1-year Clinical Outcomes After Intravenous Rt-PA for Chinese AIS Patients
Conditions: Stroke
Sponsor: Boehringer Ingelheim

ABCD 
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
Non-Interventional Study (NIS) Protocol
Document Number: 
F-01
BI Study Number: 
0135-0350
BI Investigational 
Product(s):
Actilyse® (Alteplase)
Title: 
1-year clinical outcomes after intravenous rt-PA for Chinese AIS
patients
Brief lay title: 
1-year clinical outcomes in rt-PA treated Chinese AIS patients
Protocol version 
identifier: 
1.0
Date of last version of 
protocol: 
Not applicable
PASS:
NO
EU PAS register 
number: 
EUPAS41543 
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 compare the 1-year mortality of AIS patients treated with
IV rt-PA within 4.5 hours of symptom onset versus those who
arrived or were admitted to the hospital within 4.5 hours of
symptom onset and did not receive reperfusion treatment.
Secondary objective: 
x
To compare the 1-year neurological functional outcome (as
measured by Modified Rankin Scale [mRS]) of AIS patients
treated with IV rt-PA within 4.5 hours of symptom onset

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ii 
Study records ........................................................................................... 24 
1.
Source documents ............................................................................ 24 
2.
Direct access to source data and documents .................................... 24 
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 25 
A)
STUDY APPROVAL AND PATIENT INFORMATION ............................. 25 
B)
STATEMENT OF CONFIDENTIALITY ...................................................... 25 
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE
REACTIONS ....................................................................................................... 26 
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
 ............................................................................................................................. 27 
13.
REFERENCES .................................................................................................... 28 
A)
PUBLISHED REFERENCES ......................................................................... 28 
B)
UNPUBLISHED REFERENCES ................................................................... 30 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .............................................. 31 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 32 
ANNEX 3. ADDITIONAL INFORMATION .............................................................. 39 
ANNEX 4. REVIEWERS AND APPROVAL SIGNATURES ................................... 40 

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2.
LIST OF ABBREVIATIONS
AIS
Acute Ischaemic Stroke
ASD
Absolute Standardised Difference
BI
Boehringer Ingelheim
CI
Confidence Interval
DMRP
Data Management and Review Plan
GPP
Good Pharmacoepidemiology Practice
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IV
Intravenous
IVT
Intravenous Thrombolysis
mRS
Modified Rankin Scale
NIHSS
National Institutes of Health Stroke Scale
NIS
Non-Interventional Study(ies)
PS
Propensity Score
PSM
Propensity Score Matching
rt-PA
Recombinant Tissue Plasminogen Activator
SOP
Standard Operation Procedure
tPA
Tissue-type Plasminogen Activator
ZSQCC
Zhejiang Stroke Quality Control Centre

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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:
6HS 2021
0135-0350
1.0
NA
Title of study:
1-year clinical outcomes after intravenous rt-PA for Chinese AIS patients
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. 
According to the Global Burden of Disease study 2019, data for acute 
ischaemic stroke (AIS) patients in China, it is deduced that there were 12.42 
million Chinese AIS patients with 2.87 million new cases every year, and 
1.03 million patients died due to AIS in 2019. 
The benefit of intravenous thrombolysis (IVT) treatment within 4.5 hours of 
symptom onset for AIS patients has been well proven and recommended by 
international/national guidelines. Recent real-world studies from western 
countries indicated that intravenous (IV) recombinant tissue plasminogen 
activator (rt-PA) treatment of AIS patients was associated with decreased 
long-term mortality. 
However, there are very limited data in terms of the effectiveness of IV 
rt-PA treatment on the long-term clinical outcomes, especially, mortality
among AIS patients in China. In this study, we plan to evaluate the 1-year 
clinical outcomes comparing IV rt-PA treated patients versus non-
reperfusion AIS patients  18 years) based on Zhejiang Stroke Quality 
Control Centre (ZSQCC) platform data. 
Research question 
and objectives:
Research question: In a real-world clinical setting, what are the 1-year 
clinical outcomes among AIS patients who were treated with IV rt-PA 
within 4.5 hours of symptom onset compared with those who arrived or 
were admitted to the hospital within 4.5 hours of symptom onset and did not 
receive any reperfusion treatment?
Primary objective: 
x
To compare the 1-year mortality of AIS patients treated with IV
rt-PA within 4.5 hours of symptom onset versus those who arrived
or were admitted to the hospital within 4.5 hours of symptom onset
and did not receive reperfusion treatment.

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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:
6HS 2021
0135-0350
1.0
NA
Secondary objective: 
x
To compare the 1-year neurological functional outcome (as
measured by Modified Rankin Scale [mRS]) of AIS patients treated
with IV rt-PA within 4.5 hours of symptom onset versus those who
arrived or were admitted to the hospital within 4.5 hours of
symptom onset and did not receive reperfusion.
Study design:
This is a non-interventional study based on existing data from the ZSQCC
platform.
Population:
Inclusion Criteria: 
x
Patients registered in the ZSQCC platform from Jan 2017 to Mar
2020
x
 18 years of age
x
Diagnosed with AIS at admission
x
Arrived or admitted to hospital within 4.5 hours of symptom onset
x
If treated with IV rt-PA: received IV rt-PA within 4.5 hours of
symptom onset
Exclusion Criteria: 
x
Documented IVT contraindication except age to IV rt-PA treatment
according to the SmPC
x
Missing any one of the key data (age, gender, baseline National
Institutes of Health Stroke Scale [NIHSS], time of symptom onset,
time of hospital arrival or admission, IVT or not, time of IV rt-PA
treatment)
x
Received thrombolysis agents other than 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
Eligible patients from the ZSQCC platform will be divided into 2 cohorts: 
x
IV rt-PA cohort: AIS patients who received IV rt-PA within
4.5 hours of symptom onset

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001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
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:
6HS 2021
0135-0350
1.0
NA
x
Non-reperfusion cohort: AIS patients who arrived or were admitted
to the hospital and did not receive any reperfusion treatments
Variables:
Primary outcomes:
x
All-cause mortality at 1 year (mRS=6)
Secondary outcomes: 
x
Functional independence (mRS 0-2) at 1 year
x
Favourable clinical outcome (mRS 0-1) at 1 year
x
mRS 5-6 at 1 year
x
Distribution of mRS score at 1 year
Covariates:
x
Demographic and sociological characteristics
o
Age
o
Gender (male, female)
o
Body weight
o
Medical insurance status (urban employee basic medical
insurance, urban resident basic medical insurance, new rural
cooperative medical insurance, other insurance, no
insurance)
x
Lifestyle related characteristics
o
Smoking status (current smoker, former smoker, never
smoker)
x
Stroke severity (baseline NIHSS)
x
Pre-stroke mRS
x
Time from symptom onset to hospital admission
x
For patients in the IV rt-PA cohort:
o
Time from symptom onset to treatment
o
Time from hospital admission to treatment
o
rt-PA dosage (dichotomised as standard dosage and low
dosage)
x
Comorbidities at baseline
o
Diabetes

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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:
6HS 2021
0135-0350
1.0
NA
o
Coronary artery disease
o
Atrial fibrillation
o
Prior stroke/transient ischaemic attack
o
Hypertension
x
Co-medication at baseline
o
Anti-platelet
o
Oral anticoagulation
o
Lipid lowering
x
Hospital level
o
Grade 2
o
Grade 3
x
Duration of hospitalization
x
Reasons for not being treated with rt-PA for rt-PA non treatment
group
Data sources:
ZSQCC platform
Study size:
Approximately 11700 patients; There are roughly8500 AIS patientsı 18 
years of age who have been treated with IV rtPA and 3200 patients who 
admitted to hospital within 4.5 hours of onset and did not receive 
reperfusion treatment from Jan 2017 to Mar 2020. 
In the China National Stroke Registry I (2007-2008) the 12-month mortality 
rate for post-stroke patients is around 14%.  For this study, it is assumed that 
1-year mortality is 12% and 15% for the rt-PA treatment group and the
group who did not receive reperfusion. In total, 6069 patients with treatment
ratio 2:1are needed to observe 855 events and to detect the difference
(HR=0.79) with 2-sideded alpha of 0.05 and 90% power. In addition,
considering a treatment ratio 1:1 with the same assumption described above
with power of 90% at a 2-sided, 5% significant level, roughly 5400 patients
are needed to observe 756 events to detect the difference.

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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:
6HS 2021
0135-0350
1.0
NA
Data analysis:
To account for potential confounding, the study cohorts (patients who 
received IV rt-PA and patients who did not receive reperfusion treatment) 
will be matched using the propensity score matching (PSM) method. 
Propensity score will be derived from predicted probabilities of treatment 
initiation. The PSM aims to balance the 2 treatment cohorts on baseline 
covariates. The feasibility of PSM will be evaluated based on available 
sample size and descriptive results. If patient characteristic between the two 
groups are significantly different, i.e., less than 50% of patients in the iv. rt-
PA group can be matched to the non-reperfusion group based on PSM, then 
the study design will be re-evaluated before proceeding to analysis. The 
Nearest Neighbour method of PSM will be used to select the matched 
samples. All the variables listed in the covariates will be considered. 
Covariables including duration of hospitalization and reasons for untreated 
with rt-PA are only for descriptive analysis. The distribution of baseline 
characteristics will be presented before and after the matching process. For 
baseline covariates that are not sufficiently balanced after PSM, the 
covariates will be included in an appropriate multivariate model to adjust for 
those differences. 
Main analysis:
Baseline characteristics of patients who received IV rt-PA and who didn’t
receive reperfusion treatments will be described, both before and after PSM.
Absolute standardised difference (ASD) between the propensity score 
(PS)-matched cohorts will be calculated, in which a  10% ASD will be 
considered a meaningful difference.
In the primary analysis, all patients who received endovascular treatment 
will be excluded. For the primary outcome, all-cause mortality at 1-year 
(mRS=6), will be evaluated using Kaplan-Meier curve. The percentage of 1-
year mortality with 95% confidence intervals (CIs) in the 2 PS-matched 
cohorts will be calculated separately. Cox regression models will be used to 
estimate the hazard ratio for the primary outcome between PS-matched 
cohorts. 
For the secondary outcomes, descriptive summaries will be conducted in the 
PS-matched cohorts separately. For categorical variables including 
functional independence (mRS 0-2), favourable clinical outcome (mRS 0-1) 
and outcome of mRS 5-6, the percentage and 95% CI will be calculated. A
logistic regression model will be used to calculate odds ratios. For the 

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5.
AMENDMENTS AND UPDATES
None 

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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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patients versus non-reperfusion AIS patients ( 18 years) based on the Zhejiang Stroke 
Quality Control Centre (ZSQCC) platform data. 

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8. RESEARCH QUESTION AND OBJECTIVES
Research question: In a real-world clinical setting, what are the 1-year clinical outcomes 
among AIS patients who were treated with IV rt-PA within 4.5 hours of symptom onset 
compared with those who arrived or were admitted to the hospital within 4.5 hours of 
symptom onset and did not receive any reperfusion treatment? 
Primary objective:
x
To compare the 1-year mortality of AIS patients treated with IV rt-PA within
4.5 hours of symptom onset versus those who arrived or were admitted to the
hospital within 4.5 hours of symptom onset and did not receive reperfusion
treatment.
Secondary objective:
x
To compare the 1-year neurological functional outcome (as measured by Modified
Rankin Scale [mRS]) of AIS patients treated with IV rt-PA within 4.5 hours of
symptom onset versus those who arrived or were admitted to the hospital within
4.5 hours of symptom onset and did not receive reperfusion.

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ii.
Study population
No sampling will be undertaken and all patients who meet all the inclusion criteria and none 
of the exclusion criteria will be included.
The inclusion and exclusion criteria are listed below:
Inclusion criteria:
x
Patients registered in the ZSQCC platform from Jan 2017 to Mar 2020
x
 18 years of age
x
Diagnosed with AIS at admission
x
Arrived or admitted to the hospital within 4.5 hours of symptom onset
x
If treated with IV rt-PA: received IV rt-PA within 4.5 hours of symptom onset
Exclusion criteria:
x
Documented IVT contraindication except age to IV rt-PA treatment according to the
SmPC
x
Missing any one of the key data (age, gender, baseline National Institutes of Health
Stroke Scale [NIHSS], time of symptom onset, time of hospital arrival or admission,
IVT or not, time of IV rt-PA treatment)
x
Received thrombolysis agents other than 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
iii.
Study visits
Not applicable. 
iv.
Study discontinuation
Boehringer Ingelheim (BI) 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
C) VARIABLES
i.
Exposures
The exposure of this study is IV rt-PA treatment within 4.5 hours of symptom onset. 
ii.
Outcomes
1.
Primary outcome:
x
All-cause mortality at 1 year (mRS=6)

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2.
Secondary outcomes:
x
Functional independence (mRS 0-2) at 1 year
x
Favourable clinical outcome (mRS 0-1) at 1 year
x
mRS 5-6 at 1 year
x
Distribution of mRS score at 1 year
iii.
Covariates
The covariates to be collected at baseline are as follows:
x
Demographic and sociological characteristics
o
Age
o
Gender (male, female)
o
Medical insurance status (urban employee basic medical insurance, urban
resident basic medical insurance, new rural cooperative medical insurance,
other insurance, no insurance)
x
Lifestyle related characteristics
o
Smoking status (current smoker, former smoker, never smoker)
x
Stroke severity (baseline NIHSS)
x
Pre-stroke mRS
x
Time from symptom onset to hospital admission
x
For patients in the IV rt-PA cohort:
o
Time from symptom onset to treatment
o
Time from hospital admission to treatment
o
rt-PA dosage (dichotomised as standard dosage and low dosage)
x
Comorbidities at baseline
o
Diabetes
o
Coronary artery disease
o
Atrial fibrillation
o
Prior stroke/transient ischaemic attack
o
Hypertension
x
Co-medication at baseline
o
Anti-platelet
o
Oral anticoagulation
o
Lipid lowering
x
Hospital level
o
Grade 2
o
Grade 3
Other covariates including: 
x
Duration of hospitalization
x
Reasons for not being treated with rt-PA for rt-PA non treatment group
D) DATA SOURCES
The current study will be conducted based on data from ZSQCC platform, which is a 
continuous comprehensive reporting system that collects approximately 100000 patient-level 
data from 80 stroke centres from January 2017 to March 2020. 

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All medical documents for consecutive acute stroke patients admitted in the stroke centre will 
be provided by investigators from ZSQCC. Only the de-identified scanned documents will be 
preserved as images in a safe information database. The local infrastructure and 
characteristics of each recruited centre will also be recorded. 
The database includes patient demographic information, baseline clinical characteristics,
indicators related to diagnosis and treatment during hospitalisation and follow-up after 
discharge. The platform staffs tried to follow up all discharged patients by a phone call at 1-
year discharge. Telephone follow-up of the platform was conducted by platform staffs. The 
follow-up standards were unified, and telephone recordings were all kept. Neurologists 
conducted trainings at regular intervals for platform staffs and randomly checked the 
telephone recordings. Several studies based on this dataset were approved by the Second 
Affiliated Hospital of Zhejiang University Institutional Review Board (IRB) and were 
published in peer-reviewed journals.[P21-04780], [P21-04783], [P21-04784], [P21-04779], [P21-04782]
E) STUDY SIZE
There were approximately 8500 AIS patients ( 18 years of age) who were treated with IV 
rt-PA and 3200 patients who were admitted to the hospital within 4.5 hours of symptom onset 
and did not receive reperfusion treatment from Jan 2017 to Mar 2020. 
In the China National Stroke Registry I (2007-2008), the 12-month mortality rate for 
post-stroke patients was approximately 14%.[R21-1852] For this study, it is assumed that 1-year 
mortality is 12% and 15% for the rt-PA treatment cohort and the cohort who did not receive 
reperfusion, respectively. In total, 6069 patients with a treatment ratio 2:1 are needed to 
observe 855 events and to detect the difference (hazard ratio=0.79) with a 2-sided alpha of 
0.05 and 90% power. In addition, considering a treatment ratio 1:1 with the same assumption 
described above with power of 90% at a 2-sided, 5% significant level, roughly 5400 patients
are needed to observe 756 events to detect the difference.
F)
DATA MANAGEMENT
The data will be managed by ZSQCC. The source codes for data management and data 
analyses will be kept for inspection for at least 5 years after publication of the results.
Full details of the data management plan are documented in a separate NIS-Data 
Management and Review Plan (NIS-DMRP).
G) DATA ANALYSIS
For the purpose of this study, analyses will generally be descriptive in nature and will be 
conducted using SAS statistical software (version 9.3 or higher). Descriptive data regarding 
patient demographic and clinical characteristics will be calculated. For categorical measures, 
data will include the frequency (number of cases [n]) and percentage (%) of total study 
patients observed in each category (N). All variables will be summarised descriptively 
through tabular displays of mean, median, ranges and standard deviations of continuous 
variables and frequency distributions of categorical variables. When necessary, continuous 

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variables also will be categorised into intervals, with the distribution of patients (n, N, %) for 
each interval provided.  
The statistical analysis plan for the study is summarised below. Full details of the statistical 
analysis will be documented in the statistical and epidemiological analysis plan, which will 
be finalised before the end of data extraction. 
As this is a NIS based on existing data, no formal hypothesis testing or comparisons between 
treatment cohorts are planned. 
i.
Main analysis
To account for potential confounding, the study cohorts (patients who received IV rt-PA and 
patients who did not receive reperfusion treatment) will be 1:1 or 2:1 matched by baseline 
characteristics using the propensity score matching (PSM) method. Propensity score (PS) will 
be derived from predicted probabilities of treatment initiation. The PSM aims to balance the 2
treatment cohorts on baseline covariates. The feasibility of PSM will be evaluated based on 
available sample size and descriptive results. If patient characteristics between the 2 cohorts 
are significantly different, i.e., less than 50% of patients in the IV rt-PA cohort can be 
matched to the non-reperfusion cohort based on PSM, the study design will be re-evaluated 
before proceeding to analysis. The Nearest Neighbour method of PSM will be used to select 
the matched samples. All the variables listed in the covariates will be considered. Covariables 
including duration of hospitalization and reasons for untreated with rt-PA are only for 
descriptive analysis. The distribution of baseline characteristics will be presented before and 
after the matching process. For baseline covariates that are not sufficiently balanced after 
PSM, the covariates will be included in an appropriate multivariate model to adjust for those 
differences.
Baseline characteristics of patients who received IV rt-PA and who didn’t receive reperfusion 
treatments will be described, both before and after PSM. The absolute standardised difference 
(ASD) between the PS-matched cohorts will be calculated, where an ASD of at least 10% 
ASD will be considered a meaningful difference.
In the primary analysis, all patients who received endovascular treatment will be excluded. 
For the primary outcome, all-cause mortality at 1-year (mRS=6), will be evaluated using 
from the Kaplan-Meier curve. The percentage of 1-year mortality with 95% CIs in the 2 PS-
matched cohorts will be calculated separately. Cox regression models will be used to estimate 
the hazard ratio for the primary outcome between PS-matched cohorts. 
For the secondary outcomes, descriptive summaries will be conducted in the PS-matched 
cohorts separately. For categorical variables including functional independence (mRS 0-2), 
favourable clinical outcome (mRS 0-1) and outcome of mRS 5-6, the percentage and 95% CI
will be calculated. A logistic regression model will be used to calculate odds ratios for 
functional independence (mRS 0-2), favourable clinical outcome (mRS 0-1) and outcome of 
mRS 5-6. For the distribution of mRS at 1 year, an ordinal logistic regression model will be 
used to calculate the odds ratio and 95% CI. 

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x
The treatment adapted for AIS patients may be different among stroke centres.
x
The completeness of the captured data and potential for misclassification of data
could differ among stroke centres.
x
Some important variables may not be collected in the database. For example,
patients’ education level was not available in the database.
J)
OTHER ASPECTS
i.
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. 
ii.
Study records
1.
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data extracted.  
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/documents. 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.  
A)
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.
B)
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[R11-4318] 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 the 
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
A) 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. 
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. 
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. 

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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. 
P18-01688 
Walter Muruet, Anthony Rudd, Charles D.A. Wolfe, and Abdel Douiri. 
Long-Term Survival After Intravenous Thrombolysis for Ischaemic Stroke. 
A Propensity Score-Matched Cohort With up to 10-Year Follow-Up. Stroke. 
2018; 49:607–613. 
P14-13950 
Marie Louise Schmitz, Claus Z. Simonsen, Heidi Hundborg, Hanne 
Christensen, Karsten Ellemann, Karin Geisler, Helle Iversen, Charlotte 
Madsen, Mary-Jette Rasmussen, Karsten Vestergaard, Grethe Andersen, and 
Soeren P. Johnsen. Acute Ischemic Stroke and Long-Term Outcome After 
Thrombolysis Nationwide Propensity Score–Matched Follow-Up Study. 
Stroke. 2014; 45:3070–3072. 
P16-12462 
Terkelsen T, Schmitz ML, Simonsen CZ, Hundborg HH, Christensen HK, 
Gyllenborg J, et al. Thrombolysis in acute ischaemic stroke is associated 
with lower long-term hospital bed day use: a nationwide propensity score-
matched follow-up study. Int J Stroke. 2016 Oct;11(8):910-916. 
P21-04780 
Zhang CC, Lou M, Chen ZC, Chen HF, Xu DJ, Wang ZM, Hu HF, Wu CL, 
Zhang XL, Ma XD, Wang YX, Hu HT. Analysis of intravenous 
thrombolysis time and prognosis in patients with in-hospital stroke. J 
Zhejiang Univ (Med Sci). 2019; 48(3):260-266. 
P21-04783 
Chen HF, Gong XX, Xu DJ, Wang ZM, Hu HF, Wu CL, Zhang XL, Ma 
XD, Wang YX, Hu HT, Lou M, Chen ZC. Advanced treatment time 
improves outcomes of patients with ischaemic stroke undergoing reperfusion 
therapy. J Zhejiang Univ (Med Sci). 2019; 48(3):247-253. 
P21-04784 
Zhong WS, Chen ZC, Chen HF, Xu DJ, Wang ZM, Hu HF, Wu CL, Zhang 
XL, Ma XD, Wang YX, Hu HT, Lou M. Effects of emergency medical 
service on prognosis of ischaemic stroke patients treated with intravenous 
thrombolysis. J Zhejiang Univ (Med Sci). 2019; 48(3):241-246. 
P21-04779 
Pan FH, Lou M, Chen ZC, Chen HF, Xu DJ, Wang ZM, Hu HF, Wu CL, 
Zhang XL, Ma XD, Wang YX, Hu HT. Effect of different working time on 
the prognosis of ischemic stroke patients undergoing intravenous 
thrombolysis. J Zhejiang Univ (Med Sci). 2019; 48(3):267-274. 
P21-04782 
Tao AY, Wang ZM, Chen HF, Xu DJ, Hu HF, Wu CL, Zhang XL, Ma XD, 
Wang YX, Hu HT, Lou M. Association of atrial fibrillation with 
hemorrhagic transformation after intravenous thrombolysis in patients with 
ischaemic stroke. J Zhejiang Univ (Med Sci). 2019; 48(3): 254-259. 

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R21-1852 
Zhan Wang, Jingjing Li, Chunxue Wang, Xiaomei Yao, Xingquan Zhao, 
Yilong Wang,Hao Li, Gaifen Liu, Anxin Wang, Yongjun Wang. Gender 
Differences in 1-Year Clinical Characteristics and Outcomes after Stroke: 
Results from the China National Stroke Registry. PLoS ONE 8(2): e56459. 
doi:10.1371/journal.pone.0056459. 
R11-4318 
Guidelines for Good Pharmacoepidemiology Practices (GPP) (revision 2: 
April 2007). Source: 
http://www.pharmacoepi.org/resources/guidelines_08027.cfm (access date: 
13 September 2011); Bethesda: International Society for 
Pharmacoepidemiology (ISPE); 2007. [B(MB1]. 
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). 
B) 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
1.
Study title: 1-year clinical outcomes after intravenous rt-PA for Chinese AIS
patients
2.
EU PAS Register® number:
3.
Study reference number (if applicable):
4.
Section 1: Milestones
Yes
No
N/A
Section 
Number
1.1
Does the protocol specify timelines for 
1.1.1 Start of data collection1
6
1.1.2 End of data collection2
6
1.1.3 Progress report(s)
NA
1.1.4 Interim report(s)
NA
1.1.5 Registration in the EU PAS Register®
6
1.1.6 Final report of study results.
6
Comments:
5.
Section 2: Research question
Yes
No
N/A
Section 
Number
2.1
Does the formulation of the research question and 
objectives clearly explain: 
7 and 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)
7
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)
9.2.2
2.1.4 Which hypothesis(-es) is (are) to be tested?
NA
2.1.5 If applicable, that there is no a priori hypothesis?
NA
Comments:
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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6.
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? 
9.1 and 
9.3.2
3.3
Does the protocol specify measures of occurrence? 
(e.g., rate, risk, prevalence)
9.2.2
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))
NA
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)
9.7.3 and 
11
Comments:
7.
Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.1
Is the source population described?
9
4.2
Is the planned study population defined in terms of:
4.2.1 Study time period
6
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
9.4.1
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:
8.
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

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8.
Section 5: Exposure definition and
measurement
Yes
No
N/A
Section 
Number
5.2
Does the protocol address the validity of the exposure 
measurement? (e.g. precision, accuracy, use of 
validation sub-study)
NA
5.3
Is exposure categorised according to time windows? 
9.3.1
5.4
Is intensity of exposure addressed? (e.g. dose, 
duration)
9.3.3
5.5
Is exposure categorised based on biological mechanism 
of action and taking into account the pharmacokinetics 
and pharmacodynamics of the drug?
NA
5.6
Is (are) (an) appropriate comparator(s) identified?
NA
Comments:
9.
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)
NA
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)
NA
Comments:
10.
Section 7: Bias
Yes
No
N/A
Section 
Number
7.1
Does the protocol address ways to measure 
confounding? (e.g. confounding by indication)
9.7.1
7.2
Does the protocol address selection bias? (e.g. healthy 
user/adherer bias)
9.2.1, 9.7, 
and 9.9
7.3
Does the protocol address information bias? 
(e.g. misclassification of exposure and outcomes, time-
related bias)
9.7

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Comments:
11.
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)
9.7.1
Comments:
12.
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)
9.3.1 and 
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)
9.3.2
9.1.3 Covariates and other characteristics?
9.3.3
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)
9.3.1
9.2.2 Outcomes? (e.g. date of occurrence, multiple event, 
severity measures related to event)
9.3.2
9.2.3 Covariates and other characteristics? (e.g. age, sex, 
clinical and drug use history, co-morbidity, co-
medications, lifestyle)
9.3.3
9.3
Is a coding system described for: 
9.3.1 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC) Classification System)
NA
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD), Medical Dictionary for Regulatory 
Activities (MedDRA))
NA
9.3.3 Covariates and other characteristics?
NA
9.4
Is a linkage method between data sources described? 
(e.g. based on a unique identifier or other) 
NA
Comments: 

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13.
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?
NA
10.5 Does the plan describe methods for analytic control of 
confounding?
9.7.1
10.6 Does the plan describe methods for analytic control of 
outcome misclassification?
NA
10.7 Does the plan describe methods for handling missing 
data?
NA
10.8 Are relevant sensitivity analyses described?
9.7.2
Comments:
14.
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)
9.8
11.2 Are methods of quality assurance described?
9.10.1
11.3 Is there a system in place for independent review of 
study results? 
NA
Comments:
15.
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).
NA

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15.
Section 12: Limitations
Yes
No
N/A
Section 
Number
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:
16.
Section 13: Ethical/data protection issues
Yes
No
N/A
Section 
Number
13.1 Have requirements of Ethics Committee/ Institutional 
Review Board been described?
10
13.2 Has any outcome of an ethical review procedure been 
addressed?
10
13.3 Have data protection requirements been described?
10
Comments:
17.
Section 14: Amendments and deviations
Yes
No
N/A
Section 
Number
14.1 Does the protocol include a section to document 
amendments and deviations?
5
Comments:
18.
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)? 
12
15.2 Are plans described for disseminating study results 
externally, including publication?
12
Comments:

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ANNEX 3. ADDITIONAL INFORMATION
None. 

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Study Title: 1-year clinical outcomes after intravenous rt-PA for Chinese AIS patients
Study Number: 0135-0350 
Protocol Version: 1.0 
I herewith certify that I agree to the content of the study protocol and to all documents 
referenced in the study protocol.
Position: ________ 
Name/Date: _______________________
Signature: _______________ 
Position: ________
Name/Date: _______________________
Signature: _______________
Position: ________
Name/Date: _______________________
Signature: _______________
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Signature: _______________
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Signature: _______________