Safe Implementation of Treatments in Stroke (SITS) - Intravenous Thrombolysis in Acute Ischaemic Stroke Patients Over 80 Years, SITS-IVT>80 Years Study
Conditions: Ischaemic Stroke
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-124_RD-01 (4.0)
 
Protocol for non-interventional studies based on existing data
 
Document Number:
c30353958-01
BI Study Number:
  0135-0344
BI Investigational
Product(s):
Actilyse
Title:
Safe Implementation of Treatments in Stroke (SITS) -
Intravenous thrombolysis in acute ischaemic stroke patients over 
80 years, SITS-IVT>80 years study
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
na
PASS:
Yes
EU PAS register 
number:
Study not yet registered
Active substance:
Alteplase
Medicinal product:
Actilyse: Powder and solvent for solution for injection
and infusion, 10 mg, 20 mg, and 50 mg
Product reference:
DE/H/0015/004
Procedure number:
DE/H/0015/004/IB/135
Joint PASS:
No
Research question and 
objectives:
Pooled analysis of randomized controlled trials (RCTs) of 
intravenous thrombolysis (IVT) with Alteplase, a recombinant 
tissue plasminogen Activator (rt-PA) for acute ischemic stroke, 
has shown that patients >80 years treated with IVT versus 
control derived equal benefit compared to patients 18-80 years. 
The SITS-ISTR (Safe Implementation of Treatment in Stroke-
International Stroke Thrombolysis Register)-VISTA analysis 
demonstrated benefit of IVT in patients >80 years compared to 
control, and found no difference in the slope of benefit versus 
treatment delay for younger versus elderly patients3, a finding 
that was confirmed in the RCT dataset.  The European guideline 
recommends use of IVT within 4.5h of symptom onset also in 
the elderly. Until recently, most European regulatory agencies 

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
Study Number 0135-0344
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01- MCS-90-124_RD-01 (4.0)
had not approved marketing of IVT with Alteplase for use in 
ischemic patients >80 years. A recently published SITS study 
showed that unselected patients >80-years treated with IVT after 
3h versus earlier, had a slightly higher rate of SICH but similar 
unadjusted functional outcome and poorer adjusted outcome. 
IVT with Alteplase in >80 years old patients treated within 4.5h 
of symptom onset is now approved in a number of European and 
non-European countries.
Safety and outcome of a treatment in acute ischaemic stroke may 
be different in the RCT settings in patients over 80 years. 
Although IVT in patients >80 years has been used off-label in 
many countries prior to approval, use of IVT in patients>80 
years will probably be more frequent after approval. The 
proposed SITS-ISTR provides an opportunity for continuous 
monitoring of thrombolysis treatment in stroke, and provides a 
technical foundation for the SITS->80 years post-approval study. 
The SITS-IVT>80 years is a retrospective study based on data
collected in the SITS-ISTR setting from acute ischemic stroke 
patients > 80 years of age. The study aims to evaluate the 
incidence rate with 95% CI of SICH, death and functional 
independence/favourable outcome within 90 days for ischaemic 
stroke patients treated with rt-PA in clinical routine settings. In 
the proposed SITS-IVT>80 years study using the SITS registry 
we plan to identify approximately 1000 patients older than 80 
years treated with IV Alteplase otherwise fulfilling SmPC 
criteria in the post-approval period of 3 years (from 1 July 2018 
to 30 June 2021) and also to identify 1000 patients older than 80 
years treated with IV Alteplase otherwise fulfilling SmPC 
criteria in the pre-approval period of 3 years (from June 2015 to 
June 2018). In both periods, at least 500 patients should be 
registered from centres of European countries being part of the 
mutual recognition.
The objective of the SITS-IVT>80 years is to compare the safety 
and other outcome parameters between the post-approval >80 
years and pre-approval  >80 years AIS patients using the data 
already collected in SITS-ISTR.
Country(-ies) of study:
Austria, Belgium, Cyprus, Germany, Denmark, Greece, Spain, 
Finland, France, Ireland, Iceland, Italy, Luxemburg, Malta, 
Netherland, Norway, Portugal, Sweden, United Kingdom 
Author:
Phone 

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Protocol for non-interventional studies based on existing data
Study Number 0135-0344
c30353958-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
01- MCS-90-124_RD-01 (4.0)
Marketing authorisation 
holder(s):
MAH contact person:
EU-QPPV:
Boehringer Ingelheim International GmbH
Binger Strasse 173 
55216 Ingelheim am Rhein
Signature of EU-
QPPV:
Date:
25 Nov 2019
Page 1 of 47
Proprietary confidential information
© 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated 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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Protocol for non-interventional studies based on existing data
Study Number 0135-0344
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01- MCS-90-124_RD-01 (4.0)
1.
TABLE OF CONTENTS
TITLE PAGE................................................................................................1
1.
TABLE OF CONTENTS .....................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................6
3.
RESPONSIBLE PARTIES ..................................................................8
4.
ABSTRACT .......................................................................................10
5.
AMENDMENTS AND UPDATES ...................................................15
6.
MILESTONES ...................................................................................16
7.
RATIONALE AND BACKGROUND ..............................................17
8.
RESEARCH QUESTION AND OBJECTIVES................................20
9.
RESEARCH METHODS...................................................................21
9.1
STUDY DESIGN............................................................................................ 21
9.2
SETTING........................................................................................................ 21
9.2.1
Level of care............................................................................................ 21
9.3
VARIABLES .................................................................................................. 22
9.3.1
Exposures ................................................................................................ 22
9.3.2
Outcomes................................................................................................. 23
9.3.2.1
Primary outcomes..................................................................................23
9.3.2.2
Secondary outcomes..............................................................................23
9.3.3
Covariates................................................................................................ 24
9.4
Onset to treatment time DATA SOURCES.................................................... 25
9.5
STUDY SIZE.................................................................................................. 25
9.6
DATA MANAGEMENT................................................................................ 25
9.7
DATA ANALYSIS......................................................................................... 25
9.7.1
Main analysis........................................................................................... 26
9.8
QUALITY CONTROL................................................................................... 27
9.8.1
Investigators and local procedures .......................................................... 27
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 28
9.10
OTHER ASPECTS ......................................................................................... 28
9.11
SUBJECTS...................................................................................................... 29

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Protocol for non-interventional studies based on existing data
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01- MCS-90-124_RD-01 (4.0)
9.11.1
Cases........................................................................................................ 29
9.11.2
Controls................................................................................................... 29
9.12
BIAS................................................................................................................ 29
10. PROTECTION OF HUMAN SUBJECTS.........................................30
11. MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS .................................................31
12. AS AN OBSERVATIONAL STUDY, BASED ON EXISTING 
DATA, ALL PATIENT DATA IS DE-IDENTIFIED AND WILL 
BE ANALYSED IN AGGREGATE. INDIVIDUAL PATIENT 
SAFETY RELATED INFORMATION WILL NOT BE 
CAPTURED DURING THIS STUDY. THUS, INDIVIDUAL 
SAFETY REPORTING IS NOT APPLICABLE. SAFETY 
REPORTING WILL BE DONE CUMULATIVELY IN 
AGGREGATE IN THE STUDY REPORT.PLANS FOR 
DISSEMINATING AND COMMUNICATING STUDY 
RESULTS...........................................................................................31
13. REFERENCES...................................................................................32
13.1
PUBLISHED REFERENCES......................................................................... 32
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS...........................36
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ..............37
ANNEX 3. ADDITIONAL INFORMATION...........................................44

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Protocol for non-interventional studies based on existing data
Study Number 0135-0344
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01- MCS-90-124_RD-01 (4.0)
2.
LIST OF ABBREVIATIONS
AE
Adverse Event
AUC
Area under the Curve
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
CT
Case Report Form
Computer Tomogram
CTCAE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DMC
Data Monitoring Committee
eCRF
Electronic Case Report Form
EDC
EU
Electronic Data Capture
European Union
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
GCP
Good Clinical Practice
HPC
Human Pharmacology Centre
IB
ICO
Investigator’s Brochure
International Coordinating Office
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator Site File
i.v.
intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web-based Response System
MedDRA
MCA
MRI
Medical Dictionary for Drug Regulatory Activities
Middle Cerebral Artery
Magnetic Resonance Imaging
MST
NIHSS
Medical Subteam
National Institute of Health’s Stroke Scale
OPU
Operative Unit
p.o.
per os (oral)
PCC
PH
Protocol Challenge Committee
Parenchymal Haemorrhage
q.d.
quaque die (once a day)
SAE
Serious Adverse Event
s.c.
SICH
SmPC
Subcutaneous
Symptomatic Intracerebral Haemorrhage
Summary of Product Characteristics
SPC
SITS-ISTR
Summary of Product Characteristics
Safe Implementation of Treatments in Stroke- International Stroke 
Thrombolysis Registry
TCM
Trial Clinical Monitor

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Protocol for non-interventional studies based on existing data
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01- MCS-90-124_RD-01 (4.0)
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
t-PA
ter in die (3 times a day)
Tissue plasminogen activator, alteplase, Actilyse®
TMM
Team Member Medicine
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan

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3.
RESPONSIBLE PARTIES
  SITS ORGANISATION
SITS International: 
Responsibility: 
Representatives: 
SITS Scientific Committee 
! Scientific responsibility 
! Data evaluation
! Monitoring SITS 
Scientific activities, e.g. 
projects, reports and 
publications
Data management 
Data management and 
statistical analysis 
Statistical support will also 
be sought from 
 
SITS ICO (International 
Coordination Office)  
Manage centre application, 
coordinate, maintain and 
online monitoring of SITS 
registry, development and 
maintenance of database 
On behalf of SITS International:
Phone 
On behalf of Boehringer Ingelheim International GmbH:

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01- MCS-90-124_RD-01 (4.0)
Boehringer Ingelheim
Binger Strasse 173
55216 Ingelheim am Rhein

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Protocol for non-interventional studies based on existing data
Study Number 0135-0344
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01- MCS-90-124_RD-01 (4.0)
4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
If applicable, list centrally-
authorised medicinal product(s) 
subject to the study.
Name of active ingredient:
List pharmacotherapeutic 
group(s){ACT codes} and active 
substance(s) subject to the study
Alteplase
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
25 Nov 
2019
0135-0344
1.0
Title of 
study:
SITS-IVT>80 years
Safe Implementation of Treatments in Stroke (SITS) - Intravenous thrombolysis in 
acute ischaemic stroke patients over 80 years, SITS-IVT>80 years study.
A non-interventional post-approval study on SITS-ISTR existing data of intravenous 
rt-PA (0.9 mg/kg) in acute ischaemic stroke patients over 80 years, treated according 
to the Summary of Product Characteristics (SmPC) of European countries being part 
of the mutual recognition procedure within the academic SITS-ISTR (International 
Stroke Thrombolysis Registry).
Rationale 
and 
backgroun
d:
Pooled analysis of randomized controlled trials (RCTs) of intravenous thrombolysis 
(IVT) with Alteplase, a recombinant tissue plasminogen Activator (rt-PA) for acute 
ischemic stroke, has shown that patients >80 years treated with IVT versus control 
derived equal benefit compared to patients 18-80 years.9 Effectiveness of IVT 
diminished as the treatment delay increased across the first 6 hours without a 
corresponding increase in the relative risk of symptomatic intracerebral hemorrhage 
(SICH).9 Real world registry experience supports these RCT data in patients >80 
years treated within 3h.35,36 The SITS-ISTR (Safe Implementation of Treatment in 
Stroke-International Stroke Thrombolysis Register)-VISTA analysis demonstrated 
benefit of IVT in patients >80 years compared to control, and found no difference in 
the slope of benefit versus treatment delay for younger versus elderly patients,36 a 
finding that was confirmed in the RCT dataset.37  Until recently, most European 
regulatory agencies had not approved marketing of IVT with Alteplase for use in
ischemic patients >80 years, whereas the American regulatory agency supports 
promotion of IVT in patients >80 years within 3h of symptom onset. A recently 
published SITS study showed that unselected patients >80-years treated with IVT 
after 3h versus earlier, had a slightly higher rate of SICH but similar unadjusted 
functional outcome and poorer adjusted outcome.40  The European guideline38
recommends use of IVT within 4.5h of symptom onset also in the elderly and IVT 

Boehringer Ingelheim
Page 11 of 47
Protocol for non-interventional studies based on existing data
Study Number 0135-0344
c30353958-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
01- MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
If applicable, list centrally-
authorised medicinal product(s) 
subject to the study.
Name of active ingredient:
List pharmacotherapeutic 
group(s){ACT codes} and active 
substance(s) subject to the study
Alteplase
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
25 Nov 
2019
0135-0344
1.0
with Alteplase within 4.5h of symptom onset is now approved in a number of 
European and non-European countries.
Safety and outcome of a treatment in acute ischaemic stroke may be different in the 
RCT settings in patients over 80 years. Although IVT in patients >80 years has been 
used off-label in many countries prior to approval, use of IVT in patients>80 years 
will probably be more frequent after approval. The SITS-ISTR setting provides an 
opportunity for continuous monitoring of thrombolysis treatment in stroke, and 
provides a technical foundation for the SITS->80 years post-approval registry. The 
SITS-IVT>80 years is a retrospective study of existing data in the SITS-ISTR on 
acute ischaemic patients treated with IVT according to the Summary of Product 
Characteristics (SmPC) criteria. The study aims to evaluate the incidence rate of 
SICH, death and independence/favourable outcome within 90 days for ischaemic 
stroke patients over 80 years treated with rt-PA in clinical routine settings. At least  
2000 patients overall from approximately 60 European sites are planned to be 
identified for the SITS-IVT>80 years study. Safety and other outcome parameters 
will be compared between post-approval >80 years and pre-approval >80 years 
patients.
Research
question 
and 
objectives:
Safety and outcome of a treatment in acute ischaemic stroke may be different in the 
RCT settings in patients over 80 years. Although IVT in patients >80 years has been 
used off-label in many countries prior to approval, use of IVT in patients>80 years 
will probably be more frequent after approval. The study aims to evaluate the 
incidence rate of SICH, death and independence/favourable outcome within 90 days 
for ischaemic stroke patients treated with rt-PA in clinical routine settings.
The SITS-IVT>80 years Study will primarily investigate the safety and outcome of 
IVT in acute ischaemic stroke in patients >80 years collected during the post-
approval period and to compare the safety outcome with existing pre-approval 
patients >80 years collected in routine clinical practice and recorded in the SITS 
registry.

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
Study Number 0135-0344
c30353958-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
01- MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
If applicable, list centrally-
authorised medicinal product(s) 
subject to the study.
Name of active ingredient:
List pharmacotherapeutic 
group(s){ACT codes} and active 
substance(s) subject to the study
Alteplase
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
25 Nov 
2019
0135-0344
1.0
Study 
design:
This is a retrospective observational study using existing data from the SITS registry.
Population
:
Post-approval: Patients over 80 years old presenting with acute ischaemic stroke 
symptoms for which thrombolysis treatment was initiated within 4.5 hours after 
stroke onset according to the SmPC during the study period July 2018 to June 2021.
Pre-approval: Patients aged over 80 years presenting with acute ischaemic stroke 
symptoms for which thrombolysis treatment was initiated within 4.5 hours after 
stroke onset otherwise according to SmPC during the period of approximately 3 
years prior to approval (June 2015 to June 2018)
Variables:
Standard SITS-ISTR safety parameters: 
!
Symptomatic intracerebral haemorrhage (SICH):
Intracerebral haemorrhage (parenchymatous haemorrhage type 2), at post-treatment 
scan combined with neurological deterioration leading to an increase of 4 points on 
the NIH Stroke Scale (SITS-MOST definition)
!
Mortality:
Death (mRS = 6) at day 90 
!
Independence / favourable outcome:
Independence for the activities of daily living at day 90. Good functional outcome is 
defined as a modified Rankin Scale (mRS) score of both 0-2 (independence) and 0-1 
(favourable)
!
Baseline and demographic variables available in the SITS registry for 
describing patient characteristics.
!
Patient management variables
o
Time from onset to door
o
Door to needle (treatment) time 

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Protocol for non-interventional studies based on existing data
Study Number 0135-0344
c30353958-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
01- MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
If applicable, list centrally-
authorised medicinal product(s) 
subject to the study.
Name of active ingredient:
List pharmacotherapeutic 
group(s){ACT codes} and active 
substance(s) subject to the study
Alteplase
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
25 Nov 
2019
0135-0344
1.0
o
Onset to treatment time
Data 
sources:
The SITS-ISTR 
Study size:
Approximately 1000 patients above 80 years treated with IV Alteplase according to 
SmPC after approval of indication and approximately 1000 patients above 80 years 
treated with IV Alteplase within 4.5 hours otherwise according to SmPC before the 
approval of the indication. Of these at least 500 patients each from the pre-approval 
and post-approval period from centres of European countries being part of SITS 
registry. The sample size of the study is not based on any formal power calculation, 
but chosen in consultation with authorities, based on numbers considered to be 
achievable within a 3-year period.
Data 
analysis:
Descriptive and exploratory analyses in the unmatched and propensity score matched 
groups. Multivariable analysis with adjustment for differences or imbalances in 
prognostic variables for outcome comparisons.
Milestones:
Planned milestones
Estimated timelines
Post approval data collection is 
planned after the majority of the 
participating countries received 
approval of the label change for >80 
years with acute ischaemic stroke
Q3 2018 or Q2 2021
Last patient out October 2021
Interim reports
Yearly 
Final report to be available within 6 
months of the database lock
April 2022
Final report to be submitted two 
months after its availability
June 2022

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Protocol for non-interventional studies based on existing data
Study Number 0135-0344
c30353958-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
01- MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
If applicable, list centrally-
authorised medicinal product(s) 
subject to the study.
Name of active ingredient:
List pharmacotherapeutic 
group(s){ACT codes} and active 
substance(s) subject to the study
Alteplase
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
25 Nov 
2019
0135-0344
1.0
Re-assessment of the timelines will be performed as study progresses

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Protocol for non-interventional studies based on existing data
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01- MCS-90-124_RD-01 (4.0)
5.
AMENDMENTS AND UPDATES
None

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6.
MILESTONES
Planned milestones
Estimated timelines
Post approval data collection is 
planned after the majority of the 
participating countries received 
approval of the label change for >80 
years with acute ischaemic stroke
Q3 2018 or Q2 2021
Last patient out October 2021
Interim reports
Yearly 
Final report to be available within 6 
months of the database lock
April 2022
Final report to be submitted two 
months after its availability
June 2022

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01- MCS-90-124_RD-01 (4.0)
7.
RATIONALE AND BACKGROUND
Stroke – a growing disease
Stroke is the third leading cause of death and the number one cause of neurological disability 
in adults globally, not only in the elderly, but also in younger age groups.1
About one million strokes occur annually within the European Union. Stroke patients often 
require extended hospital stays followed by rehabilitation, ongoing support from the 
community, and nursing-home care.2
Alarmingly, stroke incidence is expected to increase considerably over the next decades 
because of an increase in the elderly population. The proportion of people over the age of 70, 
which was 13% in year 2000, is expected to be 20% in year 2050. It is predicted that stroke 
will account for 6.2% of the total burden of illness in 2020. Thus, without major advances to 
improve prevention and treatment, the cost of this disease will increase dramatically.3,4
Treatment strategies for stroke
Stroke unit care5,6 and reperfusion therapy by iv thrombolysis within 4.5 hours of symptom 
onset7-12, and/or endovascular thrombectomy within 6 hours of symptom onset in anterior 
circulation stroke13-19, are the only evidence-based treatments for acute ischemic stroke, and 
are recommended by national and international practice guidelines.20-21
Stroke unit care 
Stroke unit care is the evidence-based treatment for patients with all types of acute stroke in 
all ages and severity grades. The aggregate of multidisciplinary treatment, monitoring and 
care measures in dedicated stroke units prevents complications, improves functional 
outcomes, and reduces stroke mortality. Stroke unit care increases chance of independent 
survival by an absolute of 5-6 % compared to treatment in general medical wards, and the 
effect is sustainable for 10 years or more.5,6 In Sweden, approximately 91 % of all stroke 
patients are admitted to a stroke unit.1   
Intravenous thrombolysis
Intravenous thrombolysis with tissue plasminogen activator (tPA) within 4.5 hours of 
ischaemic stroke onset is an established and approved treatment7-12. The effect of iv 
thrombolysis is time-dependent. Among patients treated within one hour, every second 
patient is expected to fully recover within three months, among those treated within 90 
minutes, every third, and within 3 hours every seventh patient. For patients treated within the 
time interval of 3-4.5 hours, 14 patients need to be treated for one additional patient to 
recover fully.8,9 IV thrombolysis given within three hours from stroke onset increases the 
chance of reaching good functional outcome (defined as having exactly the same functional 
level as before the stroke) from 23% to 33%, and when given between 3 and 4.5 hours from 
onset, by a more modest but still substantial absolute 5%.8,9 The use of iv thrombolysis is 
increasing but still used in only 10-15% of all ischaemic stroke patients. Meanwhile, 2-7% of 
patients treated with iv thrombolysis suffer symptomatic intracerebral haemorrhage (ICH) as 
a complication, leading to death in 1.5-2%, and worsening functional outcome in survivors.8,9

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Endovascular thrombectomy 
Endovascular thrombectomy,13-19 although highly effective in reducing stroke disability and 
potentially mortality, is only indicated in large artery occlusion, feasible in a minority of 
patients, and is most commonly used in addition to iv thrombolysis. 
The rationale for thrombolytic treatment
Thromboembolic occlusion of an artery leading to the brain or in the brain, is a major cause 
of stroke. An occlusion of an artery leads to immediate drop of blood flow into the 
corresponding arterial territory. The size and site of the occlusion, and the efficiency of 
compensatory flow through collateral arteries determine the amplitude and the extension of 
the drop in the blood flow. If the flow is reduced to about 20 ml/100 g/minute (about 40% of 
the normal value), neurological symptoms occur. A blood flow below 10 ml/100 g/min is not 
compatible with cell survival, and the brain tissue is infarcted. Brain tissue with a blood flow 
between 10 and 20 ml/100g/min may survive for a few hours, but is likely to die if blood 
flow is not re-established.22
Spontaneous reperfusion may occur through endogenous release of plasminogen activator, 
which stimulates plasmin formation from plasminogen. For larger occlusions, this release 
seems insufficient to induce reperfusion in time to avoid a cerebral lesion. 
Administration of plasminogen activator as an intravenous infusion is thus a method to 
enhance this endogenous procedure. Reperfusion should of course be done as early as 
possible to avoid a cerebral lesion, and to avoid complications caused by ischaemic injury to 
blood vessel walls and the blood-brain barrier. 
Evidence from randomised controlled trials
In total, 17 randomised trials with 5,216 patients form the evidence base for thrombolysis in 
stroke. Of the data derived from these trials, 42% relate to streptokinase, 3% to intravenous 
urokinase and 5% to intra-arterial pro-urokinase. 50% of the data comes from trials using 
intravenous rt-PA. The results of these trials and agents are frequently discussed together,
which may give a more unfavourable impression of the effect of thrombolysis than if only 
intravenous rt-PA is studied. Whether there is true heterogeneity between thrombolytic agents 
is still not quite clarified, but there are differences between e.g. streptokinase and rt-PA in the 
effect on blood pressure (streptokinase reduces blood pressure) which may cause differential 
effects on collateral blood flow to the ischaemic area of the brain. 
A meta-analysis9 of individual patient data from 6756 patients in 9 randomised trials 7,11,23-27
comparing intravenous thrombolysis with Alteplase with placebo or open control in acute 
ischemic stroke shows that Alteplase significantly improves the overall odds of a good stroke 
outcome (defined by a modified Rankin score (mRS) of 0–1 ) when given within 4·5 h of 
stroke onset. The earlier treatment is associated with higher proportional benefits. Although 
Alteplase treatment significantly increased the odds of symptomatic intracranial haemorrhage 
and of fatal intracranial haemorrhage within 7 days but by 3–6 months this risk was offset by 
an average absolute increase in disability- free survival of about 10% for patients treated 
within 3 hours and about 5% for patients treated between >3 and 4.5 hours.
For rt-PA, data from 2,955 patients are available for analysis. Of these, 869 were included 
within three hours after onset of clinical symptoms. The results are more favourable for 
patients included within three hours compared to those included between three and six hours. 
The number needed to treat to get one more favourable outcome increases from 4.5, during 
the first 90 minutes, to 9 between 1.5 and 3 hours, and to 14 between 3 and 4.5 hours.28

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Pooled analysis of randomized controlled trials (RCTs) of intravenous thrombolysis (IVT) 
with Alteplase, a recombinant tissue plasminogen Activator (rt-PA) for acute ischemic stroke, 
has shown that patients >80 years treated with IVT versus control derived equal benefit 
compared to patients 18-80 years.9 Effectiveness of IVT diminished as the treatment delay 
increased across the first 6 hours without a corresponding increase in the relative risk of 
symptomatic intracerebral haemorrhage (SICH).9 Real world registry experience supports 
these RCT data in patients >80 years treated within 3h.35,36 The SITS-ISTR (Safe 
Implementation of Treatment in Stroke-International Stroke Thrombolysis Register)-VISTA 
analysis demonstrated benefit of IVT in patients >80 years compared to control, and found no 
difference in the slope of benefit versus treatment delay for younger versus elderly patients,36
a finding that was confirmed in the RCT dataset.37  
Experiences from post-trial treatments
Several open studies have been performed to address the issue of safety and efficacy of 
routine thrombolysis in acute stroke29-34. In the absence of control groups, the outcome of 
these studies must be compared with the results of randomised controlled trials. Such 
comparisons have been difficult since the baseline characteristics in most of the studies have 
not been comparable. This is illustrated by Katzan et al31 who reported the highest rate of 
cerebral haemorrhages of all studies. Initial stroke severity, the most important predictor of 
haemorrhagic complication risk was reported in only 40 % of all patients and in only 27 % of 
those with haemorrhage. 
Guideline recommendation and approval status
The European guideline38 recommends use of IVT within 4.5h of symptom onset also in the 
elderly, but North American guidance does not recommend IVT in the >3-4.5h window in 
patients >80 years.39 Until recently, most European regulatory agencies had not approved 
marketing of IVT with Alteplase for use in ischemic patients >80 years, whereas the 
American regulatory agency supports promotion of IVT in patients >80 years within 3h of 
symptom onset. A recently published SITS study showed that unselected patients >80-years 
treated with IVT after 3h versus earlier, had a slightly higher rate of SICH but similar 
unadjusted functional outcome and poorer adjusted outcome.40  IVT with Alteplase within 
4.5h of symptom onset is now approved in a number of European and non-European 
countries.

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8.
RESEARCH QUESTION AND OBJECTIVES
Safety and efficacy of a treatment in acute ischaemic stroke may be different in the RCT 
settings in patients over 80 years. Although IVT in patients >80 years has been used off-label 
in many countries prior to approval, use of IVT in patients>80 years will probably be more 
frequent after approval. The SITS-ISTR provides an opportunity for continuous monitoring 
of thrombolysis treatment in stroke, and provides a technical foundation for the SITS->80 
years post-approval registry. The proposed SITS-IVT>80 years is a retrospective study of 
existing data in the SITS-ISTR for the ischaemic stroke patients treated with IVT according 
to the Summary of Product Characteristics (SmPC) criteria. The study aims to evaluate the 
incidence rate of SICH, death and independence/favourable outcome within 90 days for 
ischaemic stroke patients treated with rt-PA in clinical routine settings. At least 2000 (1000 in 
the post-approval and 1000 in the pre-approval) patients overall from approximately 60 
European sites are planned to be identified in the SITS-IVT>80 years study. Safety and other 
outcome parameters will be compared between post-approval >80 years and pre-approval
>80 years patients.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
The SITS-IVT>80 years is an observational, multinational, multicenter study in patients with 
acute ischaemic stroke treated with IV thrombolysis according to SmPC. This is a 
retrospective study based on existing data collected in the registry for patients treated 
according to the revised and approved Summary of Product Characteristics (SmPC) of 
IVT>80 years in European countries.
Approximately 1000 patients older than 80 years treated with IV Alteplase are expected to be 
identified for the proposed SITS-IVT>80 year study in the post-approval period of 3 years (1 
July 2018 to 30 June 2021) and also approximately 1000 patients above 80 years treated with 
IV Alteplase within 4.5 hours otherwise according to SmPC in the pre-approval period (June 
2015 to June 2018). Of these, at least 500 patients each should be registered from European 
centers (see list of European countries being part of the mutual recognition procedure) during 
the pre-approval as well as in the post-approval period. If the target 1000 patient is not 
reached during the 3 year period (post-approval phase), the data exchange will stop provided 
at least 500 patients registered from European centers have been included into the analysis.
The aim is to investigate the incidence rate of SICH, death and functional independence
(mRS) / favorable outcome (primary endpoints) at day 90 in post-approval registered group 
of >80 year old patients and to compare with pre-approval registered group of >80 year old 
patients, comparison will be in both unmatched and the propensity score matched groups in 
the SITS-ISTR registry.
Additional analyses will be made with regards to patient’s characteristics, management time 
(secondary endpoints): onset of symptoms to time of treatment initiation, and its components: 
onset of symptoms to door; door to treatment initiation.
9.2
SETTING
The SITS-IVT>80 years Study is driven by the SITS International according to SITS policy, 
and data will be provided to the Regulatory Authorities as needed. Acute ischaemic stroke 
patients aged >80 years who received IV thrombolysis according to SmPC during the period 
June 2015 to June 2021 were considered. Of these, pre-approval sample will consist at least 
1000 patients from June 2015 to June 2018 and post-approval sample of 1000 patients from 
July 2018 to June 2021.
9.2.1
Level of care 
!
Thrombolysis treatment should be given at a semi-intensive care unit within a stroke 
unit, or an intensive care unit or semi-intensive care unit in close collaboration with 
the stroke unit, under the responsibility of an experienced stroke neurologist/stroke 

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physician. This stroke neurologist/stroke physician should have personal experience 
from thrombolysis treatment in stroke.
Inclusion criteria
!
Patients over 80 years old presenting with acute ischaemic stroke symptoms for which 
thrombolysis treatment was initiated within 4.5 hours after stroke onset according to 
SmPC are included.
!
Patients over 80 years who received thrombolysis according to SmPC for AIS within 
4.5 hours after stroke onset during the period (approximately 3 years) prior to July 
2018 are included.
Exclusion criteria
!
Contraindication(s) to the use of IV thrombolysis per local SmPC.
!
Documentation that the patient was enrolled or is planned to be enrolled in an 
investigational clinical trial at the time of the onset of index event and for the duration 
of the data collection.
9.3
VARIABLES
9.3.1
Exposures
Intravenous thrombolysis
Index date is defined as the date of initiation of IV thrombolysis with alteplase (Actilyse®).
Intravenous thrombolysis with tissue plasminogen activator (tPA) within 4.5 hours of 
ischaemic stroke onset is an established and approved treatment.7-12 The effect of iv 
thrombolysis is time-dependent. Among patients treated within one hour, every second 
patient is expected to fully recover within three months, among those treated within 90 
minutes, every third, and within 3 hours every seventh patient. For patients treated within the 
time interval of 3-4.5 hours, 14 patients need to be treated for one additional patient to 
recover fully.8,9 IV thrombolysis given within three hours from stroke onset increases the 
chance of reaching good functional outcome (defined as having exactly the same functional 
level as before the stroke) from 23% to 33%, and when given between 3 and 4.5 hours from 
onset, by a more modest but still substantial absolute 5%.8,9 The use of iv thrombolysis is 
increasing but still used in only 10-15% of all ischaemic stroke patients. Meanwhile, 2-7% of 
patients treated with iv thrombolysis suffer symptomatic intracerebral haemorrhage (ICH) as 
a complication, leading to death in 1.5-2%, and worsening functional outcome in survivors.8,9
Administration of plasminogen activator as an intravenous infusion is thus a method to 
enhance this endogenous procedure. Reperfusion should of course be done as early as 
possible to avoid a cerebral lesion, and to avoid complications caused by ischaemic injury to 
blood vessel walls and the blood-brain barrier.
Treatment with Actilyse must be started as early as possible within 4.5 hours of the onset of 
symptoms. Beyond 4.5 hours after onset of stroke symptoms there is a negative benefit risk 
ratio associated with Actilyse administration and so it should not be administered.

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The recommended total dose is 0.9 mg alteplase/kg body weight (maximum of 90 mg) 
starting with 10% of the total dose as an initial intravenous bolus, immediately followed by 
the remainder of the total dose infused intravenously over 60 minutes.
Patients in general will be exposed once to Actilyse for the treatment of the acute ischemic 
index event. 
9.3.2
Outcomes
9.3.2.1
Primary outcomes
Primary outcome 
!
Safety: SICH per SITS-MOST definition 
!
Mortality (mRS=6) within 90 days
!
Outcome: Functional Independency as defined by mRS 0-2 within 90 days
A modified Rankin score, mRS, is used to evaluate daily activity of the patient at day 90 
(described in Attachment 8.3). The scores are entered in the on-line entry form. The score 0-1 
is defined as favourable outcome and 0-2 as independence of the patient.
Symptomatic intracerebral haemorrhage, SICH, is defined as 'Intracerebral haemorrhage’ 
(parenchymatous haemorrhage type 2, PH2), at the 22-36 hours post-treatment scan 
combined with neurological deterioration leading to an increase of 4 points on the NIH 
Stroke Scale' (SITS-MOST definition). 
The evaluation of post-treatment haemorrhage is done using the CT/MRI scan performed 
between 22-36 hours after start of treatment or earlier if clinically indicated.
Death within 90 days as classified by the investigator according to cause: cerebral infarct, 
cerebral haemorrhage, cerebral infarct and haemorrhage unspecified, myocardial infarct, 
pulmonary embolism, pneumonia, other vascular cause, unknown and other cause of death 
(ICD 10 to be provided).  
9.3.2.2
Secondary outcomes
Secondary outcomes
!
Patient characteristics at baseline including stroke severity (NIHSS)
!
Outcomes: Favourable outcome as defined by mRS 0-1 within 90 days
!
Secondary safety: SICH per ECASS 2 within 90 days
!
Delays of management
o
Time from onset of symptoms – start of treatment
o
Time from onset of symptoms – door (or as captured in the registry arrival at 
hospital)
o
Door – needle time

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9.3.3
Covariates
Specification of data collection from the index stroke event
At baseline: Demographic data (age, sex, weight), NIHSS and pre-stroke mRS, blood 
pressure, laboratory values (plasma glucose, cholesterol) medical history including 
comorbidities and concomitant medication, results of imaging scans, time logistics
At 24 hours: NIHSS score, blood pressure, laboratory and imaging scans if performed. 
During hospital stay: details of concomitant medications, additional imaging scans 
At 7 day or discharge if occurred earlier than 7 days: Date/time discharge, NIHSS scores, 
blood pressure, type of stroke and AF, medications
At 3-months follow up: mRS scale, any events including recurrent stroke (haemorrhagic or 
ischaemic), major extracranial haemorrhage
The analysis will include standard covariates.
Standard SITS-ISTR safety parameters: 
•
Baseline and demographic variables available in SITS for describing patient 
characteristics such as but not limited to stroke severity, age, gender etc. (standard covariates)
•
Symptomatic intracerebral haemorrhage (SICH):
Intracerebral haemorrhage (parenchymatous haemorrhage type 2), at post-treatment scan 
combined with neurological deterioration leading to an increase of 4 points on the NIH 
Stroke Scale (SITS-MOST definition)
•
Mortality:
Death (mRS = 6) at day 90
•
Independence / favourable outcome:
Independence for the activities of daily living at day 90. Good functional outcome is defined 
as a modified Rankin Scale (mRS) score of both 0-2 (independence) and 0-1 (favourable)and 
independency / favourable outcome at 90 days (mRS 0-2, mRS 0-1
Patient management variables
o
Time from onset to door
o
Door to needle (treatment) time 
Onset to treatment time

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9.4
ONSET TO TREATMENT TIME DATA SOURCES
Data is collected within the SITS-ISTR registry according to their standard procedures.  
SITS is an academic-driven, non-profit, international collaboration. It is an initiative by the
medical profession aimed at driving excellence in acute and secondary stroke treatment, and
to develop new knowledge and leading research. SITS-ISTR is an ongoing, prospective, 
multinational and academic driven registry for centres using thrombolysis for the treatment of 
acute ischaemic stroke patients. The registry contains data about alteplase treatment 
independent of the time since stroke onset. Information related to patient demographics, 
baseline characteristics, stroke severity at baseline, onset to treatment time, risk factors, drug 
treatment history, admission time and data on baseline and follow-up imaging scans are 
collected in SITS-ISTR
9.5
STUDY SIZE
The sample size was not based on any formal power calculation, rather chosen pragmatically 
in consultation with authorities and based on numbers achievable within a 3-year period. 
Approximately 2000 acute ischaemic patients who were treated with IV thrombolysis within 
4.5 hours within symptom onset constitute the main analysis population. Data from a 
minimum of 500 European patients are expected within the database during post approval 
phase as well as equal number during the pre-approval phase in patients > 80 years old acute 
ischemic stroke patients. 
9.6
DATA MANAGEMENT
Data in the SITS registry are entered on-line through the SITS website.
SITS uses the two-factors authentication to login to the registry, i.e. first by username and 
password and then by a code which is sent to the user either by SMS or by e-mail. Each 
investigator/study nurse has a personal access code which must be kept secret and used
only by the owner. All data entry from a centre can be made by each member of the local
team, but once the data entry is confirmed (i.e. cannot be changed), the person who made the
confirmation will be identified on the data entry form.
For the purpose of analysis, a download will be made in Excel/ CSV format which will then
be transferred in the appropriate advance data analysis software such as STATISTICA/ SAS.
Data collection in this study is approved as part of the SITS-ISTR study framework by the 
Regional Research Ethics Committee in Stockholm, Sweden. Data analyses are performed 
according to SITS policy and under the responsibility of the Scientific Committee. 
9.7
DATA ANALYSIS
A non-interventional post-approval study on SITS-ISTR existing data of intravenous rt-PA 
(0.9 mg/kg) in acute ischaemic stroke patients over 80 years, according to the Summary of 

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Product Characteristics (SmPC) of European countries being part of the mutual recognition 
procedure within the academic SITS-ISTR (International Stroke Thrombolysis Registry,
ongoing since December 2002). 
Descriptive statistics (absolute and relative frequencies, means, standard deviations, medians,
inter quartile ranges, minimum and maximum values, 95% confidence intervals and
proportions, as appropriate) for baseline and demographic characteristics for all included 
patients will be provided. To compare demographic and clinical baseline characteristics 
between pre-approval and post-approval patients over >80years, standardized differences will 
be used. Multivariable analyses (exploratory) with adjustment for differences or imbalances 
in prognostic variables for outcome comparison will be performed. 
9.7.1
Main analysis
We will compare the outcome of interest both in unmatched and propensity score matched 
patient sets as described below. The primary analysis will be on propensity score matched 
patient sets and we will compare the post-approval >80 year old patients with the pre-
approval retrospective >80 year olds regarding baseline demographics, clinical and 
radiological parameters, as well as treatment logistics, safety outcomes, functional outcome 
and death. Secondary analysis will be on unmatched patient sets, i.e. all patients fulfilling the 
inclusions-exclusions criteria will be included in this analysis. A sensitivity analysis restricted 
to European and non-European patients might be considered if minimum sample size 
required for analysis is met in the matched patient set.
Patient sets analysed includes “unmatched” and “matched”. “Unmatched” patients set 
composed of IV thrombolysis treated patients >80 years from both pre-approval and post-
approval phase those who fulfil the inclusions-exclusions criteria. Matched patient set 
constitute propensity score matched pair (1:1 greedy nearest neighbour matching using 
calipers equal to 0.2*SD of the logit of the propensity score).
The incidence rate and corresponding 95% CI of patients with primary and secondary 
outcome events will be calculated within the following cohorts: 
a) Patients >80 years after approval
b) Patients >80 years before approval
The incidence rate for the outcome of interest using as-treated approach will be calculated on 
the unmatched (all eligible patients) and the matched patient sets. 
In the primary analysis, post-approval >80 year old patients will be matched to pre-approval 
>80 year old patients using a structured, iterative propensity score model with the primary 
objective to maximize the balance in the distribution of possible confounders between these 
two groups [9].
In the propensity score-matching algorithm, all baseline characteristics will be included. The 
corresponding propensity score of the post-approval >80 years group will be calculated for 

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each subject and a nearest neighbour matching algorithm will then be used to match patients 
in the post-approval >80 years group to patients in the pre-approval >80 years group within 
0.2*SD of the logit of the propensity score. To determine whether the propensity score 
approach achieved balance in all potential confounders, we will compare all baseline 
characteristics of patients in the post-approval >80 years group to their propensity score 
matched pre-approval >80 year old patients using standardized difference.
We will also compare baseline characteristics between the unmatched and propensity 
matched subgroups to detect potential imbalances between the two populations. Differences 
of outcome between post-approval >80 years and pre-approval >80 years will be evaluated 
with univariable and multivariable binary logistic regression models adjusting for potential 
confounders. In these models the factors that contribute to the outcome of interest in the 
initial univariable analyses at p values <0.1, will be included in the multivariable model as 
candidate variables. The final variables that will be independently associated in the 
multivariable logistic regression analyses with the outcome of interest will be selected by 
backward stepwise selection procedures using a p value <0.05.
9.8
QUALITY CONTROL
European Stroke Centres (approx. 60) continuously registering patients into SITS-ISTR 
having 
-
a typical experience from acute stroke treatment 
-
high quality (at least 90% complete data entered at acute phase and 70% data entered at 
3m follow up) in both prospective and retrospective groups 
-
a willingness to participate in SITS-IVT>80 years registry
9.8.1
Investigators and local procedures
According to the current processes in SITS described on the SITS web site 
(www.sitsinternational.org) the following persons are involved;
National Coordinator
A National Coordinator (NC) is appointed by SITS as to be the responsible person for the 
SITS activity in the specific country. The NC has an overview of the infrastructure in regards 
to stroke care treatments in the country. The role of NC is to coordinate among the different 
centers in the country. SITS has engaged leading stroke scientists as National Coordinators in 
each participating country.
Local coordinator/ Centre coordinator
The Local Coordinator (LC) is responsible for the centre activity and ultimate responsibility 
of the data entered in the SITS registry from the hospital. The LC must be a doctor authorised 
by the medical head of the department.

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Local user
The Local User (LU) is responsible for entering data in the SITS registry. The LU must be 
appointed by the LC and operating within the stroke unit.
Internal data quality controls will be done by the SITS Coordinating Office, which will 
include:
1. Validation rules for key data parameters so that impossible data will not be possible to 
enter
2. Online monitoring to find out inconsistent data entry, data completeness
3. In addition to online data monitoring, inconsistency and completeness check every 6 
months. Normally investigators are informed by newsletter regarding the 
completeness of data entry for overall registry and asked to complete the missing data. 
In case of major inconsistency or high rate of missing data investigators are contacted 
personally by e-mail.
9.9
LIMITATIONS OF THE RESEARCH METHODS
Non-interventional study based on existing data
The quality of a study based on existing data relies on accuracy of recorded data. Important
data may not be available. 
Selection bias
There is a risk of selection bias at the patient level. Sites might preferentially include
"interesting" cases to the SITS study. To minimize selection bias at the patient level, centres
were reminded by e-mail every 3 months that all consecutive patients from each site who
meet entry criteria must be included in the SITS-Registry.
Lost to follow up
As with all observational studies a loss to follow up can occur. In this study this will affect
the patients with a pre-planned follow up (patients initiating IV thrombolysis within the 3 
months after the index event). However, considering the short time period of the follow up 
and the lost to follow up at 3 months in the general SITS Registry being 20%, a similar 
percentage of lost to follow up is expected in this study as well.
For the analysis of clinical outcome events we do not exclude patients lost to follow-up after
IV thrombolysis initiation and before the 3 months after index event, which could lead to 
underidentification of clinical outcome events.
9.10
OTHER ASPECTS
Not applicable.

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9.11
SUBJECTS
Patients over 80 years old presenting with acute ischaemic stroke symptoms for which 
thrombolysis treatment was initiated within 4.5 hours after stroke onset according to the 
SmPC during the study period June 2015 to June 2021 divided into pre-approval (June 2015 
to June 2018) and post-approval (July 2018 to June 2021).
9.11.1
Cases
Not applicable.
9.11.2
Controls
Please refer to Section 9.7.1
9.12
BIAS
To assess potential channeling bias, baseline characteristics of all patients fulfilling the
in/exclusion criteria and were included in SITS-ISTR registry in the defined time period will 
be described based on the IV thrombolysis treatment they receive for ischemic stroke within 
4.5 hours from symptoms onset.

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10.
PROTECTION OF HUMAN SUBJECTS
Regulated under the SITS ISTR registry. All data entered into the SITS International 
Thrombolysis registry are encrypted in order to maintain patient data privacy. The individual 
patient and its research data is identified by a unique registry identification number. Access to 
data is strictly controlled by permitting two-way authentication, i.e. each user a unique 
username and password and a code received by sms or e-mail. Additionally, each user has 
restrictions in viewing data sets, depending on their activity role in the database. Each data 
entry is centrally monitored by internal quality checks, such as automatic range checks and a 
full audit trail is maintained.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
According to the European Medicines Agency (EMA) Guideline on Good Pharmacovigilance
Practices (GVP), Adverse Event (AE) reporting is not required for Non-Interventional Study
(NIS) which is based on secondary data use.
12.
AS AN OBSERVATIONAL STUDY, BASED ON EXISTING 
DATA, ALL PATIENT DATA IS DE-IDENTIFIED AND WILL 
BE ANALYSED IN AGGREGATE. INDIVIDUAL PATIENT 
SAFETY RELATED INFORMATION WILL NOT BE 
CAPTURED DURING THIS STUDY. THUS, INDIVIDUAL 
SAFETY REPORTING IS NOT APPLICABLE. SAFETY 
REPORTING WILL BE DONE CUMULATIVELY IN 
AGGREGATE IN THE STUDY REPORT.PLANS FOR 
DISSEMINATING AND COMMUNICATING STUDY 
RESULTS
The results will be disclosed on EnCEPP, Publications will be prepared and the full study 
report will be submitted to the authorities. 

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13.
REFERENCES
.
13.1
PUBLISHED REFERENCES
Include references with P, R, and S numbers here.
1. Johnson W, Onuma O, Owolabi M, Sachdev S. Stroke: a global response is 
needed.  Bull World Health Organ. Switzerland2016. p. 634-a.
2. Feigin VL et al. Atlas of the global burden of stroke (1990-2013): The GBD 2013 
Study. Neuroepidemiology 2015; 45(3):230-6
3. Wahlgren NG. Introduction to Karolinska Stroke Update 2000. In: Update on 
Stroke Therapy 2000-2001, NG Wahlgren, ed, Karolinska Stroke Update, 
Stockholm, 2001; 17-19. 
4. Menken M, Munsat TL, Toole JF. The global burden of disease study. Implications 
for neurology. Arch Neurol. 2000; 57: 418–420.
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8. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, 
Frankel M, Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu 
M,Lyden P, Marler JR, Patel S, Tilley BC, Albers G: Association of outcome with 
early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA 
stroke trials. Lancet 2004;363:768-774
9. Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, et al. Effect of 
treatment delay, age, and stroke severity on the effects of intravenous 
thrombolysis with alteplase for acute ischaemic stroke: a metaanalysis of 
individual patient data from randomised trials. Lancet. 2014;384(9958):1929-35 
10. Wahlgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W, Hennerici MG, 
Kaste M, Kulkens S, Larrue V, Lees KR, Roine RO, Soinne L, Toni D, Vanhooren G: 
Thrombolysis with alteplase for acute ischaemic stroke in the Safe 
Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an 
observational study. Lancet 2007;369:275-282.
11. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, Larrue V, Lees 
KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, for 
the ECASS Investigators. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute 
Ischemic Stroke. New Engl J Med 2008; 359: 1317-1329.

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12. Wahlgren N, Ahmed N, Davalos A, Hacke W, Millan M, Muir K, Roine RO, Toni D, 
Lees KR. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-
ISTR): an observational study. Lancet 2008; 372: 1303-1309.
13. Berkhemer OA, Fransen PS, Beumer D et al. A randomized trial of intraarterial 
treatment for acute ischaemic stroke. N Engl J Med 2015; 372: 11–20.
14. Goyal M, Demchuk AM, Menon BK et al. Randomized assessment of rapid 
endovascular treatment of ischaemic stroke. N Engl J Med 2015; 372: 1019–30.
15. Campbell BC, Mitchell PJ, Kleinig TJ et al. Endovascular therapy for ischaemic 
stroke with perfusion-imaging selection. N Engl J Med 2015; 372: 1009–18.
16. Saver JL, Goyal M, Bonaf_e A et al. Stent-retriever thrombectomy after 
intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 2015; 372: 2285–95.
17. Jovin TG, Chamorro _A, Cobo E et al. Thrombectomy within 8 hours after 
symptom onset in Ischaemic stroke. N Engl J Med 2015; 372: 2296–306.
18. Wahlgren N, Moreira T, Michel P, et al; for ESO-KSU, ESO, ESMINT, ESNR and 
EAN. Mechanical thrombectomy in acute ischemic stroke: Consensus statement 
by ESO-Karolinska Stroke Update 2014/2015, supported by ESO, ESMINT, ESNR 
and EAN. Int J Stroke. 2016 Jan;11(1):134-47.
19. Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, 
Dávalos A,Majoie CB, van der Lugt A, de Miquel MA, Donnan GA, Roos YB, Bonafe 
A, Jahan R,Diener HC, van den Berg LA, Levy EI, Berkhemer OA, ereira VM, 
Rempel J, Millán M, Davis SM, Roy D, Thornton J, Román LS, Ribó M, Beumer D, 
Stouch B, Brown S, Campbell BC, van Oostenbrugge RJ, Saver JL, Hill MD, Jovin 
TG; HERMES collaborators.. Endovascular thrombectomy after large-vessel 
ischaemic stroke: a meta-analysis of individual patient data from five randomised 
trials. Lancet. 2016 Apr 23;387(10029):1723-31. doi: 10.1016/S0140-
6736(16)00163-X. PubMed PMID: 26898852.
20. Socialstyrelsen. Nationella riktlinjer för strokesjukvård 2009 - stöd för styrning 
och ledning. 2009. 
21. Powers WJ, Derdeyn CP, Biller J, Coffey CS, Hoh BL, Jauch EC, et al. 2015 
american heart association/american stroke association focused update of the 
2013 guidelines for the early management of patients with acute ischemic stroke 
regarding endovascular treatment: A guideline for healthcare professionals from 
the american heart association/american stroke association. Stroke. 
2015;46:3020-3035
22. Hossman KA. Pathophysiology of cerebral infarction. In: Wilken PJ, Bruyn GW, 
Klawans HL, eds.Handbook of Clinical Neurology, Vol 53. Amsterdam, Elsevier 
Science Publishers 1988, 107-153
23. Hacke W, Kaste M, Fieschi C, et al, and the European Cooperative Acute Stroke 
Study (ECASS). Intravenous thrombolysis with recombinant tissue plasminogen 
activator for acute hemispheric stroke. JAMA 1995; 274: 1017–25. 
24. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled 
trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke 
(ECASS II). Lancet 1998; 352: 1245–51. 

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25. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S, for 
the ATLANTIS Study Investigators. Recombinant tissue-type plasminogen 
activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The 
ATLANTIS Study: a randomized controlled trial. JAMA 1999; 282: 2019–26.
26. Davis SM, Donnan GA, Parsons MW, et al, and the EPITHET investigators. Effects 
of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic 
Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol 
2008; 7: 299–309. 
27. Sandercock P, Wardlaw JM, Lindley RI, et al, and the IST-3 collaborative group. 
The benefits and harms of intravenous thrombolysis with recombinant tissue 
plasminogen activator within 6 h of acute ischaemic stroke (the third 
international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012; 379: 
2352–63.
28. Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, Albers GW, Kaste 
M, Marler JR, Hamilton SA, Tilley BC, Davis SM, Donnan GA, Hacke W; ECASS, 
ATLANTIS, NINDS and EPITHET rt-PA Study Group, Allen K, Mau J, Meier D, del 
Zoppo G, De Silva DA, Butcher KS, Parsons MW, Barber PA, Levi C, Bladin C, 
Byrnes G. Time to treatment with intravenous alteplase and outcome in stroke: 
an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. 
Lancet 2010; 375:1695-703
29. Chiu D, Krieger D, Villar-Cordova C, Kasner SE, Morgenstern LB, Bratina PL, Yatsu 
FM, Grotta JC. Intravenous tissue plasminogen activator for acute ischemic 
stroke. Feasibility, Safety and efficacy in the first year of clinical practice. Stroke. 
1998;29:18-22
30. Trouillas P, Nighoghossian N, Derex L, Adeleine P, Honnorat J, Neuschwander P, 
Riche G, Getenet JC, Li W, Froment JC, Turjman F, Malicier D, Fournier G, Gabry 
AL, Ledoux X, Berthezène Y, Ffrench P, Dechavanne M. Thrombolysis with 
intravenous rtPA in a series of 100 cases of acute carotid territory stroke. 
Determination of etiological, topographic, and radiological outcome factors. 
Stroke 1998;29:2529-40
31. Katzan IL, Furlan AJ, Lloyd LE, Frank JI, Harper DL, Hinchey JA, Hammel JP, Qu A, 
Sila CA. Use of tissue-type plasminogen activator for acute ischemic stroke. The 
Cleveland experience. JAMA 2000;283:1151-58
32. Schmülling S, Grond M, Rudolf J, Heiss WD. One-year follow-up in acute stroke 
patients treated with rtPA in clinical routine. Stroke 2000;31:1552-54
33. Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA. Intravenous tissue-
type plasminogen activator for treatment of acute stroke. The standard 
treatment with alteplase to reverse stroke (STARS) study. JAMA 2000;283:1145-
50
34. Tanne D, Demchuk A., Kasner SE, Grond M, Hanson S, Hamilton S, Buchan AM, 
Wang DZ, Wechsler LR, Zweifler R, Levine SR, for the t-PA in acute stroke 
collaborators. A large multinational investigation to predict t-PA related 
symptomatic ICH in patients with acute ischemic stroke.Stroke 30, 248, 1999

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35. Ford GA, Ahmed N, Azevedo E, et al. Intravenous alteplase for stroke in those 
older than 80 years old. Stroke. 2010 Nov;41(11):2568-74. doi: 
10.1161/STROKEAHA.110.581884. Epub 2010 Oct 7. PubMed PMID: 20930163.
36. Mishra NK, Ahmed N, Andersen G, et al; VISTA collaborators; SITS collaborators. 
Thrombolysis in very elderly people: controlled comparison of SITS International 
Stroke Thrombolysis Registry and Virtual International Stroke Trials Archive. BMJ. 
2010 Nov 23;341:c6046. doi: 10.1136/bmj.c6046.. PubMed PMID: 21098614; 
PubMed Central PMCID: PMC2990864.
37. Whiteley WN, Emberson J, Lees KR, et al; Stroke Thrombolysis Trialists' 
Collaboration.. Risk of intracerebral hemorrhage with alteplase after acute 
ischaemic stroke: a secondary analysis of an individual patient data meta-
analysis. Lancet Neurol. 2016 Aug;15(9):925-33. doi: 10.1016/S1474-
4422(16)30076-X. 
38. ESO Guidelines: webpage: eso-stroke.org/eso-stroke/education/education-
guidelines.html, ESO guideline Updated 2009)
39. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al; American Heart 
Association Stroke Council and Council on Epidemiology and Prevention. 
Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous 
Alteplase in Acute Ischemic Stroke: A Statement for Healthcare Professionals 
From the American Heart Association/American Stroke Association. Stroke. 2016 
Feb;47(2):581-641. doi: 10.1161/STR.0000000000000086. Epub 2015 Dec 22. 
Review. PubMed PMID: 26696642
40. Ahmed N, Lees KR, Ringleb PA, Bladin C, Collas D, Toni D, Ford GA; The SITS 
Investigators. Outcome after stroke thrombolysis in patients >80 years treated 
within 3 hours vs >3-4.5 hours. Neurology. 2017 Oct 10;89(15):1561-1568. 
doi:10.1212/WNL.0000000000004499. Epub 2017 Sep 8. PubMed PMID: 
28887377

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01- MCS-90-124_RD-01 (4.0)
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
Reference Number
Date
Title
1
not applicable
September 2019
common-
combined-Actilyse-
en-clean-September
2019
2
not applicable
September 2019
SITS- IVTP
Standard data entry 
form_2019 
September

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01- MCS-90-124_RD-01 (4.0)
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS
A copy of the ENCePP Checklist for Study protocols available at website: 
encepp.eu/standards_and_guidances/index.html completed and signed by the main author of 

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01- MCS-90-124_RD-01 (4.0)

Boehringer Ingelheim
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Study Number 0135-0344
c30353958-01
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01- MCS-90-124_RD-01 (4.0)

Boehringer Ingelheim
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Study Number 0135-0344
c30353958-01
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01- MCS-90-124_RD-01 (4.0)

Boehringer Ingelheim
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Study Number 0135-0344
c30353958-01
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01- MCS-90-124_RD-01 (4.0)

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
Study Number 0135-0344
c30353958-01
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01- MCS-90-124_RD-01 (4.0)

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
Study Number 0135-0344
c30353958-01
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01- MCS-90-124_RD-01 (4.0)

Boehringer Ingelheim
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Study Number 0135-0344
c30353958-01
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
01- MCS-90-124_RD-01 (4.0)
ANNEX 3. ADDITIONAL INFORMATION
National Institute of Health Stroke Scale, NIHSS
The NIH stroke scale, NIHSS, is described in Attachment 1.1. The scores are entered in 
the on-line entry form. 
Global Evaluation Scale, GES
The Global Outcome Evaluation Scale, is described in Attachment 1.2 and the questions 
to answer are specified at the on-line entry form.
Modified Rankin Scale (Mrs)
mRS is described in Attachment 1.3 and the questions to answer are specified at the 
on-line entry form
Brain CT/MR scan
All CT/MR scans are reviewed at the participating centre according to the local routine 
procedure and the outcome of the evaluation is entered in the database. 
!
Baseline readings
The CTs will be evaluated with respect to haemorrhage, any sign of acute cerebral 
ischemic injury in the symptomatic vascular territory, or other pathology. Preferably, 
CTA (CT angiography) imaging will be used for identification of cerebral artery 
occlusion.
!
Day 2 readings (22-36 hours after start of treatment) 
Intracerebral haemorrhage, ICH, will be classified according to the SITS-ISTR data 
collection format.

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1a.Level of consciousness
0
Alert
1
Not alert, but arousable with minimal stimulation
2
Not alert, requires repeated stimulation to attend
3
Coma
1b. Ask patient the month and 
their age
0
Answers both correctly
1
Answers one correctly
2
Both incorrect
1c.Ask patient to open/close 
eyes and form/release fist
0
Obeys both correctly
1
Obeyrs one correctly
2
Both incorrect
2.Best gaze (only horisontal 
eye movements)
0
Normal
1
Partial gaze palsy
2
Forced gaze deviation
3. Visual field testing
0
No visual field loss
1
Partial hemianopia
2
Complete hemianopia
3
Bilateral hemianopia (blind, incl. Cortical blindness)
4. Facial paresis (Ask patient 
to show teeth or raise 
eyebrows and close eyes 
tightly)
0
Normal symmetrical movement
1
Minor paralysis (flattened nasolabial  fold, asymmetry on smiling), 
2
Partial paralysis (total or near total paralysis of lower face)
3
Complete paralysis of one or both sides (abscence of facial movement in the 
upper and lower face)
5a.Motor function
- right arm
0
Normal (extends arm 90  or 45  for 10 sec without drift)
1
Drift
2
Some effort against gravity
3
No effort against gravity
4
No movement
9
Untestable (joint fused or limb amputated)
5b. Motor Function
- left arm
0
Normal (extends arm 90  or 45  for 10 sec without drift)
1
Drift
2
Some effort against gravity
3
No effort against gravity
4
No movement
9
Untestable (joint fused or limb amputated)
6a. Motor Function -  right leg
0
Normal (holds leg in 30  position for 5 sec without drift)
1
Drift
2
Some effort against gravity
3
No effort against gravity
4
No movement
9
Untestable (joint fused or limb amputated)
6b. Motor Function – left leg
0
Normal (holds leg in 30  position for 5 sec without drift)
1
Drift
2
Some effort against gravity
3
No effort against gravity
4
No movement
9
Untestable (joint fused or limb amputated)
7. Limb ataxia
0
No ataxia
1
Present in one limb
2
Present in two limbs
8. Sensory (use pinprick to test 
arms, legs trunk and face, 
compare side to side)
0
Normal
1
Mild to moderate decrease in sensation
2
Severe to total sensory loss
9. Best language (describe 
picture, name items)
0
No aphasia
1
Mild to moderate aphasia
2
Severe aphasia
3
Mute
10. Dysarthria (read several 
words)
0
Normal articulation
1
Mild to moderate slurring of words
2
Near unintelligible or unable to speak
9
Intubated or other physical barrier
11. Extinction and inattention 
(use visual double stimulation 
or sensory double stimulation)
0
Normal
1
Inattention or extinction to bilateral simultaneous stimulation in one of the 
sensory modalities
2
Severe hemi-inattention or hemi-inattention to more than one modality

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Study Number 0135-0344
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01- MCS-90-124_RD-01 (4.0)
1.2
Global evaluation scale, GES
Has a change in the patient’s clinical condition occurred after treatment?
Check one alternative:
Much better
+2
Better
+1
Unchanged
0
Worse
-1
Much worse
-2
Dead                                           -3

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01- MCS-90-124_RD-01 (4.0)
1.3 Modified Rankin Scale, mRS
Score
Description
0
No symptoms at all
1
No significant disability despite symptoms; able to carry out all 
usual duties and activities 
2
Slight disability; unable to carry out all previous activities, but able 
to look after own affairs without assistance
3
Moderate disability; requiring some help, but able to walk without 
assistance
4
Moderately severe disability; unable to walk without assistance and 
unable to attend own bodily needs without assistance
5
Severe disability; bedridden, incontinent and requiring constant 
nursing care and attention
6
Dead
Total (0-6): __________

 
 
 
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