(s) used in the 
study for the ascertainment of:
9.1.1 Exposure? (e.g. pharmacy dispensing, general practice 
prescribing, claims data, self-report, face-to-face 
interview)
9.1.2 Outcomes? (e.g. clinical records, laboratory markers or 
values, claims data, self-report, patient interview 
including scales and questionnaires, vital statistics)
9.1.3 Covariates and other characteristics?
9.2
Does the protocol describe the information available 
from the data source(s) on:
9.2.1 Exposure? (e.g. date of dispensing, drug quantity, dose, 
number of days of supply prescription, daily dosage,  
prescriber)
9.2.2 Outcomes? (e.g. date of occurrence, multiple event, 
severity measures related to event)
9.2.3 Covariates and other characteristics? (e.g. age, sex, 
clinical and drug use history, co-morbidity, co-
medications, lifestyle)
9.3
Is a coding system described for: 
9.3.1 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC) Classification System)
9.3.2 Outcomes? (e.g. International Classification of Diseases 
(ICD), Medical Dictionary for Regulatory Activities 
(MedDRA))
9.3.3 Covariates and other characteristics?
9.4
Is a linkage method between data sources described? 
(e.g. based on a unique identifier or other) 
Comments:
Section 10: Analysis plan
Yes
No
N/A
Section 
Number
10.1 Are the statistical methods and the reason for their 
choice described? 
10.2 Is study size and/or statistical precision estimated?
10.3 Are descriptive analyses included?
10.4 Are stratified analyses included?
10.5 Does the plan describe methods for analytic control of 
confounding?
10.6 Does the plan describe methods for analytic control of 
outcome misclassification?
10.7 Does the plan describe methods for handling missing 
data?
10.8 Are relevant sensitivity analyses described?

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Comments:
Section 11: Data management and quality control
Yes
No
N/A
Section 
Number
11.1 Does the protocol provide information on data storage? 
(e.g. software and IT environment, database maintenance 
and anti-fraud protection, archiving)
11.2 Are methods of quality assurance described?
11.3 Is there a system in place for independent review of 
study results? 
Comments:
Section 12: Limitations
Yes
No
N/A
Section 
Number
12.1 Does the protocol discuss the impact on the study results 
of:
12.1.1 Selection bias?
12.1.2 Information bias?
12.1.3 Residual/unmeasured confounding? (e.g. anticipated 
direction and magnitude of such biases, validation sub-
study, use of validation and external data, analytical 
methods).
12.2 Does the protocol discuss study feasibility? (e.g. study 
size, anticipated exposure uptake, duration of follow-up 
in a cohort study, patient recruitment, precision of the 
estimates)
Comments:
Section 13: Ethical/data protection issues
Yes
No
N/A
Section 
Number
13.1 Have requirements of Ethics Committee/ Institutional 
Review Board been described?
13.2 Has any outcome of an ethical review procedure been 
addressed?
13.3 Have data protection requirements been described?
Comments:
Section 14: Amendments and deviations
Yes
No
N/A
Section 
Number

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Section 14: Amendments and deviations
Yes
No
N/A
Section 
Number
14.1 Does the protocol include a section to document 
amendments and deviations?
Comments:
Section 15: Plans for communication of study results
Yes
No
N/A
Section 
Number
15.1 Are plans described for communicating study results 
(e.g. to regulatory authorities)? 
15.2 Are plans described for disseminating study results 
externally, including publication?
Comments:
Name of the main author of the protocol:
Date: dd/Month/year
Signature: 

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ANNEX 3. ADDITIONAL INFORMATION
A3-1
DIVISION OF EASTERN, CENTRAL, AND WESTERN CHINA [R20-1011]
The eastern region includes 11 provinces and municipalities in Beijing, Tianjin, Hebei, 
Liaoning, Shanghai, Jiangsu, Zhejiang, Fujian, Shandong, Guangdong, and Hainan; the 
central region includes 8 provinces in Shanxi, Jilin, Heilongjiang, Anhui, Jiangxi, Henan, 
Hubei, and Hunan; the western region includes 12 provinces, autonomous regions, and 
municipalities in inner Mongolia, Chongqing, Guangxi, Sichuan, Guizhou, Yunnan, Tibet, 
Shaanxi, Gansu, Qinghai, Ningxia, and Xinjiang.
A3-2
DOCUMENTED INTRAVENOUS THROMBOLYTICS ABSOLUTE 
CONTRAINDICATIONS
For CNSR I:

Aged above 80 years; 

CT evidence of intracranial haemorrhage;

CT evidence of early signs of large cerebral infarction;

Concurrence of epileptic seizures during ischemic;

Have suffered a stroke or severe head injury in the past 3 months;

Uncontrolled hypertension despite active treatment. Uncontrolled 
hypertension refers to systolic blood pressure > 185 mmHg or diastolic blood 
pressure > 110 mmHg, measured at least 10 minutes apart and repeated 
3 times;

Known hemorrhagic condition with significant bleeding disorder at onset or 
within the past 6 months;

Acute pancreatitis or proven ulcerative gastrointestinal disease within 
3 months;

Recent invasive cardiopulmonary resuscitation or childbirth within 10 days. 
Non-stress vascular puncture (such as subclavian vein or femoral vein 
puncture);

Blood glucose < 50 mg/dl (2.7 mmol/l) or > 400 mg/dl (22.2 mmol/l);

Platelet count < 105/mm3;

Prothrombin time (PT) (international normalized ratio [INR]) > 1.5 or PT > 15 
or activated partial thromboplastin time (APTT) > 40 sec.
For CNSRII and III:

Uncontrolled hypertension despite active treatment. Uncontrolled 
hypertension refers to systolic blood pressure > 185 mmHg or diastolic blood 
pressure > 110 mmHg （;

Concurrence of epileptic seizures during ischemic stroke;

Recent surgery or trauma within 15 days;

Recent intracranial or spinal surgery, head trauma, or stroke within 3 months;

Previous history of intracranial haemorrhage, aneurysm, vascular 
malformation, or brain tumor;

Active visceral bleeding within 22 days;

Boehringer Ingelheim
Page 39 of 39
Protocol for non-interventional studies based on existing data
BI Study Number 0135-0343
c31688667-01
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)

Platelet count <105/mm3, APTT (after heparin treatment) > 40 sec, PT > 15 or 
PT (INR) > 1.7, or known hemorrhagic condition/suspected subarachnoid 
hemorrhage

CT evidence of ICH, SAH, or signs of large infarction.