Characteristics and In-hospital Outcomes of Chinese Elderly (>80 Years) Patients With Acute Ischemic Stroke Receiving Intravenous Recombinant Tissue Plasminogen Activator Treatment Within 4.5 Hours of Symptom Onset
Conditions: Stroke
Sponsor: Boehringer Ingelheim

 
ABCD 
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
Protocol for non-interventional study
Document Number: 
c36696074-01
BI Study Number: 
0135-0348
BI Investigational 
Product(s):
Actilyse® (Alteplase)
Title:
Characteristics and in-hospital outcomes of Chinese elderly (>80 years)
patients with acute ischemic stroke receiving intravenous recombinant 
tissue plasminogen activator treatment within 4.5 hours of symptom onset
Brief lay title: 
Alteplase in elderly AIS during hospitalization
Protocol version 
identifier: 
1.0
Date of last version of 
protocol: 
Not applicable
PASS:
No
EU PAS register 
number: 
EUPAS41509
Active substance: 
Alteplase
Medicinal product:
Actilyse® (Alteplase)
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
Boehringer Ingelheim (China) Investment Co., Ltd 
Joint PASS:
No
Research question and 
objectives:
Primary objective:
x
To describe all-cause mortality during hospitalization of acute 
ischemic stroke (AIS) patients who were treated with intravenous 
recombinant tissue plasminogen activator (IV rt-PA) within 4.5 
hours of symptom onset, among those aged 18 to 80 years and >80 
years, respectively.
Secondary objectives: 
x
To describe other in-hospital clinical outcomes (including 
proportion of patients with hemorrhagic stroke during 

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hospitalization, change of NIHSS score from before IV rt-PA 
treatment to 24 hours after IV rt-PA treatment, mRS score at 
discharge, proportion of patients with stroke recurrence during 
hospitalization, and length of hospitalization) of AIS patients who 
were treated with IV rt-PA within 4.5 hours of symptom onset, 
among those aged 18 to 80 years and >80 years, respectively 
x
To describe the characteristics of AIS patients who arrived or were
admitted to the hospital within 4.5 hours of symptom onset and
were treated with or without IV rt-PA among different age groups
(18 to 80 years and above 80 years).
x
To describe the percentage of patients receiving IV rt-PA
treatment within 4.5 hours of symptom onset among AIS patients
aged 18 to 80 years and above 80 years who arrived at or were
admitted to the hospital within 4.5 hours of symptom onset.
Country(-ies) of study:
China 
Author: 
Medical Advisor 
In case of PASS, add:
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: 
2 Sep 2021
Page 1 of 41
Proprietary confidential information
© 2021 Boehringer Ingelheim Group of companies. All rights reserved.
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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1.
TABLE OF CONTENTS
TITLE PAGE .................................................................................................................. 1 
1.
TABLE OF CONTENTS ....................................................................................... 3 
2.
LIST OF ABBREVIATIONS ................................................................................ 5 
3.
RESPONSIBLE PARTIES .................................................................................... 6 
4.
ABSTRACT ........................................................................................................... 7 
5.
AMENDMENTS AND UPDATES...................................................................... 
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 ........................................................................................................ 20 
9.2.1 
Study sites ............................................................................................... 20 
9.2.2 
Study population ..................................................................................... 20 
9.2.3 
Study visits .............................................................................................. 21 
9.2.4 
Study discontinuation .............................................................................. 21 
9.3 
VARIABLES .................................................................................................. 21 
9.3.1 
Exposures ................................................................................................ 21 
9.3.2 
Outcomes ................................................................................................. 21 
9.3.2.1 
Primary outcome .............................................................................. 21 
9.3.2.2 
Secondary outcomes ......................................................................... 21 
9.3.3 
Covariates ................................................................................................ 22 
9.4 
DATA SOURCES ........................................................................................... 23 
9.5 
STUDY SIZE .................................................................................................. 23 
9.6 
DATA MANAGEMENT ................................................................................ 24 
9.7 
DATA ANALYSIS ......................................................................................... 24 
9.7.1 
Main analysis ........................................................................................... 24 
9.7.3 
Safety Analysis ........................................................................................ 25 
9.8 
QUALITY CONTROL ................................................................................... 25 
9.9 
LIMITATIONS OF THE RESEARCH METHODS ...................................... 25 
9.10 
OTHER ASPECTS ......................................................................................... 26 

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9.10.1 
Data quality assurance ............................................................................. 26 
9.10.2 
Study records ........................................................................................... 26 
9.10.2.1 
Source documents ............................................................................ 26 
9.10.2.2 
Direct access to source data and documents .................................... 26 
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 27
10.1    STUDY APPROVAL AND PATIENT INFORMATION…………………..2
10.2     STATEMENT OF CONFIDENTLALITY…………………………………..2
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 ................................................................... 31 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .............................................. 32 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 33 
ANNEX 3. ADDITIONAL INFORMATION .............................................................. 39 
ANNEX 4. REVIEWERS AND APPROVAL SIGNATURES ................................... 40 

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2.
LIST OF ABBREVIATIONS
AIS
Acute Ischemic Stroke
ASD
Absolute Standardized Difference
BI
Boehringer Ingelheim
CDE
Chinese Centre for Drug Evaluation
CI
Confidence Intervals
CSA
Chinese Stroke Association
CSCA
Chinese Stroke Centre Alliance
eCRF
Electronic Case Report Form
EVT
Endovascular Treatment
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IQR
Interquartile Range
IRB
Institutional Review Board
IV
Intravenous
IVT
Intravenous Thrombolysis
NIHSS
National Institutes of Health Stroke Scale
NIS
Non-interventional Study
NIS-DMRP
Non-interventional Study-data Management and Review Plan
PT
Prothrombin Time
RCTs
Randomized Controlled Trials
rt-PA
Recombinant Tissue Plasminogen Activator
RWE
SEAP
Real-world Evidence
Statistical and Epidemiological Analysis Plan
SOPs
Standard Operation Procedures
TIA
Transient Ischemic Attack
ZSQCCP
Zhejiang Stroke Quality Control Center Platform

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3.
RESPONSIBLE PARTIES
Boehringer Ingelheim Contact Person:
Contact details: 
Principal Investigator:
Contact details: 

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Actilyse
Name of active ingredient:
Alteplase
Study number:
Version/Revision:
Version/Revision date:
Protocol date:
2 Sep 2021 
0135-0348
1.0
Title of study:
Characteristics and in-hospital outcomes of Chinese elderly (>80 years) 
patients with acute ischemic stroke receiving intravenous recombinant tissue 
plasminogen activator treatment within 4.5 hours of symptom onset 
Rationale and 
background:
Actilyse® was first approved for the treatment of acute ischaemic stroke 
(AIS) for patients aged 18 to 80 years. Data from recent studies have shown 
that patients aged >80 years may also benefit from intravenous (IV)
recombinant tissue plasminogen activator (rt-PA) when given within 
4.5 hours of symptom onset. The benefit of intravenous thrombolysis (IVT) 
within 4.5 hours of symptom onset for AIS patients has been well proven and 
recommended by international/national guidelines. 
All countries in the European Union including Germany, Austria, and 
Belgium have successively approved Actilyse® to remove the age restriction 
of 80 years since Jun 2018. Most of the data supporting this clinical 
overview came from western countries. As there is limited data regarding the 
safety or effectiveness of IV rt-PA among Chinse AIS patients 
aged >80 years, the age restriction has not been removed yet by National 
Medical Products Administration. However, Chinese Guidelines for 
Diagnosis and Treatment of AIS 2014 and 2018 removed the age restriction 
of 80 years in the recommendations for IV thrombolysis with alteplase 
within 3 hours and 3 to 4.5 hours of stroke onset, respectively. In addition, 
Chinese AIS patients aged >80 years have been treated with IV thrombolytic 
therapy in clinical practice according to local guidelines.
In this study, we propose to use the Chinese Stroke Centre Alliance (CSCA) 
data to describe the in-hospital clinical outcomes regarding safety and 
effectiveness for AIS patients who were treated with IV rt-PA within 4.5 hours 
of symptom onset, aged above 80 years, as well as between 18 and 80 years. 
We plan to apply and incorporate the results of this study (providing in-
hospital outcomes), together with another non-interventional study in China 
(providing 1-year clinical outcomes), as well as results from randomized 
controlled trials conducted in other countries, to support local label update: to 
remove the age restriction (>80 years) from the label of Actilyse in China.
Research question 
and objectives:
Research question: What are the in-hospital clinical outcomes among 
Chinese AIS patients, who were treated with IV rt-PA within 4.5 hours of 
symptom onset in different age groups (18 to 80 years and above 80 years). 

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Actilyse
Name of active ingredient:
Alteplase
Study number:
Version/Revision:
Version/Revision date:
Protocol date:
2 Sep 2021 
0135-0348
1.0
Primary objective:
x
To describe all-cause mortality during hospitalization of AIS patients who
were treated with IV rt-PA within 4.5 hours of symptom onset, among
those aged 18 to 80 years and >80 years, respectively.
Secondary objectives: 
x
To describe other in-hospital clinical outcomes (including proportion of
patients with hemorrhagic stroke during hospitalization, change of
NIHSS score from before IV rt-PA treatment to 24 hours after IV rt-PA
treatment, mRS score at discharge, proportion of patients with stroke
recurrence during hospitalization, and length of hospitalization) of AIS
patients who were treated with IV rt-PA within 4.5 hours of symptom
onset, among those aged 18 to 80 years and >80 years, respectively
x
To describe the characteristics of AIS patients who arrived or were
admitted to the hospital within 4.5 hours of symptom onset and were
treated with or without IV rt-PA among different age groups (18 to 80 years 
and above 80 years).
x
To describe the percentage of patients receiving IV rt-PA treatment within
4.5 hours of symptom onset among AIS patients aged 18 to 80 years and
above 80 years who arrived at or were admitted to the hospital within
4.5 hours of symptom onset.
Study design:
This is a non-interventional study based on existing data from CSCA platform.
Population:
Inclusion Criteria:
x
Patients registered in the CSCA platform from Aug 2015 to Jul 2019
x
\HDUs old

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Actilyse
Name of active ingredient:
Alteplase
Study number:
Version/Revision:
Version/Revision date:
Protocol date:
2 Sep 2021 
0135-0348
1.0
x
Diagnosed as AIS at admission
x
Arrived or admitted to hospital within 4.5 hours of symptom onset
x
For patients in the IV rt-PA groups only: received IV rt-PA within
4.5 hours of symptom onset
Exclusion Criteria:
x
Documented 
intravenous 
thrombolytics 
(IVT) 
absolute
contraindication except age to IV rt-PA treatment according to the SmPC.
x
Key data missing (age, gender, baseline National Institutes of Health
Stroke Scale [NIHSS], time of symptom onset, IVT treated or not,
time of IV alteplase treatment)
x
Received thrombolysis agents other than IV rt-PA (urokinase,
tenecteplase, recombinant plasminogen activator, prourokinase,
streptokinase)
x
Received endovascular treatment
x
Received IV rt-PA after 4.5 hours of symptom onset
Patient groups:
Patients in this study will be divided into 4 groups: 
x
Group 1: AIS patients aged >80 years who received IV rt-PA within
4.5 hours of symptom onset
x
Group 2: AIS patients aged 18 to 80 years who received IV rt-PA
within 4.5 hours of symptom onset
x
Group 3: AIS patients aged >80 years who arrived or were admitted
to the hospital within 4.5 hours of symptom onset and did not receive
thrombolysis treatment
x
Group 4: AIS patients aged 18 to 80 years who arrived or were
admitted to the hospital within 4.5 hours of symptom onset and did
not receive thrombolysis treatment
Variables:
Covariates include the following variables at baseline:
x
Age
x
Gender (male, female)
x
Stroke severity (baseline NIHSS)
x
Time from symptom onset to hospital arrival or admission
x
Smoking (current smoker, former smoker, never smoker)

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Actilyse
Name of active ingredient:
Alteplase
Study number:
Version/Revision:
Version/Revision date:
Protocol date:
2 Sep 2021 
0135-0348
1.0
x
Alcohol consumption (yes, no)
x
Comorbidities at baseline (diabetes, prior coronary heart disease
/myocardial infarction, atrial fibrillation/flutter, prior heart failure, carotid 
stenosis, peripheral vascular disease, prior stroke/transient ischemic
attack, hypertension, dyslipidaemia)
x
Comedication at baseline (antiplatelet, anticoagulation, antidiabetics,
antihypertensive drug, lipid-lowering drug)
x
For IV rt-PA treated patients: time from symptom onset to treatment, time 
from hospital arrival or admission to treatment (door-to-needle time),
dosage of rt-PA
x
For No IV rt-PA treated patients: Reasons for not being treated with IV
rt-PA
x
Education (primary school or below, junior high school, senior high
school, junior college or above)
x
Medical insurance status (urban employee basic medical insurance, urban
resident basic medical insurance, new rural cooperative medical
insurance, other medical insurance, no insurance)
x
Hospital level (Grade 2, Grade 3).
Variables collected during hospitalization: 
x
Lab values: blood-glucose, C-reactive protein;
x
Clinical symptoms: evaluation of swallowing ability, pneumonia;
Primary outcomes:
x
All-cause mortality during hospitalization of patients in Group 1 and
Group 2.
Secondary outcomes:
x
Proportion of patients with hemorrhagic stroke during hospitalization
x
Change of NIHSS score from before IV rt-PA treatment to 24 hours after
IV rt-PA treatment
x
mRS score at discharge
x
Proportion of patients with stroke recurrence during hospitalization
x
Length of hospitalization;
x
All the above in-hospital secondary outcomes will be observed in Group 1
and Group 2.
x
Percentage of IV rt-PA treatment among AIS patients arrived or were 

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Actilyse
Name of active ingredient:
Alteplase
Study number:
Version/Revision:
Version/Revision date:
Protocol date:
2 Sep 2021 
0135-0348
1.0
admitted to the hospital within 4.5 hours of symptom onset.
x
Percentage of IV rt-PA treatment within 4.5 hours of symptom onset 
among eligible AIS patients (3.5-hour arrival or admission)
The percentage of IV rt-PA treatment will be calculated based on age groups 
(18-80 years and > 80 year). 
Data sources:
Data for this study will come from the CSCA platform.The CSCA is a 
national, hospital-based, multicentre, voluntary, multifaceted intervention and 
continuous quality improvement initiative, launched by Chinese Stroke 
Association (CSA) in 2015. This programme is made available to all Chinese 
Grade 2 and Grade 3 hospitals. Hospitals continued to join the programme in 
a staggered manner. By Jul 2019, 1476 hospitals (720 Grade 2 hospitals, 756 
Grade 3 hospitals) had participated into this programme. Hospital 
characteristics, including geographic region, teaching status, hospital volume 
(grade 2 and 3) and annual stroke volume, are surveyed. Data were collected 
via the web-based patient data collection and management tool (Medicine 
Innovation Research Center, Beijing, China), abstracted via chart review, 
coded, de-identified and transmitted in a secure manner to maintain patient 
confidentiality compliant with national privacy standards. The following data 
were collected for each hospitalization: patient demographics, history of 
disease and medication, hospital presentation, initial neurological status, 
medications and interventions, reperfusion strategy and in-hospital outcomes 
and complications.
Study size:
A feasibility check showed that by Jul 2019, according to the key inclusion 
and exclusion criteria, there were roughly 31,400 ( 28,100 aged 18 to 80 years, 
3,300 above 80 years) AIS patients treated with IV rt-PA and 84,000 (72,000 
aged 18 to 80 years; 12,000 above 80 years) AIS patients arrived at hospital 
within 4.5 hours of symptom onset but did not receive reperfusion treatment. 
Previous studies showed that the incidence of symptomatic intracerebral 
hemorrhage for IVT treated patients was 2.4% among 18 to 80 years age group 

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Actilyse
Name of active ingredient:
Alteplase
Study number:
Version/Revision:
Version/Revision date:
Protocol date:
2 Sep 2021 
0135-0348
1.0
and 3.7% among >80 years age group. Table 1 showed the 95% confidence 
intervals (CI) with the current sample size and the incidence rates from 
previous studies:
Table 1       Estimated rates of in-hospital hemorrhage stroke and 95% CI 
Age Group 
Current 
Sample Size
Incidence 
Based on 
Previous 
Studies
95%CI 
ı18 years 
N=31400 
3.6% 
3.40%, 3.82%
18-80 years
N=28100 
2.4% 
2.22%, 2.59%
>80 years
N=3300 
3.7% 
3.07%, 4.41%
Data analysis:
The primary and secondary outcomes will be analysed by using descriptive 
statistics for group 1 and group 2. The baseline characteristics (covariates) 
will be  described descriptively for all 4 groups in this study. 
To evaluate the potential channelling, the baseline characteristics of AIS
patients aged >80 years treated with iv rtPA within 4.5 hours of symptom 
onset (group 1) will be compared with the following 2 groups: 
Patients aged >80 years who did not receive reperfusion and who arrived at 
or admitted to the hospital within 4.5 hours of symptom onset (group 3)
Patients aged 18-80 years who received iv rtPA and who arrived at or 
admitted to the hospital within 4.5 hours of symptom onset (group 2) 
Absolute standardized difference (ASD) between the compared groups will 
be calculated, in which a ı10% ASD will be considered a meaningful 
difference. 

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Actilyse
Name of active ingredient:
Alteplase
Study number:
Version/Revision:
Version/Revision date:
Protocol date:
2 Sep 2021 
0135-0348
1.0
For general statistical considerations, the descriptive statistics for continuous 
variables will include mean, standard deviation, 95% CI of mean,median, 
interquartile range; for categorical variables, counts, percentages and 95% CI
will be included. For categorical variables, 95% Clopper-Pearson confidence 
interval will be used.  
Milestones:
Protocol finalisation: Oct 2021
Start of data collection: NA
End of data collection:  NA
Statistical and epidemiological analysis plan completion: Apr 2022 
Final report of study results: Jul 2022

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5.
AMENDMENTS AND UPDATES
Not applicable.

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6.
MILESTONES 
Milestone
Planned Date
Protocol Approval  
Oct 2021 
IRB/IEC approval 
Dec 2021
Statistical and epidemiological analysis plan completion
Apr 2022 
Final report of study results: 
Jul 2022 

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7.
RATIONALE AND BACKGROUND
Stroke is the leading cause of mortality and disability among adults in China, which is 
characterized by high morbidity, disability and mortality. With the aging of society, the 
acceleration of urbanization, and popular unhealthy lifestyle among residents, the stroke 
burden in China displayed an explosive growth trend and elderly patients with AIS are
becoming common in China. [R19-3903],[R21-1796],[P21-04631] According to the 2018 data in Chinese 
acute ischaemic stroke (AIS) patients, it was deduced that there were 12.42 million Chinese
AIS patients and 1.96 million patients died due to AIS.[R19-3903] In addition, according to the 
report of the Chinese Stroke Alliance from 2015 to 2017, about one fourth of the AIS patients 
recorded in the China Stroke Centre Alliance (CSCA) platform were elderly patients 
aged >75 years.[P21-04633] Therefore, the prevention and treatment of stroke is still facing huge 
challenges in China, and further strengthening the prevention and treatment system and 
improving the prognosis of stroke patients are urgent needs in stroke management.
The benefit of intravenous thrombolysis (IVT) within 4.5 hours of symptom onset for AIS 
patients has been well proven and recommended by international/national guidelines.[P19-
10385],[P21-02289],[P19-10855] A meta-analysis of randomised controlled trials (RCTs) demonstrated 
a positive benefit-risk ratio for alteplase when used according to label criteria.[P20-06029] The
benefit–risk ratio changed with time to treatment: earlier treatment was associated with better
outcomes, while delayed treatment was associated with reduced benefit.
When Actilyse® was first approved for the treatment of AIS, it was indicated only for patients
aged 18 to 80 years. Recent studies suggested that patients aged > 80 years may also benefit
from IV recombinant tissue plasminogen activator (rt-PA) when given within 4.5 hours of
symptom onset. [P21-04636]Data from both RCTs and observational studies showed consistent 
results: patients aged > 80 years who received IV rt-PA within 4.5 hours of symptom onset 
had improved outcomes without increasing haemorrhage rates, although this elderly patient 
population had a higher mortality rate and poorer functional outcomes than younger patients 
do. In addition, the international guidelines recommends the IV thrombolysis with alteplase
within 3 hours and 3 to 4.5 hours of stroke onset in suitable AIS patients aged >80 years.[P19-
10385]
All countries in the European Union including Germany, Austria, and Belgium have
successively approved Actilyse® to remove the age restriction of 80 years since Jun 2018. 
Until now, there is limited data regarding the safety or effectiveness of IV rt-PA among
Chinse AIS patients aged > 80 years. Therefore, in China the age restriction of 80 years has
not been removed yet by National Medical Products Administration. However, Chinese 
Guidelines for Diagnosis and Treatment of AIS 2014[P21-04636] and 2018[P19-10855] removed the 
age restriction of 80 years in the recommendations for IV thrombolysis with alteplase within
3 hours and 3 to 4.5 hours of stroke onset, respectively. In addition, it is common to give IV
thrombolytic therapy to Chinese AIS patients aged > 80 years in clinical practice according to
local guidelines.[P19-10855],[P21-04637]
In January 2020, the Chinese Centre for Drug Evaluation (CDE) released Guidelines for
Real-World Evidence to Support Drug Development and Review (Interim). In this guideline, 
China CDE listed several scenarios demonstrating how real-world evidence (RWE) can be 
used to support drug development and regulatory decision making. One of the scenarios was 

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to use RWE to provide evidence for changing leaflets of approved drugs, including adding 
new applicable populations. 
In this study, we propose to use the Chinese Stroke Centre Alliance (CSCA) data to describe 
the in-hospital clinical outcomes regarding safety and effectiveness for AIS patients who were 
treated with IV rt-PA within 4.5 hours of symptom onset, aged >80 years, as well as between 
18 and 80 years.  

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8.
RESEARCH QUESTION AND OBJECTIVES
Research question:
What are the in-hospital clinical outcomes among Chinese AIS patients, who were treated with 
IV rt-PA within 4.5 hours of symptom onset in different age groups (18 to 80 years and above 
80 years). 
Primary objective:
To describe  all-cause mortality during hospitalization of AIS patients who were treated with 
IV rt-PA within 4.5 hours of symptom onset, among those aged 18 to 80 years and >80 years, 
respectively.
Secondary objectives: 
x
To describe other in-hospital clinical outcomes (including proportion of patients with 
hemorrhagic stroke during hospitalization, change of NIHSS score from before IV rt-PA 
treatment to 24 hours after IV rt-PA treatment, mRS score at discharge, proportion of 
patients with stroke recurrence during hospitalization, and length of hospitalization) of AIS 
patients who were treated with IV rt-PA within 4.5 hours of symptom onset, among those 
aged 18 to 80 years and >80 years, respectively.
x
To describe the characteristics of AIS patients who arrived or were admitted to the hospital 
within 4.5 hours of symptom onset and were treated with or without IV rt-PA among 
different age groups (18 to 80 years and above 80 years).
x
To describe the percentage of patients receiving IV rt-PA treatment within 4.5 hours of 
symptom onset among AIS patients aged 18 to 80 years and above 80 years who arrived 
at or were admitted to the hospital within 4.5 hours of symptom onset.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a non-interventional study based on existing data from CSCA platform. 
Patients in this study will be divided into 4 groups: 
x
Group 1: AIS patients aged >80 years who received IV rt-PA within 4.5 hours of 
symptom onset 
x
Group 2: AIS patients aged 18 to 80 years who received IV rt-PA within 4.5 hours of 
symptom onset 
x
Group 3: AIS patients aged >80 years who arrived or were admitted to the hospital 
within 4.5 hours of symptom onset and did not receive thrombolysis treatment 
x
Group 4: AIS patients aged 18 to 80 years who arrived or were admitted to the hospital 
within 4.5 hours of symptom onset and did not receive thrombolysis treatment. 
The baseline characteristics will be described in groups 1 to 4. 
The clinical outcomes during hospitalization will be observed in groups 1 to 2.  
In addition, the percentage of AIS patients who received IV rt-PA treatment within 4.5 hours 
of onset will be calculated among 4.5 hours hospital arrival AIS patients, and IVT eligible
patients (3.5 hours hospital arrival or admission and without IVT absolute contraindication), in 
each age group of 18 to 80 years and >80 years, respectively.
In China, rt-PA is only indicated in AIS patients aged 18 to 80 years. Therefore, it is possible 
that AIS patients aged >80 years who received IV rt-PA are different from other patients in 
terms of their baseline characteristics (channeling). To evaluate the potential channeling, in this 
study we will compare the baseline characteristics of AIS patients aged >80 years treated with 
IV rt-PA within 4.5 hours of symptom onset (Group 1) with those in Group 2 and Group 3. 
The flow of data selection for each of the 4 reporting patient groups is depicted in Figure 1
below. 

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Exclusion Criteria:
x
Documented IVT absolute contraindication 
x
Key data missing (age, gender, baseline National Institutes of Health Stroke Scale 
[NIHSS], time of symptom onset, IVT treated or not, time of IV alteplase treatment)
x
Received thrombolysis agents other than IV rt-PA (urokinase, tenecteplase, recombinant 
plasminogen activator, prourokinase, streptokinase) 
x
Received endovascular treatment
x
Received IV rt-PA after 4.5 hours of symptom onset.
9.2.3
Study visits
Not applicable.
9.2.4
Study discontinuation
Boehringer Ingelheim reserves the right to discontinue the study at any time for the following 
reason: 
x
Violation of Good Pharmacoepidemiology Practice (GPP), the study protocol, or the
contract by study site, investigator or research collaborator, disturbing the appropriate
conduct of the study. 
9.3
VARIABLES
9.3.1
Exposures
The exposure in this study is the use of IV rt-PA among AIS patients within 4.5 hours of 
symptom onset. 
9.3.2
Outcomes
9.3.2.1
Primary outcome 
x
All-cause mortality during hospitalization of patients in Group 1 and Group 2.  
9.3.2.2
Secondary outcomes 
x
Proportion of patients with hemorrhagic stroke during hospitalization 
x
Change of NIHSS score from before IV rt-PA treatment to 24 hours after IV rt-PA 
treatment
x
mRS score at discharge
x
Proportion of patients with stroke recurrence during hospitalization
x
Length of hospitalization; 
All the above in-hospital secondary outcomes will be observed in Group 1 and Group 2. 
x
Percentage of IV rt-PA treatment among AIS patients arrived or were admitted to the 
hospital within 4.5 hours of symptom onset 
x
Percentage of IV rt-PA treatment within 4.5 hours of symptom onset among eligible AIS 

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patients (3.5-hour arrival or admission)
The percentage of IV rt-PA treatment will be calculated based on age groups (18-80 years 
and > 80 year).
9.3.3
Covariates 
Covariates include the following variables at baseline: 
x
Age
x
Gender (male, female)
x
Stroke severity (baseline NIHSS)
x
Time from symptom onset to hospital arrival or admission 
x
Smoking (current smoker, former smoker, never smoker) 
x
Alcohol consumption (yes, no) 
x
Comorbidities at baseline: 
o
Diabetes
o
Prior coronary heart disease /myocardial infarction
o
Atrial fibrillation/flutter
o
Prior heart failure
o
Carotid stenosis 
o
Peripheral vascular disease
o
Prior stroke/Transient Ischemic Attack (TIA) 

Prior stroke

Prior TIA
o
Hypertension 
o
Dyslipidaemia
x
Comedication at baseline (antiplatelet, anticoagulation, antidiabetics, antihypertensive 
drug, lipid-lowering drug) 
x
For IV rt-PA treated patients:
o
Time from symptom onset to treatment
o
Time from hospital arrival or admission to treatment (door-to-needle time)
o
Dosage of rt-PA
x
For No IV rt-PA treated patients:
o
Reasons for not being treated with IV rt-PA
x
Education 
o
Primary school or below 
o
Junior high school 
o
Senior high school 

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o
Junior college or above 
x
Medical insurance status (urban employee basic medical insurance, urban resident 
basic medical insurance, new rural cooperative medical insurance, other medical 
insurance, no insurance) 
x
Hospital level
o
Grade 2 
o
Grade 3 
Variables collected during hospitalization:
x
Lab values: blood-glucose, C-reactive protein;
x
Clinical symptoms: evaluation of swallowing ability, pneumonia;
9.4
DATA SOURCES
The CSCA is a national, hospital-based, multicentre, voluntary, multifaceted intervention and 
continuous quality improvement initiative, launched by Chinese Stroke Association (CSA) in 
2015. This programme is made available to all Chinese Grade 2 and Grade 3 hospitals. 
Hospitals continued to join the programme in a staggered manner. By Jul 2019, 1476 hospitals 
(720 Grade 2 hospitals, 756 Grade 3 hospitals) had participated into this programme. Hospital 
characteristics, including geographic region, teaching status, hospital volume (grade 2 and 3)
and annual stroke volume, are surveyed. Data were collected via the web-based patient data 
collection and management tool 
, 
abstracted via chart review, coded, de-identified and transmitted in a secure manner to maintain 
patient confidentiality compliant with national privacy standards. The following data were 
collected for each hospitalization: patient demographics, history of disease and medication, 
hospital presentation, initial neurological status, medications and interventions, reperfusion 
strategy and in-hospital outcomes and complications. 
9.5
STUDY SIZE
A feasibility check showed that by Jul 2019, according to the key inclusion and exclusion 
criteria, there were roughly 31,400 (28,100 aged 18-80 years, 3,300 above 80 years) AIS 
patients treated with IV rt-PA and 84,000 (72,000 aged 18 to 80 years; 12,000 above 80 years) 
AIS patients arrived at hospital within 4.5 hours of symptom onset but did not receive 
reperfusion treatment.
Previous studies showed that the incidence of symptomatic intracerebral hemorrhage for IVT 
treated patients was 2.4% among 18 to 80 years age group and 3.7% among > 80 years age 
group. [P14-16838] Table 1 showed the 95% confidence intervals with the current sample size and 
the incidence rates from previous studies: 
Table 1
Estimated rates of in-hospital hemorrhage stroke and 95% CI
Age Group
Current Sample 
Size
Incidence Based on 
Previous Studies
95%CI
ı18 years 
N=31,400 
3.6% 
3.40%, 3.82% 
18-80 years
N=28,100 
2.4% 
2.22%, 2.59% 

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>80 years
N=3,300 
3.7% 
3.07%, 4.41% 
9.6
DATA MANAGEMENT
Full details of the data management plan are documented in a separate Non-Interventional 
Study-Data Management and Review Plan (NIS-DMRP).
Routine operations of the CSCA are conducted and managed by the CSA staff. These 
operations are as follows: update and maintain the CSCA web-based data collection and 
management tool; develop and run site feedback reports and execute research analyses as part 
of its role as the CSCA data coordinating centre. The CSCA’s data coordinating centre 
resides at the 
Hospital.
All statistical analysis will be using SAS version 9.3 or above. 
9.7
DATA ANALYSIS
The statistical analysis plan for the study is summarized below. Full details of the statistical 
analysis will be documented in the SEAP, which will be finalized before the end of data
collection.
9.7.1
Main analysis 
The baseline characteristics (covariates) as listed in Section 9.3.3 will be analysed by using 
descriptive statistics for all 4 groups in this study, where Group 1 is compared against group 2 
and Group 1 is compared against Group 3 to evaluate the potential channeling. Absolute 
standardized difference (ASD) between the compared groups will be calculated, in which a 
$6'ZLOOEHFRQVLGHUHGDPHDQLQJIXOGLIIHUHQFH
The primary outcome is the all-cause mortality during hospitalization. The primary outcome 
will be described using descriptive statistics for Group 1 and Group 2. The secondary outcome 
as listed in Section 9.3.2.2 will also be described using descriptive statistics for Group 1 and 
Group 2. Additionally, if the baseline characteristics of patients in group 1 are comparable to 
patients in group 3 (ASD<10%), then we will describe the in-hospital outcomes for group 3 
patients, including all-cause mortality during hospitalization, proportion of patients with 
hemorrhagic stroke during hospitalization, mRS score at discharge, proportion of patients with 
stroke recurrence during hospitalization, and length of hospitalization. If the baseline 
characteristics of patients in group 1 and group 3 are not comparable, then we will not describe 
the above outcomes in group 3. 
For general statistical considerations, the descriptive statistics for continuous variables will 
include mean, standard deviation, 95% confidence interval (CI) of mean, median, interquartile 
range (IQR); for categorical variables, counts, percentages, and 95% CI will be included. For 
categorical variables, 95% Clopper-Pearson confidence interval will be used.

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In terms of the display of decimal places, mean, median, and IQR will be reported to one more 
decimal place than the raw data recorded in the database. Standard deviation and 95% 
confidence interval will be reported to two more decimal places than the raw data recorded in 
the database. P-value will be reported to fourth decimal place if available.
9.7.3
Safety Analysis 
This is a NIS based on existing data. From safety information collecting and reporting 
perspective, this study will not involve individual medical record review, thus no adverse 
event/adverse drug reaction information is required to collect. The analysis please refer to 
Section 9.7.2.
9.8
QUALITY CONTROL
The quality control, review, and monitoring plan are summarized below. Greater details are 
documented in the NIS-DMRP.
The study will strictly follow BI standard operation procedures (SOPs). In addition, this study 
will follow key elements of the Guideline for GPP.[R16-5416] The statistical analytic approach 
will be reviewed/repeated by a second analyst. The study report will be reviewed, approved 
and archived per BI SOP.
9.9
LIMITATIONS OF THE RESEARCH METHODS
Hospital participation in the CSCA is voluntary. As a result, the current participating hospitals 
are more likely to be larger, tertiary centers with a myriad of resources to which smaller 
hospitals do not have access. Although hospital recruitment remains ongoing, the findings from 
CSCA may not be generalizable to patients who present with acute stroke/TIA to hospitals 
outside of the CSCA. Data collected by hospitals were not independently audited by external 
chart review. Data reliability depends on training for data abstractors and built-in automated 
checks to identify erroneous, illogical data entries. 
The CSCA data only collected in-hospital outcomes for AIS patients. Therefore, in this study 
it is not possible to look at the clinical outcomes at relatively long-term follow-up period, e.g., 
3 months or 1 year. However, we will have another non-interventional study (NIS) in parallel 
based on the Zhejiang Stroke Quality Control Center Platform (ZSQCCP) data which include 
AIS patients in Zhejiang province aged >80 years who received and who did not receive IVT 
with 12-month follow-up. 

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9.10
OTHER ASPECTS
9.10.1
Data quality assurance 
A quality assurance audit/inspection of this study may be conducted by the investigator or by 
IRBs / Independent Ethics Committee (IECs) or by regulatory authorities. The quality 
assurance auditor will have access to the investigator’s study-related files and correspondence 
of this study.  
9.10.2
Study records
9.10.2.1
Source documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data extracted. 
9.10.2.2
Direct access to source data and documents
The investigator/institution will permit study-related audits, IRB/IEC review and regulatory 
inspection, providing direct access to all related database and all source documents, including 
progress notes, must be available at all times for review by the  inspection by health 
authorities.

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10.
PROTECTION OF HUMAN SUBJECTS
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the International Conference on Harmonisation 
Harmonised Tripartite Guideline for Good Clinical Practice (to the extent applicable to the 
NIS setting and required by local regulations), Good Epidemiological Practice, guidelines for 
GPP, and the relevant BI SOPs. 
10.1
STUDY APPROVAL AND PATIENT INFORMATION
This NIS will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB/IEC and Competent Authority according to national and 
international regulations. The same applies for the implementation of changes introduced by 
amendments.
10.2
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers. 
Data generated as a result of the study need to be available for inspection upon request by the 
participating physicians, the sponsor’s representatives, by the IRB/IEC and the regulatory 
authorities.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
Based on current guidelines from the International Society for Pharmacoepidemiology[R16-5416]
and the European Medicines Agency[R13-1970], NIS such as the one described in this proposal, 
conducted using health care records, do not require expedited reporting of suspected adverse 
events/reactions. Specifically, as stated in section VI.C.1.2.1 of Guideline on Good 
Pharmacovigilance Practices, Module VI – Management and Reporting of Adverse Reactions 
to Medicinal Products, for NIS designs, which are based on use of secondary data, reporting of 
adverse reactions is not required. Not applicable based on secondary use of data without any 
potential that any employee of BI or agent working on behalf of BI will access individually 
identifiable patient data.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalisation of the study report. 
Boehringer Ingelheim intends to use data from this study to prepare peer-reviewed publications 
and other scientific communications such as abstracts, posters, and podiums presentations. 

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
R19-3903 
Wang LD, Liu JM, Yang Y, Peng B, Wang YL, and others on behalf of the 
compiling group of the Report on Stroke Prevention and Treatment in China 
2018. The Prevention and Treatment of Stroke Still Face Huge 
Challenges—Brief Report on Stroke Prevention and Treatment in China 
2018. Chin Circ J. 2019; 34(2):105–119.
R21-1796 
Gao Y, Jiang B, Sun H, Ru X, Sun D, Wang L, Wang L, Jiang Y, Feigin 
VL, Wang Y, Wang W. The burden of stroke in China: Results from a 
nationwide population-based epidemiological survey. PLoS One. 2018; 
13(12):e0208398.
P21-04631 
Wang YJ, Li ZX, Gu HQ, Zhai Y, Jiang Y, Zhao XQ, Wang YL, Yang X, 
Wang CJ, Meng X, Li H, Liu LP, Jing J, Wu J, Xu AD, Dong Q, Wang D, 
Zhao JZ; China Stroke Statistics 2019 Writing Committee. China Stroke 
Statistics 2019: A Report From the National Center for Healthcare Quality 
Management in Neurological Diseases, China National Clinical Research 
Center for Neurological Diseases, the Chinese Stroke Association, National 
Center for Chronic and Non-communicable Disease Control and Prevention, 
Chinese Center for Disease Control and Prevention and Institute for Global 
Neuroscience and Stroke Collaborations. Stroke Vasc Neurol. 2020; 
5(3):211-239.
P21-04633 
Wang YJ, Li ZX, Wang YL, Zhao XQ, Liu LP, Yang X, Wang CY, Gu HQ, 
Zhang FY, Wang CJ, Xian Y, Wang DZ, Dong Q, Xu AD, Zhao JZ, on 
behalf of Chinese Stroke Center Alliance investigators. Chinese Stroke 
Center Alliance: a national effort to improve healthcare quality for acute 
stroke and transient ischaemic attack: rationale, design and preliminary 
findings. Stroke Vasc Neurol. 2018; 3:256-262.
P19-10385 
Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, 
Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, 
Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, 
Southerland AM, Summers DV, Tirschwell DL. Guidelines for the Early 
Management of Patients With Acute Ischemic Stroke: 2019 Update to the 
2018 Guidelines for the Early Management of Acute Ischemic Stroke: A 
Guideline for Healthcare Professionals From the American Heart 
Association/American Stroke Association. Stroke. 2019; 50(12):e344-e418.
P21-02289 
Berge E, Whiteley W, Audebert H, De Marchis GM, Fonseca AC, 
Padiglioni C, de la Ossa NP, Strbian D, Tsivgoulis G, Turc G. European 
Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute
ischaemic stroke. Eur Stroke J. 2021; 6(1):I-LXII.
P19-10855 
Society of Neurology, Chinese Stroke Society. Chinese guidelines for 
diagnosis and treatment of acute ischemic stroke 2018. Chin J Neurol. 
2018; 51(9):666-682.  

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P20-06029 
Bluhmki E, Danays T, Biegert G, Hacke W, Lees KR. Alteplase for Acute 
Ischemic Stroke in Patients Aged >80 Years: Pooled Analyses of Individual 
Patient Data. Stroke. 2020; 51(8):2322-2331.
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.
P21-04636 
Society of Neurology, Chinese Stroke Society. Chinese guidelines for 
diagnosis and treatment of acute ischemic stroke 2014. Clin J Neurol. 2015; 
48(4):246-257.
P21-04637 
Liu LP, Chen WQ, Duan WY, Huo XC, Xu WH, Li SJ, Li ZX, Huang LA, 
Wang CX, Zheng GH, Wang YJ. Chinese Stroke Association Guidelines 
for Clinical Management of Cerebrovascular Disorders (Excerpts)-Clinical 
Management of Ischemic Cerebrovascular Disorders. Chin J Stroke. 2019; 
14(7):709-726.
R16-5416 
International Society for Pharmacoepidemiology (ISPE). Guidelines for 
good pharmacoepidemiology practices (GPP), Pharmacoepidemiol Drug 
Saf. 2015;25(1):2-10.
R13-1970 
European Medicines Agency (EMA), Heads of Medicines Agencies (HMA); 
2012.Guideline on good pharmacovigilance practices (GVP): module VI - 
management and reporting of adverse reactions to medicinal products (22 
June 2012,EMA/873138/2011) 
13.2
UNPUBLISHED REFERENCES
None 

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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: Characteristics and in-hospital outcomes of Chinese elderly (>80 years) patients 
with acute ischemic stroke receiving intravenous recombinant tissue plasminogen 
activator treatment within 4.5 hours of symptom onset
EU PAS Register® number: 
Study reference number (if applicable):
Section 1: Milestones
Yes
No
N/A
Section 
Number
1.1
Does the protocol specify timelines for 
6
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: 
8
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)
8
2.1.2 The objective(s) of the study?
8
2.1.3 The target population? (i.e. population or subgroup to 
whom the study results are intended to be generalised)
8
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) 
9.1
3.2
Does the protocol specify whether the study is based 
on primary, secondary or combined data collection?
9.4
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
3.3
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))
9.7.2
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?
9.4
4.2
Is the planned study population defined in terms of:
4.2.1 Study time period
9.2.1
4.2.2 Age and sex
9.2.2
4.2.3 Country of origin
9.2.2
4.2.4 Disease/indication
9.2.2
4.2.5 Duration of follow-up
9.3.2
4.3
Does the protocol define how the study population will 
be sampled from the source population? (e.g. event or 
inclusion/exclusion criteria)
9.2.2
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)
9.3.1
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)
9.7.2
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?
9.3.2
6.2
Does the protocol describe how the outcomes are 
defined and measured? 
9.3.2
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)
9.9
7.2
Does the protocol address selection bias? (e.g. healthy 
user/adherer bias)
9.9
7.3
Does the protocol address information bias? 
(e.g. misclassification of exposure and outcomes, time-
related bias)
9.9
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)
9.3.3
Comments:

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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)
9.4
9.1.2 Outcomes? (e.g. clinical records, laboratory markers or 
values, claims data, self-report, patient interview
including scales and questionnaires, vital statistics)
9.4
9.1.3 Covariates and other characteristics?
9.4
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? 
9.7
10.2 Is study size and/or statistical precision estimated?
9.5
10.3 Are descriptive analyses included?
9.7
10.4 Are stratified analyses included?
9.7
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?
9.7

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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?
9.8
11.3 Is there a system in place for independent review of 
study results? 
9.8
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?
9.9
12.1.2 Information bias?
9.9
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)
9.1 and 9.2 
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?
9.10.1
13.2 Has any outcome of an ethical review procedure been 
addressed?
13.3 Have data protection requirements been described?
10.2
Comments:

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ANNEX 3. ADDITIONAL INFORMATION
None. 

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Study Title: Characteristics and in-hospital outcomes of Chinese elderly (>80 years) AIS 
patients receiving IV rt-PA treatment within 4.5 hours of symptom onset 
Study Number: 0135-0348 
Protocol Version: 1.0 
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referenced in the study protocol.
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