Conditions: Stroke
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 120
Healthy volunteers: no

Brief summary:
To evaluate the safety and efficacy of alteplase when administered between 3 and 4.5 hours after onset of stroke symptoms in Chinese patients with acute ischemic stroke

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: alteplase
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
Clinical Trial Protocol
TITLE PAGE
Document Number:
c08776773-03
BI Trial No.:
135.331
BI Investigational 
Products:
Actilyse®, Alteplase (rt-PA)
Title:
An open label, multicenter, single-arm trial to assess safety and efficacy 
of alteplase (rt-PA) in Chinese patients with acute ischemic 
hemispheric stroke where thrombolysis is initiated between 3 and 4.5 
hours after stroke onset
Lay Title:
Stroke-Ampoule
Clinical Phase:
IIIb
Trial Clinical 
Monitor:
Tel : 
Email: 
Coordinating 
Investigator:
Tel:
Fax:
Email: 
Status:
Final Protocol (Revised Protocol based on Global Amendment 2)
Version and Date:
Version:
Date:
3.0
15 Feb 2017
Page 1 of 72
Proprietary confidential information.
2017 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.


Boehringer Ingelheim
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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Actilyse®
Name of active ingredient:
Alteplase (rt-PA)
Protocol date:
25 Apr 2016
Trial number:
135.331
Revision date:
15 Feb 2017
Title of trial:
An open label, multicenter, single-arm trial to assess safety and 
efficacy of alteplase (rt-PA) in Chinese patients with acute ischemic 
hemispheric stroke where thrombolysis is initiated between 3 and 4.5 
hours after stroke onset
Coordinating 
investigator :
Tel:
Fax:
Email: 
 
Trial sites:
Multi-center trial conducted in China (will be conducted at neurology 
clinics or stroke unites and with 24 hours access to an adequate 
imaging scanner and lab tests)
About 15 sites
Clinical phase:
III b 
Objectives:
To evaluate the safety and efficacy of alteplase when administered 
between 3 and 4.5 hours after onset of stroke symptoms in Chinese 
patients with acute ischemic stroke
Methodology:
Multi-center, open label, single arm study 
No. of patients: 
total entered:
120
Diagnosis :
Acute Ischemic Stroke (AIS)
Main criteria
for inclusion:
To be eligible, patients must fulfil the following criteria:
Main inclusion criteria:
1.
Age ≥18 years at screening(visit 1A) but ≤80 years 
2.
Signed and dated written informed consent in accordance with 
GCP and local legislation prior to admission to the trial
3.
Diagnosis of ischemic stroke with a measureable neurological 
deficit on National Institute of Health Stroke Scale (NIHSS)
4.
Thrombolytic therapy can be initiated within 3 to 4.5 hours of 
stroke onset


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Trial Protocol
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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
Actilyse®
Name of active ingredient:
Alteplase (rt-PA)
Protocol date:
25 Apr 2016
Trial number:
135.331
Revision date:
15 Feb 2017
Main exclusion criteria
1.      Evidence of intracranial haemorrhage (ICH) on the CT/MRI-
scan or symptoms suggestive of subarachnoid haemorrhage, even if 
the CT/MRI-scan is normal
2.       Acute bleeding diathesis
3.       Severe stroke as assessed clinically( e.g. NIHSS>25) and/ or 
imaging demonstrates multi-lobar infarction (hypodensity >1/3 
cerebral hemisphere)
4.       Severe uncontrolled arterial hypertension, e.g. systolic blood 
pressure>185 mmHg or diastolic blood pressure>110mmHg, or 
aggressive management (IV medication) necessary to reduce BP to 
these limits
5.       Blood glucose <50mg/ dL or >400 mg/dL
6.      Any history of prior stroke in previous 3 months, or any history 
of  prior stroke with  concomitant diabetes
7.     Seizure at stroke onset
Test product:
Alteplase
dose:
0.9 mg/kg (Maximum dose 90 mg)
mode of 
administration:
(10% bolus+90% infusion/60minutes) 10% of total dose administered 
as a bolus over 1-2 minutes and remaining 90% given by continuous 
IV infusion over 60 minutes if no allergic reaction within 5 minutes 
following administration of test dose.
Comparator products:
NA
dose:
NA
mode of 
administration:
NA
Duration of treatment:
Bolus plus one hour infusion
Efficacy Endpoints
Primary Efficacy Endpoint:
The percentage of mRS 0-1 (favourable outcome) responder at 
visit 5 (i.e., day 90)
Secondary Efficacy Endpoint:

The percentage of global outcome responder at visit 5 (i.e., day 
90) if he/she obtains the following results at visit 5 (i.e., day 90) 
(for all of the 4 endpoints)


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BI Trial No.: 135.331
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Trial Protocol
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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
Actilyse®
Name of active ingredient:
Alteplase (rt-PA)
Protocol date:
25 Apr 2016
Trial number:
135.331
Revision date:
15 Feb 2017
              mRS score of 0 to 1
              Barthel Indext score≥95
              NIHSS score of 0 to 1
              Glasgow Outcome Scale score of 1
 
  
 
 
 
  
  
Safety criteria:
Primary Safety endpoints:
The percentage of patients with symptomatic intracranial 
haemorrhage (sICH) within the whole study period centrally 
evaluated by DMC consultants, according to ECASSIII criteria, 
details refer to section 5.3.1.
Secondary Safety Endpoints:
Patient survival probability at visit 5 (censoring at 90 days)


Boehringer Ingelheim
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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
Actilyse®
Name of active ingredient:
Alteplase (rt-PA)
Protocol date:
25 Apr 2016
Trial number:
135.331
Revision date:
15 Feb 2017
Frequency of death related to stroke or of neurological causes
Frequency and severity of adverse events
The percentage of patients with cerebral herniation and 
symptomatic edema
Statistical methods:
The sICH rate will be estimated as the proportion of patients with 
sICH event within the whole study period and its exact 95% 
confidence interval will be calculated. 
Efficacy endpoints will be assessed in the treated set. The proportion 
of mRS 0-1 (favourable outcome) responders will also be calculated 
along with its 95% CI. From the historical literature review, the best 
guess of the response rate is around 50%. It is assumed that the 
primary efficacy endpoint in this study will be comparable with this 
number.
Descriptive statistics of demographic, safety and efficacy data will be 
presented as appropriate.


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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
FLOW CHART
Visit
1A
(Screening)
Trial 
Drug 
Admin
1B
1C
2
3
4
5
Day 
0
1
7
30
90
≤4.5 Hrs
1 Hr #
2 Hrs #
Time Window
±
15Mins
±30Mins
±2Hrs
±3Days 
±3Days 
±7Days 
Informed consent1
X
Demographics
X
Medical History
X
Cerebral imaging and 
interpretation
X2
X3
X4
X4
Physical Exam , vital signs
X
X
X
X
X
X
X
In- / Exclusion Criteria
X
Lab Test 
X5
X6
X 
X6
Pregnancy Test(blood or 
urine)
X7
X6
X6
Concomitant Therapy
X
X
X
X
X
X
X
Administration of  Alteplase
←
dminis
tr
Adverse Events
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
NIHSS8
X
X
X
X
X
X
Glasgow Outcome Score8
X
Modified Rankin Scale8
X
X


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Barthel Index8
X
X
Conclude subject 
participation9
X
1.
Informed consent needs to be signed before any procedure related to the study. When it is signed, all AEs and concomitant treatment 
occurring after Informed Consent have to be recorded. Procedures which are performed as part of routine clinical care prior to 
obtaining the informed consent could be used for screening if they are within the allowed time window (after stroke onset and before 
drug administration). (considered by investigator).
2.
Either CT or MRI is mandatory before Alteplase administration to exclude ICH (absolute contraindication) or mimic stroke (e.g. 
cerebral tumor) and to determine whether CT hypodensity or MRI hyperintensity of ischemia is present.
The brain imaging should be interpreted by a physician with expertise in reading CT and MRI.
Investigator could make decision whether or not an imaging outside the site could be used for evaluation of inclusion/exclusion 
criteria.
3.       Cerebral image: between 22 and 36 hours after starting the infusion of trial medication.
4.       Optional in case of clinical deterioration (considered by investigator)
5.       For some lab results used for eligibility evaluation, e.g., random blood glucose, coagulation items, platelet, it is mandatory to get their
results before drug administration. For other lab results, it is recommended but not mandatory (considered by investigator).
6.      Optional in case of clinical deterioration or clinical demand (considered by investigator)
7.       It is acceptable whether it is test with blood or urine (considered by investigator), but it is mandatory to have the test result verified by 
investigator before administration, since it might impact eligibility evaluation, too.    
8.       Strongly recommended, the same person should conduct all neurological questionnaires for each individual patient.
9.       Trial completion:

At the end of visit 5 (Day 90 per protocol) for patients who have completed the trial on treatment and came to future visits as planned.

After early discontinuation, if a patient refuses to attend future visits as originally planned.
#   Time after the start of infusion of study drug


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................11
1.
INTRODUCTION...............................................................................................13
MEDICAL BACKGROUND.............................................................................13
1.1
DRUG PROFILE................................................................................................14
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....17
RATIONALE FOR PERFORMING THE TRIAL.........................................17
2.1
TRIAL OBJECTIVES........................................................................................17
2.2
BENEFIT - RISK ASSESSMENT.....................................................................18
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................20
OVERALL TRIAL DESIGN AND PLAN .......................................................20
3.1
3.1.1
Administrative structure of the trial .................................................................20
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP...........................................................................................20
SELECTION OF TRIAL POPULATION .......................................................21
3.3
3.3.1
Main diagnosis for trial entry ............................................................................21
3.3.2
Inclusion criteria .................................................................................................21
3.3.3
Exclusion criteria ................................................................................................21
3.3.4
Removal of patients from therapy or assessments...........................................23
Removal of individual patients .............................................................................23
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................23
3.3.4.2
4.
TREATMENTS...................................................................................................24
INVESTIGATIONAL TREATMENTS ...........................................................24
4.1
4.1.1
Identity of the Investigational Medicinal Products..........................................24
4.1.2
Dosage and treatment schedule .........................................................................25
4.1.3
Method of assigning patients to treatment .......................................................25
4.1.4
Blinding and procedures for unblinding...........................................................25
4.1.5
Packaging, labelling, and re-supply...................................................................25
4.1.6
Storage conditions...............................................................................................25
4.1.7
Drug accountability.............................................................................................26
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS ................................................................................................26
4.2.1
Other treatments and emergency procedures..................................................26
4.2.2
Restrictions ..........................................................................................................27
Restrictions regarding concomitant treatment ......................................................27
4.2.2.1
Restrictions on diet and life style..........................................................................28
4.2.2.2


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Restrictions regarding women of childbearing potential......................................28
4.2.2.3
TREATMENT COMPLIANCE........................................................................28
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................29
TRIAL ENDPOINTS..........................................................................................29
5.1
5.1.1
Endpoints of efficacy...........................................................................................29
Primary Efficacy Endpoint....................................................................................29
5.1.1.1
Secondary Efficacy Endpoint................................................................................29
5.1.1.2
5.1.2
Endpoints of safety..............................................................................................30
Primary Safety endpoints......................................................................................30
5.1.2.1
Secondary Safety Endpoints .................................................................................30
5.1.2.2
ASSESSMENT OF EFFICACY........................................................................30
5.2
ASSESSMENT OF SAFETY.............................................................................31
5.3
5.3.1
Assessment of symptomatic intracranial haemorrhage (sICH)......................31
5.3.2
Physical examination ..........................................................................................32
5.3.3
Vital Signs............................................................................................................32
5.3.4
Safety laboratory parameters ............................................................................32
5.3.5
Electrocardiogram ..............................................................................................33
5.3.6
Other safety parameters.....................................................................................33
5.3.7
Assessment of adverse events.............................................................................33
Definitions of AEs ................................................................................................33
5.3.7.1
Adverse event collection and reporting ................................................................36
5.3.7.2
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................37
5.4.1
Assessment of Pharmacokinetics.......................................................................37
5.4.2
Methods of sample collection .............................................................................38
5.4.3
Analytical determinations ..................................................................................38
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship.......................................38
ASSESSMENT OF BIOMARKER...................................................................38
5.5
5.5.1
Biobanking...........................................................................................................38
OTHER ASSESSMENTS...................................................................................38
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................38
5.7
6.
INVESTIGATIONAL PLAN.............................................................................39
VISIT SCHEDULE.............................................................................................39
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................39
6.2
6.2.1
Screening period..................................................................................................39
6.2.2
Treatment period ................................................................................................39
6.2.3
Observation Period and Trial Completion .......................................................40
VISIT WINDOW AND TRIAL COMPLETION ............................................41
6.3
6.3.1
Visit schedule.......................................................................................................41
6.3.2
Criteria and rules for stopping subject treatment ...........................................41
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................42
STATISTICAL DESIGN - MODEL.................................................................42
7.1


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NULL AND ALTERNATIVE HYPOTHESES ...............................................42
7.2
PLANNED ANALYSES.....................................................................................42
7.3
7.3.1
Primary endpoint analyses.................................................................................42
7.3.2
Secondary endpoint analyses .............................................................................43
43
7.3.4
Safety analyses.....................................................................................................43
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................44
INTERIM ANALYSES ......................................................................................44
7.4
HANDLING OF MISSING DATA ...................................................................45
7.5
RANDOMISATION ...........................................................................................45
7.6
DETERMINATION OF SAMPLE SIZE .........................................................46
7.7
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................47
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT ...........................................................................................................47
DATA QUALITY ASSURANCE ......................................................................48
8.2
RECORDS...........................................................................................................48
8.3
8.3.1
Source documents ...............................................................................................48
8.3.2
Direct access to source data and documents.....................................................49
8.3.3
Storage period of records ...................................................................................50
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................50
8.4
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........50
8.5
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................50
TRIAL MILESTONES.......................................................................................50
8.6
9.
REFERENCES....................................................................................................52
PUBLISHED REFERENCES............................................................................52
9.1
UNPUBLISHED REFERENCES......................................................................56
9.2
10.
APPENDICES.....................................................................................................57
NATIONAL INSTITIUE OF HEALTH STROKE SCOR, NIHSS...............57
10.1
MODIFIED RANKIN SCALE, MRS ...............................................................59
10.2
BARTHEL INDEX .............................................................................................60
10.3
GLASGOW OUTCOME SCALE.....................................................................61
10.4
ACCORDING TO THE LOCAL APPROVED LABEL, EFFECTIVE 
10.6
DATE: 29 DEC 2014...........................................................................................62


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ABBREVIATIONS
ADL
AE
Activity Daily Living
Adverse Event
AESI
AIS
aPTT
Adverse Event of Special Interest
Acute ischaemic stroke
Activated Partial Thromboplastin Time
AUC
B.I.
BI
Area under the Curve
Boehringer Ingelheim
Barthel Index
b.i.d.
bis in die (twice daily dosing)
BIRDS
BP
Boehringer Ingelheim Regulatory Documents for Submission
Blood Pressure
CCDS
CDE
CFDA
Company Core Data Sheet
Center of drug evaluation
China Food and Drug Administration
CI
Confidence Interval
CML
CNS
CNSR
CPK
Local Clinical Monitor 
Central Nervous System
Chinese National Stroke Registry
Creatinphosphokinase
CRA
Clinical Research Associate
CRF
CRO
CT
Case Report Form
Contract Research Organisation
Computer Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
CTSU
Clinical Trial Report
Clinical Trial Supply Unit
DILI
Drug Induced Liver Injury
DMC
ECASS III
ECG
ED 
Data Monitoring Committee
European Cooperative Acute Stroke Study III
Electrocardiogram
Emergency Department
EDC
Electronic Data Capture
ePRO
Electronic Patient Reported Outcome
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
Flow Chart
GCP
r-GT
Good Clinical Practice
Gamma-Glutamyl Transpeptidase
HPC
Human Pharmacology Center
IB
ICU
Investigator’s Brochure
Intensive Care Unit
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology


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ISF
Investigator Site File
i.v.
LDH
Intravenous
Lactate Dehydrogenase
LoEE
List of Essential Element 
MedDRA
MCA
mRS
Medical Dictionary for Drug Regulatory Activities
Middle Cerebral Artery
Modified Rankin Scale
MST
NA
ND
NIHSS
NINDS
Medical Sub team
Not applicable
Not done
National Institute of Health Stroke Scale
National Institute of Neurological Disorders and Stroke
OPU
Operative Unit
PD
PIL
Pharmacodynamics
Patient Information Leaflet
PK
Pharmacokinetics
p.o.
PT
per os (oral)
Prothrombin Time
PCC
Protocol Challenge Committee
q.d.
quaque die (once a day)
REP
rt-PA
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
Recombinant Tissue Plasminogen Activator
SAE
Serious Adverse Event
s.c.
subcutaneous
SPC
SDV   
sICH
Summary of Product Characteristics
Source Data Verification
Symptomatic intracranial haemorrhage
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
TIMS-China
ter in die (3 times a day)
Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in 
China
TMF
Trial Master File
TMW
Trial Medical Writer
TSAP
UNKβHCG
Trial Statistical Analysis Plan
Unknown
βHuman Chorionic Gonadotropin


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Stroke is a major cause of death and morbidity. More than 80% of the strokes are acute 
ischaemic strokes (AIS). It has been estimated that stroke causes over 4 million deaths in the 
world each year, about 3 million of these are in developing countries, thus, stroke is the 
second most common single cause of death after ischaemic heart disease [R09-0863, R09-
0864]. In China, stroke has become the number 1 fatal disease, with ischemic stroke being the 
dominant type. Whereas stroke mortality in Europe and the USA ranges from 30 to 60 per 
100 000, it is estimated to be between 120 and 240 per 100 000 in Russia, China, and large 
parts of Africa [R12-4499]. Globally, the burden of stroke is still increasing. Economic 
studies conducted in developed countries showed that Recombinant Tissue Plasminogen 
Activator (rt-PA ) given within 4.5 hours is cost-effective or even cost-saving in the long 
term [P00-00952, P11-09116, P11-09575, P13-09520].
The ideal therapy of acute ischemic stroke is achieved by quick restoration of the blood flow 
to brain areas that are blocked by a vessel occlusion with good clinical outcome, in order to 
reduce death and dependency on others for activities of daily living.
So far, Alteplase is the only approved thrombolytic for acute ischemic stroke within 4.5 hours 
after stroke onset and the overall benefit from alteplase is substantial [P10-05924, P95-3793,
P06-00786, P98-10052, P00-01176]. Guidance and practice address opportunities for optimal 
stroke care in the acute phase of the ischemic stroke. 
Stroke accounts for 301 million disability-adjusted life-years, which makes it the first leading 
cause of death and imposing significant disease and economic burden in China [P14-10421].
Between May, 2007, and April, 2012, a total of 1440 patients who received IV-tPA were 
registered in the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in 
China (TIMS-China). Final analysis demonstrated 2 important facts regarding IV-tPA 
dosages. First, the standard-dose IV-tPA treatment protocol was safe for Chinese patients 
with stroke, without any increased rate of symptomatic intracranial haemorrhage (sICH)
according to ECASS III definition or mortality compared with the low dose group. The sICH 
mentioned below is all according to ECASS III definition unless other specified. Second, 
patients with stroke receiving standard dose IV-tPA may have more favorable outcome than 
those receiving low doses of IV-tPA [P13-12586].
The 2013 version of Chinese IV rt-PA consensus was published based on previous version of 
China guideline and all new publications on the use of IV rt-PA for AIS. The Chinese Stroke 
Therapy Expert Panel concluded that Intravenous rt-PA is currently the most effective
therapy for acute ischemic stroke and there is clinical evidence supporting the use of IV rt-PA 
between 3 and 4.5 hours after the onset with several exclusion criteria. After years of stroke 
quality care improvement, incidence of stroke has not decreased as expected. Part of the 
reasons might be due to the gap between clinical guidance and real practice. 
From the Chinese National Stroke Registry (CNSR), among 11675 acute ischemic stroke 
patients with documented acute onset time, only 189 patients finally were treated with 


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alteplase [P11-07866]. In the last five years, proportion of thrombolysis within early hours 
increased from 7% to 20%, data from the United States is around 80%, the gap is still there.  
As of June 2014, MOST data demonstrated periodical analysis: totally 5049 cases were 
reported, within which 3872 cases (77%) were administered with IV rt-PA. Of all the patients 
who received early IV rt-PA thrombolysis, 67% of the patients showed functional 
improvement measured by NIHSS score, sICH rate was 4.1%, observed death rate was 4.3%
[Other Reference]. The prognosis of Chinese patients with thrombolytic therapy is better than 
other Asian countries, however, Europe and the United States are even better. Therefore, it is 
encouraged to be more active in early thrombolysis in China.
DRUG PROFILE
1.2
For a more detailed description of the Alteplase profile please refer to the current 
Investigator’s Brochure (IB), version 1.0, 30th Nov 2001, company core data sheet (CCDS), 
04th Sep 2012 and approved patient information leaflet (PIL),29Dec2014 by China Food and 
Drug Administration CFDA. 
Chemistry
The discovery of thrombolytic agents goes back to the 1930s, when it was shown that 
substances derived from bacteria s with plasmin was recognized, but it was not until 1958 
that its first use in acute ischaemic stroke (AIS) was described. However, since computer 
tomography (CT) was not available until the middle 1970s, the potential to treat optimal 
selection of patients was not possible. Early studies with streptokinase in AIS showed an 
increased risk of intracranial haemorrhage and lack of efficacy, which was associated with 
low fibrin specificity. The search for new agents with a better risk-benefit profile continued 
until 1979 when tissue plasminogen activator (t-PA) was purified [P84-97880, P05-03664].
Tissue plasminogen activator is a serine protease which is pharmacologically classified as a 
thrombolytic enzyme. Alteplase, a recombinant single-chain human tissue-type-plasminogen 
activator (rt-PA), is an enzyme which has the property of fibrin-enhanced conversion of 
plasminogen to plasmin. When introduced into the systemic circulation at pharmacologic 
levels, alteplase binds preferentially to fibrin in a thrombus and converts the fibrin-associated 
plasminogen to plasmin. This initiates local fibrinolysis with limited systemic proteolysis. It 
produces limited conversion of plasminogen in the absence of fibrin.
Actilyse® (Alteplase, recombinant; recombinant tissue plasminogen activator, rt-PA) is 
commercially available as a lyophilized powder for reconstitution in 50- mg vial (see section 
4 for additional product information). 
Pharmacology
Zivin et al. [P00-01176] were the first to report on the use of rt-PA in an animal model of 
stroke. Small blood clots were injected into the carotid circulation of rabbits. Immediately 
thereafter, alteplase was given intravenously. A significant reduction in neurological damage 
was seen after alteplase while drug-induced hemorrhages were not observed. Zivin and 
colleagues have subsequently extended their analyses of alteplase in the rabbit model of 
embolic stroke. They reported that alteplase administration could be delayed for at least 15 


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minutes after embolus injection and significant neurological tissue protection was observed in 
the treated versus control animals. No alteplase induced hemorrhages were noted on 
neuropathological examination and documented significant neuronal protection in rabbits 
treated with alteplase versus control animals as long as 45 minutes after embolus injection 
[P87-31520, P10-08848]. Zivin and colleagues have also attempted to address the question 
whether or not post-stroke alteplase administration lead to an increase in the incidence of 
intracranial hemorrhages [P10-08848]. In their initial analyses, a large clot model was used to 
assess whether alteplase altered the frequency of intraparenchymal hemorrhages.  No 
statistically significant differences were noted in"grossly apparent hemorrhages" at 4 hours 
post embolus injection in control versus alteplase- treated animals. In another study Lyden 
and colleagues [P08-12177], studied hemorrhage rates following rt-PA in their rabbit stroke 
model. The rates of hemorrhage were similar in all groups, regardless of treatment. However, 
a significant association was observed between stroke severity and cerebral hemorrhage. 
Most recently, Lyden et al. [P08-11746] performed a study using rt-PA in rabbits. The rabbits 
received doses of 3 - 10 mg/kg rt-PA or saline. Each brain was examined for "grossly 
apparent cerebral hemorrhages". Hemorrhage occurred with equal frequency in animals 
treated with both rt-PA and saline. In addition, treatment with rt-PA was not associated with 
an increase in the size of visible hemorrhages seen. Other investigator groups have analyzed 
the efficacy and safety of alteplase in animal models of stroke. Papadopoulos et al. [P87-
31520] evaluated alteplase effects in an acute thromboembolic stroke model in rats.  Post-
mortem angiography revealed significantly more middle cerebral artery occlusions in control 
versus alteplase treated animals. Kissel et al. [P10-08848] also reported that alteplase 
significantly improved angiographic and post-mortem anatomical parameters in an embolic 
stroke model in rabbits. Finally, del Zoppo et al. [P10-05924]concluded that the incidence 
and  severity  of  hemorrhage  following  alteplase  as  well  as  duteplase  are  not  related  to 
infarction size. In addition, they found that rt-PA did not increase the incidence or severity 
(i.e., volume) of hemorrhage when given within 3.5 hours of the onset of focal cerebral 
ischemia in the baboon.
Pharmacokinetic properties
Alteplase is cleared rapidly from the circulating blood and metabolised mainly by the liver 
(plasm clearance 550-680ml/min.) The relevant plasma half-life t1/2 alpha is 4-5 minutes. 
This means that after 20minutes less than 10% of the initial value is present in the plasma. 
For the residual amount remaining in a deep compartment, a beta-half-life of about 40 
minutes was measured.
Preclinical safety data
In subchronic toxicity studies in rats and marmosets no unexpected undesirable effects were 
found. No indications of a mutagenic potential were found in mutagenic tests.
In pregnant animals no teratogenic effects were observed after intravenous infusion of 
pharmacologically effective doses. In rabbits embryotoxicity(embryolethality, growth 
retardation) was induced by more than 3mg/lg/day. No effects on peri-postnatal development 
or on fertility parameters were observed in rats with doses up to 10mg/kg/day.
Toxicology: See IB, CCDS and PIL approved by CFDA


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Clinical data:
In 1996, the Food and Drug Administration approved rt-PA in AIS patients, mainly based on 
the outcome of the NINDS-2. The safety and efficacy of rt-PA in AIS was further 
investigated between 1998 and 2008 in the ECASS-1/2/3, ATLANTIS-A/B and EPITHET
trials [P95-3793, P98-10052, P08-12177, P00-00047, P00-01176, P08-02933]. A pooled 
analysis, performed by Lees et al. [P10-04547] in 2010, showed that rt-PA is moderately 
beneficial between 3 and 4.5 h, with the greater benefit with earlier treatment [P11-02890]. 
This was confirmed by the findings in a Canadian rt-PA registry [P11-02891]. To date, rt-PA 
is still the only licensed thrombolytic agent for AIS; a dose of 0.9 mg/kg is administered 
starting with an intravenous bolus of 10% of dose, followed by intravenous infusion of the 
rest of the dose over 60 min, according to the NINDS study criteria. In 2009, the advice from 
the American Heart Association Stroke Council was published, recommending that patients 
can be treated with rt-PA within the time period of 3–4.5 h after onset of ischaemic stroke 
when additional criteria are taken into account [P09-10649]. This advice was mainly based on 
the results of the ECASS-III trial [P05-03664], the outcome of the pooled analysis performed 
by Lees et al, and the publications from the SITS-ISTR registry [P08-11746, P10-08848]. In 
2011, these findings led to the approval of rt-PA by the European Medical Agency for its use 
up to 4.5 h after onset. However, there is recent evidence supporting the use of intravenous 
thrombolysis in patients aged over 80 years as well as in patients with diabetes and prior 
stroke if they otherwise fulfil treatment criteria [P10-14128, P10-12678, P11-00417, P12-
07668]. The Food and Drug Administration has not extended the license time window 
beyond 3 h. In Japan, rt-PA (0.6 mg/kg i.v.) was approved in 2005 for use up to 3 h after 
onset [P11-00579], extended to 4.5 h in 2012.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
The main aim of this trial is to examine the safety and efficacy of alteplase between 3 to 4.5 
hours of onset of ischemic stroke symptoms for Chinese population.
Advances had been made in China during the last several years. However, still many patients 
are left untreated due to the narrow time window, unknown onset time, delayed door to 
needle, lack of awareness, and a high number of exclusion criteria for currently approved 
label indication and/ or treatment.
Trial needs for thrombolysis with Alteplase in China
The extension of time window from 0~3 hours to 0~4.5 hours had been approved in EU and 
several other non-European countries like Australia, Latin-American, etc.
In domestic and international guidelines, thrombolysis with Alteplase 3~4.5 hours after onset 
is recommended, which is already performed in clinical practice in China. Although 
thrombolysis ratio is low at present in China, thrombolysis is usually performed 3~4.5 hours 
after onset with positive evaluation for patients. Extension of time window meets the demand 
of clinical practice and patients and is socially valuable.
However, according to label of Alteplase approved in China, thrombolysis for ischemic 
stroke with alteplase can only be given within 3hours after symptom onset. There is the gap 
between treatment guidance and label, which put clinical physician in risk of the off-label use 
Alteplase. There is the registration need to extend time window of the product. ECASS III 
was a clinical study only for European patients without any data of Chinese patients. 
In TIMS-China, 409 patients were thrombolysed between 0 and 3 h, and 165 patients were 
treated between 3 and 4.5 h. Functional outcomes (independence and excellent recovery) by 
Modified Rankin Scale (mRS) at day 90 were similar to those of ECASS III. And there were 
no significant differences in sICH at 24- to 36-h post-intravenous rtPA therapy, or mortality 
between the 0- to 3-h group and the 3- to 4.5-h group in Chinese patients with AIS [P07-
01580].
TRIAL OBJECTIVES
2.2
The objective of the trial is to assess the efficacy and safety of alteplase (rt-PA) in Chinese 
patients with acute ischemic hemispheric stroke where thrombolysis is initiated between 3 
and 4.5 hours after stroke onset. 
The primary efficacy outcome is functional independence as measured by the mRS (score of 
0-1). It will be assessed at visit 5 ( Day 90 ) after stroke onset. 


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The primary safety outcome measures for the trial is symptomatic intra-cerebral haemorrhage 
(sICH), assessed for the whole study period centrally evaluated by DMC consultants. As for 
the protocol, sICH is defined as the same with ECASS III criteria, details refer to section
5.3.1.
BENEFIT - RISK ASSESSMENT
2.3
Stroke care quality improvement should be a continuous effort. There are established 
database to capture the achievement of stroke care quality improvement [P06-03224, P11-
05168, P07-00880]. The reason for these advances was multifactorial and included improved 
prevention and improved care within the first hours of acute stroke, within which intravenous 
fibrinolytic therapy increased and it is still recommended as the first-line treatment by most 
national and international association [P01-09325, P07-06240, and P04-01702].Its high 
efficacy and safety have been proved in randomized controlled clinical trials (RCTs) when 
the treatment is given within 3 hours after onset of neurological symptoms in selected 
patients with acute ischemic stroke [P95-4908, P95-3793, P98-10052, P00-00047, P00-
01176] Subsequent additional trials and analysis suggest that patient can still benefit from 
thrombolysis with alteplase after extending the treatment up to 4.5 [P08-12177, P08-11746,
P10-08848, P10-05924]. Overall, the results were consistent, which indicated that 
intravenous rtPA can be given safely to, and can improve outcomes for, carefully selected 
patients treated 3 to 4.5 hours after stroke.
In clinical practice, rt-PA is not always beneficial, since it sometimes fails in achieving rapid 
reperfusion, delivers poor recanalization rates in some vessels, and is associated with 
bleeding risk. For more details of reported adverse reaction of the product please refer to 
appendix 10.6. Adverse reaction per the local approved label, dated as 29Dec 2014.
The major risk of intravenous rtPA treatment remains sICH. Although the presence of edema 
or mass effect on baseline CT scan was associated with higher risk of sICH, patients with 
these findings were more likely to have an excellent outcome if they received fibrinolytic 
therapy [P97-10211].
Approaches for safety management: predefine etiology criteria for some predictors. eg. mRS
score, baseline NIHSS score and platelet count. 3 out of 17 clinical parameters were 
identified as independent predictors of sICH: prestroke mRS score (OR1.54, P = 0.02), 
baseline NIHSS score (OR 1.13, P = 0.002), and platelet count (OR 0.99, P = 0.04) [P15-
10504].
Given the narrow therapeutic windows of treatment of acute ischemic stroke, timely
emergency department ED evaluation and diagnosis of ischemic stroke are paramount. 
Hospitals and EDs should create efficient processes and pathways to manage stroke patients 
in the ED and inpatient settings. This should include the ability to receive, identify, evaluate, 
treat, and/or refer patients with suspected stroke, as well as to obtain access to stroke 
expertise when necessary for diagnostic or treatment purposes.
All centers should be able to offer 24/7 (24 hours per day, 7 days per week) comprehensive 
stroke care to acute stroke patients. The hospitals must be acute stroke hospitals ready to 


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organize effectively and efficiently evaluate, diagnose, and treat acute stroke. Besides key 
principle, guideline and procedures for site selection of clinical trials, the centers should 
fullfill below elements as,
•
Ability to administer intravenous rtPA
•           Ability to perform emergency brain imaging (eg, CT/MRI scan) at all times 
•
Ability to conduct emergency laboratory testing at all times
•
Maintenance of a stroke patient notes


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
3.1.1
Administrative structure of the trial
The trial is sponsored by 
A Coordinating Investigator is responsible to coordinate Investigators at different centers 
participating in this multicenter trial. Tasks and responsibilities are defined in investigator 
agreement. 
Relevant documentation on the participating (Principal) Investigators and other important 
participants, including their curricula vitae, will be filed in Investigator Study File (ISF).
A data-monitoring committee (DMC), independent of the sponsor will be established to 
assess the progress of the clinical trial, focusing on the safety outcomes for the benefit-risk 
evaluation at pre-specified time points, and to recommend to the sponsor whether to continue, 
modify, or stop the trial. DMC is constructed by three DMC members mainly monitoring the 
overall number of sICH events judged by investigators, and two DMC consultants for 
centrally evaluating sICH event. The detailed tasks and responsibilities of the DMC will be 
specified in a charter. The DMC will maintain written records of all its meetings.
. has appointed a Trial Clinical Monitor, 
responsible for coordinating all required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
The organization of the trial in China will be performed by the respective local BI-
organisation (Operating Unit, OPU) in accordance with applicable regulations and internal 
SOPs, or by a Contract Research Organisation (CRO) with which the responsibilities and 
tasks will be agreed and a written contract filed before initiation of the clinical trial.
Data Management and Statistics evaluation will be done by BI according to BI SOPs and 
CRO SOPs. The final executed contract must state the duties within the scope of work.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP
An open label, prospective, single arm study 
Study design has been fully discussed with center of drug evaluation (CDE) in CFDA with 
support from several external neurologists. This study is designed as an open label single arm 


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study for the following reasons. The new version of Chinese Intravenous rt-PA consensus 
was published in 2013 regarding the usage of IV rt-PA on patients with acute ischemic stroke. 
The Chinese Stroke Therapy Expert Panel concluded that IV rt-PA is currently the most 
effective therapy and clinical evidence supports the use of IV rt-PA between 3 and 4.5 hours 
after the onset with several exclusion criteria. Therefore it is not ethical to design a placebo-
controlled randomization study as ECASS III in China with current available evidence. 
Although urokinase is recommended in Chinese guideline, it’s only for patients that alteplase 
cannot be given. 
Furthermore, patients need to be treated immediately after AIS onset. It is impractical and not 
ethical to randomize patients to two groups as 0-3 hours and 3-4.5 hours after AIS onset for 
comparison. Without randomization, it does not add much scientific value to design the study 
including 0-3hours patients for the comparison and evaluation of safety and evaluation of 3-
4.5 hours due to the uncontrolled confounding factors. 
SELECTION OF TRIAL POPULATION
3.3
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for trial entry
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1.
Age ≥18 years at screening (visit 1A) but ≤80 years
2.
Male or female patients. Women of childbearing potential must be ready and able to 
use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate 
of less than 1% per year when used consistently and correctly. A list of contraception 
<methods meeting these criteria is provided in the patient information
3.
Signed and dated written informed consent in accordance with GCP and local 
legislation prior to admission to the trial
4.
Diagnosis of ischemic stroke with a measureable neurological deficit on National 
Institute of Health Stroke Scale (NIHSS)
Stroke symptoms should be have been present for at least 30 minutes without 
significant improvement prior treatment
5.
Thrombolytic therapy can be initiated within 3 to4.5 hours of stroke onset
6.
Willingness and ability to comply with protocol
3.3.3
Exclusion criteria
1.
Stroke onset >4.5 hours prior to infusion start or when time of symptom onset is 
unknown


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2.
Evidence of intracranial haemorrhage (ICH) on the CT/MRI-scan or symptoms 
suggestive of subarachnoid haemorrhage, even if the CT/MRI-scan is normal
3.
Patients who must or wish to continue the intake of restricted medications (see section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial
4.
Acute bleeding diathesis, including but not limited to
a.
Known genetic predisposition to bleeding or significant bleeding disorder at present 
or within the past 6 months
b.
Administration of heparin within the previous 48 hours and aPTT exceeding the upper 
limit of normal for laboratory
c.
Platelet count of below 100,000/mm3
d.
Taking oral anticoagulant 
e.
Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial 
or spinal surgery)
f.
Recent traumatic external heart massage, obstetrical delivery, within the past 10 days, 
recent puncture of a non-compressive blood-vessel (e.g subclavian or jugular vein puncture)
g.
Known history of suspected intracranial haemorrhage or suspected subarachnoid 
haemorrhage from aneurysm
h.          Neoplasm with increased hemorrhagic risk
i.          Documented ulcerative gastrointestinal disease during the last 3 months, oesophageal 
varices, arterial-aneurysm, arterial/venous malformations
j.          Any known disorder associated with a significant increased risk of bleeding
5.
Bacterial endocarditis, pericarditis
6.
Acute pancreatitis
7.         Severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension 
(oesophageal varices) and active hepatitis
8.        Significant trauma or major surgery (according to the investigator’s assessment) in 
past 3 months
9.
Severe stroke as assessed clinically (e.g. NIHSS>25) and/ or imaging demonstrates 
multi-lobar infarction (hypodensity >1/3 cerebral hemisphere)
10.       Minor neurological deficit or symptoms rapidly improving before start of infusion
11.
Severe uncontrolled arterial hypertension, e.g. systolic blood pressure>185 mmHg or 
diastolic blood pressure>110mmHg, or aggressive management (IV medication) necessary to 
reduce BP to these limits
12.       Blood glucose <50 mg/dL or >400 mg/dL
13.
Any history of prior stroke in previous 3 months, or any history of prior stroke with
concomitant diabetes
14.
Seizure at stroke onset
15.
Known hypersensitivity to active substance alteplase, gentamicin (a trace residue from 
the manufacturing process) or to any of the excipients.
16.
Currently enrolled in another investigational device or drug study, or less than 30 days 
since ending another investigational device or drug study(s), or receiving other 
investigational treatment(s)
17.
Women who are pregnant, nursing, or who plan to become pregnant while in the trial


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3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. Every effort should be made to keep patients in the trial as scheduled. This includes 
careful patient selection and appropriate explanation of the trial requirements and procedures 
prior to enrolment as well as an explanation of the consequences of premature withdrawal.
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent for trial treatment or trial participation, without the need to 
justify the decision.

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication

The patient, who had discontinued the treatment for any reasons (such as surgery, adverse 
events, other diseases), can no longer be treated with trial medication again. The patient 
has repeatedly shown to be non-compliant with important trial procedures and, in the 
opinion of both, the investigator and sponsor representative, is not willing or able to stick 
to the trial requirements in the future.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart.
For all patients the reason for withdrawal (e.g. adverse events) must be recorded in the CRF. 
These data will be included in the trial database and reported.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
INVESTIGATIONAL TREATMENTS 
4.1
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Test product: Alteplase
Substance:
Brand name:
Alteplase (rt-PA)
Actilyse®
Pharmaceutical formulation:
Lyophilisate and solvent for injection
The powder is presented as a colourless to pale yellow 
lyophilizate cake
Source:
BI Pharma GmbH & Co. KG
Unit strength:
50mg
Posology
Actilyse® 50 mg, vial containing 50 mg Alteplase 
lyophilisate plus vial of solvent containing 50 mL 
sterile water for injection.
The reconstituted solution contains 1 mg alteplase
per ml.
Route of administration:
IV
Under aseptic conditions the content of injection vial of Alteplase lyophilisate (50mg) dry 
substance is dissolved with 50ml sterile water for injection to obtain a final concentration of 
1mg alteplase per mL.
For this purpose a transfer cannula should be managed at each site. When reconstituting the 
product from the respective amount of powder and solvent, the mixture should only be 
agitated gently until complete dissolution. Any vigorous agitation should be avoided to 
prevent foam formation.
The reconstituted preparation is a clear and colourless to pale yellow solution. Prior to
administration it should be inspected visually for particles and colour. It may be diluted
further with sterile sodium chloride 9 mg/mL (0.9%) solution for injection up to a minimal
concentration of 0.2 mg/mL.
A dilution of the reconstituted solution with sterilised water for injections or in general, the
use of carbohydrate infusion solutions, e.g. dextrose is not used.
Actilyse® should not be mixed with other drugs, neither in the same infusion-vial nor the 
same venous line.


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4.1.2
Dosage and treatment schedule
The study drug will be administered as a total single dose of 0.9 mg/kg per patient. The upper 
dose limit is set to 90 mg per patient. Ten percent of the total dose will be administered as a 
bolus over 1 - 2 minutes. The remaining 90% of the dose will be given by continuous IV 
infusion over 60 minutes if there is no evidence of an allergic reaction within 5 minutes 
following the administration of the test dose.
The dose is weight adjusted, therefor investigator should try every effort to take the actual 
body weight of the patient. If it is hard to have an actual body weight due to certain reasons, 
an estimated body weight by investigator is acceptable.
The treatment effect is time-dependent; therefore earlier treatment increases the probability of 
a favourable outcome [P08-12177], so patients eligible in the 3-4.5 hrs time window should 
be treated without delay.
4.1.3
Method of assigning patients to treatment
It is an open label trial.
At visit 1A, after assessment of all in- and -exclusion criteria, each eligible patient will be 
assigned with medication manually. Site personnel will enter the medication number in the 
CRF.
4.1.4
Blinding and procedures for unblinding
It is an open label trial. Blinding concern and unblinding procedure are not applicable for this 
trial.
4.1.5
Packaging, labelling, and re-supply
The investigational products will be provided by Clinical Trial Supply Unit (CTSU). They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP).
The clinical trial supply kit consists of two vials of alteplase lyophilisate and two vials of 
sterile water. Details of packaging and description of the label will be provided in the ISF.
Initial supply and further re-supplies will be managed by an IRT, inventory needs to be 
monitored/maintained manually. To facilitate the use of the IRT, the investigator will receive all 
necessary instructions for using the IRT. Details please refer to user manual in the ISF.
4.1.6
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. The vials 
have to be stored at room temperature (not above 25OC) and have to be protected from light. 
Freeze is not allowed. A temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.


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4.1.7
Drug accountability
The Investigator and/or Pharmacist will receive the investigational drugs delivered by the 
sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the head 
of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the principal Investigator
The Investigator and/or Pharmacist must maintain records of the product’s delivery to the 
trial site, the inventory at the site, the use by each patient, and the return, including the 
unused product returned back to local depot. If applicable, the sponsor and the distributional 
partner will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / Pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. All used product will be 
destructed at sites. All unused products will be return to the local depot, At the time of return 
the Investigator / Pharmacist must verify that no remaining supplies are in the Investigator’s 
possession.
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Actilyse should be used by physician experienced in the use of thrombolytic treatment and 
with the facilities to monitor that use. As with other thrombolytics, it is recommended that 
when Actilyse is administered, standard resuscitation equipment and medication be available 
in all circumstances.
Recommendation of managing bleeding 
The most common complication encountered during Actilyse therapy is bleeding. The 
concomitant use of heparin anticoagulation may contribute to bleeding. As fibrin is lysed 
during Actilyse therapy, bleeding from recent puncture sites may occur. Thrombolytic
therapy requires careful attention to all possible bleeding sites (including those following 
catheter insertion, arterial and venous puncture cutdown and needle puncture). The use of 
rigid catheters, intramuscular injections and non-essential handling of the patient should be 
avoided during treatment with Actilyse.
Should serious bleeding occur, in particular cerebral haemorrhage, the fibrinolytic therapy
must be discontinued and concomitant heparin administration should be terminated


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immediately. Administration of protamine should be considered if heparin has been
administered within 4 hours before the onset of bleeding. In the few patients who fail to
respond to these conservative measures, judicious use of transfusion products may be
indicated.
Transfusion of cryoprecipitate, fresh frozen plasma, and platelets should be considered with 
clinical and laboratory reassessment after each administration. A target fibrinogen level of 1 
g/L is desirable with cryoprecipitate infusion. Antifibrinolytic agents should also be 
considered.
Recommendation of managing hypersensitivity
No sustained antibody formation to the recombinant human tissue-type plasminogen activator 
molecule has been observed after treatment. There is no systematic experience with re-
administration of Actilyse. Anaphylactoid reactions associated with administration of 
Actilyse are rare.
If an anaphlactoid reaction occurs, the infusion should be discontinued and appropriate 
treatment should be initiated.  Monitoring is recommended particularly for patients receiving 
ACE-inhibitors concomitantly. 
Recommendation of managing other AEs
During and following a subject’s participation in a trial, the investigator should ensure that 
adequate medical care is provided to a subject for any adverse events, including clinically 
significant laboratory values, related to the trial. 
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
Additional thrombolytic medication (e.g. urokinase or streptokinase) is forbidden. 
Heparin: In exceptional circumstances, low dose subcutaneous heparin may be given 
concomitantly during the first 24 hours in order to prevent deep venous thrombosis provided 
that the aPTT will not be prolonged for more than 2 times over the baseline value. APTT 
must be determined regularly during the subcutaneous (SC) administration of heparin. The 
SC heparin dose must not exceed 10,000 IU of sodium heparin during 24 hours or equivalent 
doses of low molecular weight heparin. Simultaneous administration of heparin and other 
antithrombotic drugs is strongly discouraged.
IV heparin at any dose is forbidden before and during the study drug administration and 
during the initial 24 hours after completion of administration of study drug.
Thereafter intravenous heparin must not be started before the second CT is evaluated and 
reveals no signs of intracranial bleeding.
Other medication: 


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Administration of oral anticoagulants, antiplatelet agents (i.e. aspirin), hemorrheologic agents, 
and brain protective drugs (e.g. calcium channel blockers) is prohibited during the first 24 
hours after completion of the study drug administration.
The use of volume expanders, such as dextran and hydroxyethyl starch, is prohibited within 
the first 24 hours after completion of study drug infusion.
Traditional Chinese medicine which had been demonstrated with evidence of effect as 
anticoagulants, antiplatelet agent, hemorrheologic agents and brain protective agents is 
prohibited during the first 24 hours after completion of the study administration P14-16668.
Other drug therapy may be given according to patient needs. Osmotic agents (mannitol, 
glycerol) may be given if the intracranial pressure is increased.
Restrictions on diet and life style
4.2.2.2
Not applicable
Restrictions regarding women of childbearing potential 
4.2.2.3
Women of childbearing potential must use the contraception methods described in the patient 
information.
TREATMENT COMPLIANCE
4.3
The investigator will maintain accurate records of receipt of all study medication, including 
the date, exact time point of receipt. In addition, accurate records will be kept regarding the 
total dosage administered to each individual patient in the study.
Actual weighing of the patient is preferred when it can be perform without inducing delays.
The treatment effect is time-dependent; therefore treatment must be started as early as 
possible within 4.5 hours after onset of stroke symptoms.


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5.
VARIABLES AND THEIR ASSESSMENT
TRIAL ENDPOINTS
5.1
5.1.1
Endpoints of efficacy
Primary Efficacy Endpoint
5.1.1.1
The primary efficacy endpoint is the percentage of patients with mRS 0-1 (favourable 
outcome) at visit 5 (i.e., day 90) after stroke onset by face-to-face interview with patient.
Secondary Efficacy Endpoint
5.1.1.2
The percentage of global outcome responder at visit 5 (i.e., day 90) if he/she obtains the 
following results at visit 5 (i.e., day 90) (for all of the 4 endpoints)
              mRS score of 0 to 1
              Barthel Indext score≥95
              NIHSS score of 0 to 1
              Glasgow Outcome Scale score of 1
 
  
 
 
 
  


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5.1.2
  Endpoints of safety
Primary Safety endpoints
5.1.2.1
The percentage of patients with symptomatic intracranial haemorrhage (sICH) centrally 
evaluated by DMC consultants according to ECASS III definition within the whole study 
period.
Secondary Safety Endpoints
5.1.2.2

Patient survival probability at visit 5 (censoring at day 90)

Frequency of death related to stroke or of neurological causes

Frequency and severity of adverse events

Incidence of cerebral herniation and symptomatic edema
ASSESSMENT OF EFFICACY
5.2
The primary study endpoint is functional independence as measured by the mRS (score of 0-1) 
assessed at 90 days after stroke onset by face-to-face interview with patient.
Functional outcome (day 90) is defined by mRS, excellent (mRS 0-1) vs. unfavourable 
outcome (mRS 2-6), which is the primary study endpoint.
The secondary efficacy endpoint will be global outcome analysis of four neurological and 
disability scores combined.
Modified Rankin Scale: 
The mRS is a tool used to evaluate disability after a stroke and will be collected at day 30 and 
at day 90.  
The grading of the score is as follows:
Grade 0: 
no symptoms at all
Grade 1: 
no significant disability despite symptoms;
able to carry out all usual duties and activities
Grade 2: 
slight disability: unable to carry out all previous activities but able to look after 
own affairs without assistance
Grade 3*: 
moderate disability: requiring some help but able to walk without assistance
Grade 4: 
moderate-severe disability: unable to walk without assistance and unable to 
attend to own bodily needs without assistance
Grade 5: 
severe disability: bedridden, incontinent, and requiring constant nursing care 
and attention.
Grade 6: 
Dead


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Barthel Index score
It will be used to evaluate the recovery of neurological functions at day 30 and day 90.
Glasgow Outcome Scale score
The Glasgow Outcome Score applies to patients with brain damage allowing the objective 
assessment of their recovery in five categories. This allows a prediction of the long-term 
course of rehabilitation to return to work and everyday life. It will be collected at day 90.
The Glasgow Outcome Scale is a 5-level score:
1. Good Recovery 
2. Moderately Disabled 
3. Severely Disabled 
4. Vegetative State 
5. Dead
National Institutes of Health Stroke Scale (NIHSS)
The NIHSS will be recorded, if it had been collected at the time of qualifying (index) stroke. 
In patients, where NIHSS has not been done at the time of index stroke, it will be performed 
at study entry (at Visit 1). It is a tool used by healthcare providers to objectively quantify the 
impairment caused by a stroke. The NIHSS is composed of 11 items, and for each item a 
score of 0 typically indicates normal function in that specific ability, while a higher score is 
indicative of some level of impairment. The individual scores from each item are summed in 
order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the 
minimum score being a 0. Clinical outcome will also be assessed by NIHSS scoring at 2 
hours, 24 hours, and on day 7, 30 and 90.
ASSESSMENT OF SAFETY
5.3
Patients are monitored in the stroke unit or Intensive Care Unit (ICU). For assessment of 
safety, incidence and severity of adverse events including mortality at day 90, stroke-related 
and neurological, including cerebral herniation rate and symptomatic oedema, deaths, and 
symptomatic cerebral bleeding will be evaluated. Intracranial haemorrhage will be assessed 
separately. 
Safety monitoring is performed by an independent Data Monitoring Committee (DMC). The 
details will be described in the DMC Charter.
5.3.1
Assessment of symptomatic intracranial haemorrhage (sICH)
According to this protocol, sICH (ECASS III criteria) is defined as: any apparently 
extravascular blood in the brain or within the cranium that was associated with clinical 


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deterioration (defined by an increase in the NIHSS score of 4 or more points), or that led to 
death and that was identified as the predominant cause of the neurological deterioration.
sICH event will be firstly evaluated by investigator. The DMC consultants will evaluate all
the patients with NIHSS score increase of at least 4 any time after treatment (including all the 
sICH events evaluated by investigator).
5.3.2
Physical examination 
A physical examination will be performed for all patients at screening visit (Visit 1A) and 
repeated at all predefined treatment time points (Visit 1B and Visit 1C) as of the 
administration day and visit 2,3,4, and 5. All abnormal findings at baseline will be recorded 
on the Medical History/Baseline Condition page in the patient’s electronic case report form 
(eCRF). New abnormal findings or worsening of baseline conditions detected at follow-up 
physical examinations will be recorded as adverse events on the appropriate eCRF page.
The measurement of height (in cm) and body weight (in kg) will only be performed at the 
screening visit.
5.3.3
Vital Signs
Vital signs include blood pressure, pulse rate, respiratory rate and armpit temperature (the 
locations should be specified in the medical notes and the same location should be used at 
each time point when body temperature is measured). 
The measurements of blood pressure will always be obtained with the patient seated and 
rested for a minimum of five minutes. Vital signs will be measures every 30 minutes for 6 
hours, then hourly until 24 hours after the start of infustion.
5.3.4
Safety laboratory parameters
An abbreviated hematology and chemistry panel including liver and renal function testing 
will be analysed for safety at specific time-points throughout the trial by a certified laboratory. 
The laboratory tests will include:
Category
Laboratory test
Haematology
Red blood cell count (RBC)
Haemoglobin (Hb)
Haematocrit (HCT)
Mean corpuscular volume
White blood cell count including differential
Platelet count
Biochemistry
Aspartate aminotransferase (AST)
Alanine transaminase (ALT)
Gamma-glutamyl trasferase (GGT)
Alkaline phosphatase (ALP)
Total bilirubin


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Creatinine
Glucose
Uric acid (optional)
  ß- Human Chorionic Gonadotropin(HCG)*
Electrolytes
Sodium
Potassium
Calcium
Inorganic phosphorus
Coagulation
International normalized ratio (INR)
Partial thromboplastin time (ptt)
Prothrombin time (PT)
Urinalysis 
pH, glucose, erythrocytes, leukocytes, 
protein, nitrite (semi quantitative 
measurements; (-, +, ++, +++), pregnancy 
test*
Both of the two types of pregnancy tests are acceptable for this trial, whatever test it may be, 
it should be carried out appropriately, according to the routine practice of local lab of selected 
sites.
Note: for the urgent indication, if patient could not provide urine at the time point of 
screening for the routine urine test, investigator should judge, according to the baseline 
condition of the patients, to decide whether the missing data of routine urine test will impact 
patients’ participate in the clinical trial. Urine test should be conducted at the earliest time 
when it is available afterwards for safety consideration.
5.3.5
Electrocardiogram
Printed paper traces from 12 lead ECGs (I, II, III, aVR, aVL, aVF, V1-V6) will be collected 
at visit 1 and 3 for all patients. In the event of any cardiac symptoms (i.e. suspicion of heart 
rhythm disorders or cardiac ischemia), an additional ECG will be recorded. All ECGs will be 
evaluated, (signed, dated and commented upon) by the treating physician/investigator and 
stored locally. Any clinically relevant changes in the ECG will be reported as AEs and 
followed up and/or treated locally until normal or stable condition.
5.3.6
Other safety parameters
For further safety parameters see section 5.1.2
5.3.7
Assessment of adverse events
Definitions of AEs 
5.3.7.1
Adverse event


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An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.

requires inpatient hospitalisation or 

prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasia or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse.
Any suspected transmission via a medicinal product of an infectious agent is also 
considered a serious adverse reaction.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.


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The latest list of “Always Serious AEs” can be found in the RDC system. These events 
should always be reported as SAEs as described above.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).


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•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Adverse event collection and reporting
5.3.7.2
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:
•
From signing the informed consent onwards through the Residual Effect Period (REP), 
until individual patient’s end of trial (per protocol: Visit 5, Day 90). 
-all AEs (serious and non-serious).
•
After the individual patient’s end of trial: 
the Investigator does not need to actively monitor the patient for AEs but should only 
report relevant SAEs of which the Investigator may become aware of.
*The REP is defined as the number of days after the last trial medication application. 
According to CCDS of the product, after 20 minutes less than 10% of the initial value is 
present in the plasma. For the residual amount remaining in a deep compartment, a beta-half-
life of about 40 minutes was measured. The REP is quite short. To be consistent with 
statistical analysis plan in previous trial, e.g. ECASSIII, REP is defined as 7days after the last 
trial medication application in this protocol.
All AEs which occurred through the treatment phase and throughout the REP will be 
considered as on treatment, please see section 7.3.4. 
Events which occurred after the REP will be considered as post treatment.
AE reporting to sponsor and timelines
The Investigator must report SAEs, and non-serious AEs which are relevant for the reported 
SAE, on the BI SAE form via fax immediately (within 24 hours) to the sponsor’s unique 
entry point (country specific contact details will be provided in the ISF). The same timeline 
applies if follow-up information becomes available. In specific occasions the Investigator


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could inform the sponsor upfront via telephone. This does not replace the requirement to 
complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form. The Investigator should determine the causal relationship 
to the trial medication.
The following should also be recorded as an (S)AE in the CRF and SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the sponsor’s 
unique entry point (country-specific contact details will be provided in the ISF). The 
Pregnancy Monitoring Form for Clinical Trials (Part A) should be used.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
Not applicable since no pharmacokinetic data will be collected or analysed in this trial.


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5.4.2
Methods of sample collection
Not applicable
5.4.3
Analytical determinations
Not applicable
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship
Not applicable since no pharmacodynamics data will be collected or analysed in this trial
ASSESSMENT OF BIOMARKER 
5.5
Not applicable since no biomarker data will be collected and analysed in this trial
5.5.1
Biobanking
Not applicable since no sample will be collected and analysed for biobanking in this trial.
OTHER ASSESSMENTS
5.6
Not applicable since there is no other assessments will be done.
APPROPRIATENESS OF MEASUREMENTS
5.7
All measurements conducted in the trial are using standard methods.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
Informed consent of all study patients will be obtained in compliance with ICH and GCP 
guidelines and the principles stipulated in the Declaration of Helsinki prior to any study 
related procedure.
After informed consent procedure, a patient may be enrolled into the study when entering the
clinic with acute stroke symptoms and being liable to be treated between 3 and 4.5 hours after
stroke onset. All inclusion and exclusion criteria have to be checked prior to administration of 
the test dose of study medication. The cerebral imaging scan and its evaluation has to be done
with due diligence. Investigator and/or co-investigator must agree with the radiologist that
there are no imaging exclusion criteria prior to administration of the test dose of study
medication.
The study will consist of 5 visit days. The visits will be conducted during the study, among 
which, the visit 1 is divided into three sub-visits, the schedule for trial visits is summarized in 
the study Flow Chart including time windows for study visits. 
All visit dates are calculated from the date of drug administration. In the event that visits are 
missed or out of sequence, subsequent visits will be planned according to the date of visit 1.
No protocol waivers will be given (e.g. Sponsor will not grant permission to include a known 
ineligible patient). In the case of medical emergencies, prior approval from the Sponsor for 
protocol deviations (e.g. visit schedule) will not be required, but BI should be notified as soon 
as possible. The relevance of any such protocol deviation will be assessed prior to analysing 
the data.
The procedures to be conducted at each visit are provided in the Flow Chart and further 
described below.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening period
At visit 1A (baseline) the documentation of demographics, medical history, physical
examination, vital signs, resting 12-lead ECG, concomitant therapy, NIH Stroke Scale, and a 
cerebral imaging scan will be performed.
6.2.2
Treatment period
After consent procedure had been completed, eligibility has been confirmed and all Visit 1A
procedures completed, drug administration can be conducted.
The test dose of rt-PA will be administered. Ten percent of the total dose will be administered
as a bolus over 1 - 2 minutes. The remaining 90% of the dose will be given by continuous IV 


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infusion over 60 minutes if there is no evidence of an allergic reaction within 5 minutes
following the administration of the test dose.
6.2.3
Observation Period and Trial Completion
A physical examination, the documentation of adverse events and of concomitant medication
will be performed for all patients at all predefined treatment time points (Visit 1B and Visit 
1C) as of the administration day and visit 2,3,4, and 5.
Lab test at visit 1A and visit 3 are mandatory. It will be optional at visit 2 and visit 5 in case 
of clinical deterioration (considered by investigator)   
At visit 1B (i.e., 1 hour after the start of infusion of study drug), vital signs will be measured
every 30 minutes until Hour 2. An 12-lead ECG recording will be made.
At visit 1C (i.e., 2 hours after the start of infusion of study drug), the NIH Stroke Scale will
be performed. Vital signs will be measured every 30 minutes for 6 hours, then hourly until 24 
hours. An 12-lead An 12-lead ECG recording will be made.
At visit 2 (24 hours), vital signs will be measured. The NIH Stroke Scale will be performed. A 
second imaging (CT/MRI) scan will be done within Hour 22 and Hour 36 after start of 
infusion of study drug.
At visit 3 (on day 7), vital signs will be measured. The NIH Stroke Scale will be performed.
An 12-lead ECG recording will be made. A CT/MRI scan will be performed in case of clinical
deterioration
At visit 4 (on day 30), vital sign will be measured. The NIH Stroke Scale, the modified
Rankin Scale, and the Barthel Index will be performed. A CT/MRI scan will be performed in
case of clinical deterioration.
At visit 5 (on day 90), vital sign will be measured. The NIH Stroke Scale, the Glasgow 
Outcome Score, the modified Rankin Scale, and the Barthel Index will be performed. A 
physical examination takes place. The patient termination record will be filled in. Length of
stay in hospital will be assessed as well.
The trial completion (end of the trial) eCRF page has to be filled-in when patient has 
terminated the trial.
The end of the trial is:
•
At the end of visit 5(Day 90 per protocol) for patients who have completed the trial on 
treatment and came to future visits as planned.
•
After early discontinuation, if a patient refuses to attend future visits as originally 
planned.
If a patient discontinues from the trial after treatment, this will be documented and the reason 
for discontinuation will be recorded in the eCRFs. At the time of discontinuation, a 
completed end-of-trial evaluation (Visit 5, Day 90) will be performed whenever possible and 
the data collected from these patients will be included in the trial database and will be 
reported.


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VISIT WINDOW AND TRIAL COMPLETION
6.3
6.3.1
Visit schedule
For visit 1A (D0) there is no time window.  
For visit 1B, a window between +15 and - 15 minutes is acceptable. 
For visit 1C, a window between +30 and -30 minutes is acceptable. 
For visit 2 (D1), a window between +2 and -2 hours is acceptable. The second cerebral 
CT/MRI may be done between Hour 22 and Hour 36 after start of infusion of study drug.
For visit 3 (D7), a window between +3 and -3 days is acceptable. 
Visit 4 (D30) may take place between 27 and 33 days. 
Visit 5 (D90) may take place between 83 and 97 days.
6.3.2
Criteria and rules for stopping subject treatment
Each patient may terminate the study prematurely without giving any reason. If possible, the 
patient should discuss her/his decision with the investigator. The investigator may terminate 
the administration of study drug prematurely for any medical reason. Reason, date, and clock 
time of terminating have to be documented. Each of these patients must be followed up for 90 
days if possible. Drop-outs and withdrawals will not be replaced.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is an open-label, single-arm, multi-center. Phase III trial that is designed to assess the 
safety and efficacy on alteplase (rt-PA) of 0.9 mg/kg rt-PA (intravenously infused over 1 
hour) in acute ischemic stroke patients within 3-4.5 hrs from onset of symptoms in the
Chinese population. Considering the design of single-arm study and binary nature of primary 
endpoints, the point estimators will be mainly presented along with the corresponding 95% 
confidence intervals.
NULL AND ALTERNATIVE HYPOTHESES
7.2
Alteplase (rt-PA) has been approved and widely used in more than 100 countries for about 20
years. Many studies were conducted by the sponsors and researchers to understand the 
efficacy and safety profiles of the drug for patients treated within 3-4.5 hours after AIS onset 
in both controlled clinical studies and real world setting. The percentage of mRS 0-1 
responder at day 90 was 40.9% in SITS-ISTR [P15-11922] 52.4% in ECASS III (ITT 
population) and 60.9% in TIMS-China [P13-12586]. The estimation from historical review 
varies from 40% to 60%. 
In this study, we are aiming to rule out a response rate of 40% or lower, which is considered 
as insufficient level of efficacy for alteplase treated within 3-4.5 hrs from stroke onset in 
Chinese acute ischemic stroke patients [P13-12586]. Therefore, a null hypothesis of p ≤
40% versus an alternative hypothesis of p > 40% will be tested using a one sample test at 
two-sided significance level of 0.05, where  p denotes the response rate in Chinese patients 
who are treated within 3-4.5 hrs after stroke onset. 
PLANNED ANALYSES
7.3
All enrolled patients who received Actilyse treatment at any dose will be included in the 
treated set (TS). This is also the full analysis set (FAS) since all treated patients will be 
evaluated. The primary efficacy analysis and the safety analysis will be performed on the TS.
7.3.1
Primary endpoint analyses
The primary efficacy endpoint is the percentage of mRS 0-1 (favourable outcome) responder 
at day 90 after stroke onset by face-to-face interview with patient. The proportion of patients 
with mRS 0-1 will be presented with corresponding 95% confidence intervals (CIs). 
The primary safety endpoint is the percentage of patients with symptomatic intracranial 
haemorrhage (sICH) centrally evaluated by DMC consultants according to ECASS III 
definition within the whole study period. The proportion of patients with sICH will also be 
presented along with corresponding 95% CIs. 
 


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Regarding the safety endpoint, the event rate of sICH observed from these studies arranged 
from 2.4% to 4.9% using ECASS III definition [P05-03664]. 
 
 
 
 
 
 
7.3.2
Secondary endpoint analyses
The secondary efficacy endpoint is the percentage of global outcome at day 90. A global 
outcome responder is defined as patient with outcomes at day 90 of a score of 0 or 1 on the 
mRS, a score of 95 or higher on the Barthel Index, a score of 0 or 1 on the NIHSS, and a 
score of 1 on the Glasgow Outcome Scale. The proportion of global outcome responders will 
be displayed along with corresponding 95% CIs.
Each item of the composite criteria global outcome responder will be evaluated separately as 
well.
7.3.4
Safety analyses
Safety analysis will be performed based on full analysis set.
Patient’s survival at Day 90 (censoring at 90 days) will be analysed using the Kaplan-Meier 
method. The median survival along with 95% confidence interval, using Greenwood’s 
standard error estimate, will be presented. The Kaplan-Meier estimates will also be plotted 
over the observation period of 90 days.
The frequency of death related to stroke or of neurological causes and the incidence of 
cerebral herniation and symptomatic edema will be analysed descriptively.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. The frequency, severity and causal relationship of adverse 
events will be tabulated by system organ class and preferred term after coding according to 
MedDRA. Because this study is a single dose drug administration (duration of approximately 
one hour), the incidence and severity of adverse events will be displayed by treatment periods. 
All AEs which occurred through the single dose treatment phase and throughout the REP will 
be considered as on treatment. Events which occurred after the REP will be considered as 
post treatment. The frequency of on-treatment AEs will be summarized as primary interest. 
The frequency of all AEs collected until the end of the study will also be summarized. More


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details will be specified in Statistical Analysis Plan. Standard BI summary tables and listings 
will be produced. 
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
Not applicable.
INTERIM ANALYSES
7.4
An interim analysis will be performed when 60 patients enter and complete the study. All the 
first 60 patients who complete the study will be included in this interim analysis. Both safety 
and efficacy will be evaluated at interim analysis. 
For efficacy, a predictive probability approach in the Bayesian setting is used to help to make 
the decision whether the study should continue to the full enrolment and whether an early 
application should be submitted to CFDA upon the promising interim results.
We target 
 = 55% as a promising response rate in the end of study. The Bayesian analysis 
will be performed to estimate predictive probability (PP), which is the probability that the 
response rate reaches 
 or above in the final study result, given the data observed at interim 
time-point. If the predictive probability is greater than 90%, it shows the high potential of 
reaching promising result in the end given interim data. 
In addition, we also consider a futile response rate lower than 
 = 40% in the end of study
for early stop at the interim. We estimate the predictive probability of observing the response 
rate lower than 
 in the end of study given interim data. If the predictive probability is 
greater than 90%, it shows high potential of futility in the end. Appendix 10.5 elaborates how 
the predictive probability is calculated. 
In summary, there are 3 scenarios suggested by the interim results as below,
•
Scenario A - Early submission upon promising efficacy (i.e., promising zone): PP 
(
̂ ≥55%) ≥90%, equivalently, 37 or more responders among 60 patients at interim;
•
Scenario B - Early stopping upon futile efficacy (i.e., Futlity zone): PP (
̂ ≤40%) ≥
90%, equivalently, 20 or fewer responders among 60 patients at interim;
•
Scenario C - Competitive zone: the rest other than promising and futility zones;
For both scenarios A and C, if there is no safety alert from independent Data Monitoring 
Committee (DMC), the trial will continue for the completion of recruitment of 120 patients to 
the end as planned to collect the sufficient safety information.
In addition to the efficacy evaluation, an independent Data Monitoring Committee (DMC) 
will be constituted for continuously monitoring and reviewing the safety data during the 
study conduction. The details of the safety monitoring scheme will be specified in DMC SAP. 


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At the interim, it is envisioned that the DMC may make two types of recommendations, 
namely:
1. No safety issues or concerns, ethical to continue the trial as planned
2. Warning of significant safety concerns and recommendation of stopping the trial for 
patients’ safety. 
Table 7.4:1 Guidance for decision making at interim analysis
Timing and Results
Action
First 60 patients complete study
Efficacy
Safety
Promising Zone: >=37 
patients with favourable
outcome
AND
DMC declare no safety 
issues
Continue enrolment
and early submission
Competitive Zone: <37 
but >20 patients with 
favourable outcome
AND
DMC declare no safety 
issues
Continue enrolment 
without early 
submission
Futility Zone: <=20 patients 
with favourable outcome
OR
DMC declare warning of 
significant safety issues
early trial stopping 
The guidance described in the Table 7.4.1 serves as decision base for early trial stopping or 
early submission to CFDA. The interim analysis in conjunction with other safety and efficacy 
data will be used to allow BI, in consultation with the investigators and DMC, to make a join 
decision on whether the benefit and risk support continuation of the trial to the full enrolment
up to 120 patients, and will help BI to make the decision on whether an early application 
should be submitted to CFDA.
The interim analysis will not lead to sample size recalculations and adjustment of enrolment 
targets.
HANDLING OF MISSING DATA
7.5
Every effort will be made to collect complete information according to the protocol. No 
missing values regarding vital status and intracranial bleeds are expected. However, for 
functional outcome parameters of surviving patients missing values might occur. The last 
observation carried forward (LOCF) method will be applied in the sense that data from the 
previous visit or measurement will substitute the missing data. In case of missing values due 
to death, the worst score principle will be applied.
RANDOMISATION
7.6
No randomisation is required since all patients will be treated with rt-PA.


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DETERMINATION OF SAMPLE SIZE
7.7
The study will enrol approximately 120 patients. The sample size calculation takes account 
into both safety and efficacy considerations. 
Regarding the primary safety endpoint, an observed sICH rate of 2.4%, i.e., 3 sICH events 
out of 120 patients, will result in an exact binomial 95% CI (0.48%, 6.99%) with the 
confidence width as 6.51%, which is considered as reasonable estimation precision. 
The percentage of mRS 0-1 (favourable outcome) responder at day 90 is the primary efficacy 
endpoint. The range of the response rate from historical review was from 40% to 60% [P05-
03664].  If assuming an underlying response rate of 55% of rt-PA treatment in Chinese 
patients, for the planned sample size of 120 patients, a power of 91.5% can be achieved. The 
sample size calculations in Table 7.7.1 have been performed based on a one sample test for 
proportion with a two-sided significance level of 0.05 and power ranging from 80% to 90%. 
Calculations were performed using ADDPLAN version 6.
Table 7.7:1
Sample size calculations based on a one sample test with a two-sided 
significance level of 0.05 and various assumptions of percentages of 
mRS 0-1 responders (n=120)
Assumed mRS 
response rate
Number of mRS 0-1 responders
Power(%)
52.5%
63
79.4
53.3%
64
84.2
55.0%
66
91.5


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC) 
and the harmonised standards for Medical Devices (ISO 14155, current version).
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs) and 
local GCP regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP*.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor
with regard to publication of the results of this trial are described in the Investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF (Investigator Site File).
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
The Investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. The patient must be given sufficient time to consider 
participation in the trial. The Investigator obtains written consent of the patient’s own free 
will with the informed consent form after confirming that the patient understands the contents. 
The Investigator must sign (or place a seal on) and date the informed consent form. If a trial 


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collaborator has given a supplementary explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
RECORDS
8.3
Case Report Forms (CRF) for individual patients will be provided by the sponsor.
8.3.1
Source documents
In accordance with regulatory requirements the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the Investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the Investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
Before providing any copy of patients’ source documents to the sponsor the investigator must 
ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social 
security number) have properly been removed or redacted to ensure patient confidentiality.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, date or year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))


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
Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of Patient’s Participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of on-site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology and the 
degree of any deviations of the intervention from normal clinical practice.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). The CRA and auditor may review all CRFs and informed consents. The accuracy 
of the data will be verified by direct comparison with the source documents described in 
section 8.3.1. The sponsor will also monitor compliance with the protocol and ICH GCP.
An adaptive approach to clinical trial monitoring will be utilised. The sponsor will perform a 
risk assessment of the trial to determine the extent and nature of monitoring required in order 
to ensure the reliability and robustness of the results. Regular review of risk reports will 
provide sponsor oversight during trial conduct and direct monitoring activities to the areas of 
greatest risk which have the most potential impact to subject safety and data quality.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access should be granted to all source documents 
(paper and e-records) including progress notes, copies of laboratory and medical test results. 
The CRA and auditor may review all CRFs and informed consents. The accuracy of the data 
will be verified by direct comparison with the source documents described in section 8.3.1. 
The sponsor will also monitor compliance with the protocol and ICH GCP.
An adaptive approach to clinical trial monitoring will be utilised. This is initiated by an 
assessment of the risk associated with the trial combined with identification of critical data 
and processes. An Integrated Quality and Risk Management Plan documents the strategies 
involved with the implementation of onsite, offsite and central monitoring activities in order 
to direct focus to the areas of greatest risk which have the most potential impact to subject 
safety and data quality. Trial oversight is achieved by regular review of a report of risk which 
then influences any monitoring adaptations. 
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB/IEC 
review and regulatory inspections. Direct access should be granted to all source documents 
(paper and e-records) including progress notes, copies of laboratory and medical test results


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The CRA and auditor may review all CRFs and informed consents. The accuracy of the data 
will be verified by direct comparison with the source documents described in section 
8.3.1. The sponsor will also monitor compliance with the protocol and ICH GCP.
8.3.3
Storage period of records
Trial sites:
The trial sites must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
Details will be defined in investigator agreement.
EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
8.5
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Not applicable
TRIAL MILESTONES
8.6
The start of the trial is defined as the date of the enrolment of the first patient in the whole 
trial.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Out”).
Individual Investigators will be notified of SUSARs occurring with the trial medication until 
30 days after LPO at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.


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Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
A final report of the clinical trial data will be written only after all patients have completed 
the trial to incorporate and consider all data in the report.


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
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Lorenzi G. Regarding 'endovascular treatment of renal artery thrombosis 
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Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0-
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Kaste M, Thomassen L, Grond M, Hacke W, Roine RO. Thrombolysis for 
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Hacke W, Kaste M, Bogousslavsky J, Brainin M, Gugging, Lees K. 
European Stroke Initiative recommendations for stroke management -
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P05-03664
Collen D, Lijnen HR. Tissue-type plasminogen activator: a historical 
perspective and personal account. J Thromb Haemost 2004. 2(4):541-546.  
P06-00786
Wardlaw JM, Zoppo G del, Yamaguchi T, Berge E. Thrombolysis for 
acute ischaemic stroke (Review). Cochrane Database Syst Rev 2003(3) 
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P06-03224
Deng YZ, Reeves MJ, Jacobs BS, Birbeck GL, Mullard AJ, Paul 
Coverdell National Acute Stroke Registry Michigan Prototype 
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Wahlgren N, Ahmed N, Davalos A, Ford GA, Hennerici MG, SITS-
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Reeves MJ, Broderick JP, Frankel M, LaBresh KA, Weiss P, Paul 
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Adams HP, Zoppo G del, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb 
RL. Guidelines for the Early Management of Adults with Ischemic 
Stroke. Stroke 2007. 38(5):1655-1711.


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Davis SM, et al, EPITHET Investigators. Effects of alteplase beyond 3 h 
after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial 
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Wahlgren N, Ahmed N, Davalos A, Hacke W, Millan M, Muir K, Roine 
RO. Thrombolysis with alteplase 3 - 4.5 h after acute ischaemic stroke 
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Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, 
Larrue V. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic 
stroke. N Engl J Med 2008. 359(13):1317-1329.
P09-10649
Zoppo GJ del, Saver JL, Jauch EC, Adams HP, American Heart 
Association Stroke Council. Expansion of the time window for treatment 
of acute ischemic stroke with intravenous tissue plasminogen activator: a 
science advisory from the American Heart Association/American Stroke 
Association. Stroke 2009. 40(8):2945-2948.
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Lees KR, Bluhmki E, Toni D, Kummer R von, Marler J, Hacke W, 
ECASS I-III, ATLANTIS and NINDS Investigators. Time dependent 
response to treatment with intravenous rtPA for stroke: an updated pooled 
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Conf 2010, San Antonio, 23 - 26 Feb 2010 Stroke 2010. 41(4):e247-e248. 
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treatment with intravenous alteplase and outcome in stroke: an updated 
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Lancet 2010. 375(9727):1695-1703.
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Ahmed N, Wahlgren N, Grond M, Hennerici M, Lees KR, Mikulik R, 
Parsons M. Implementation and outcome of thrombolysis with alteplase 3 
- 4.5 h after an acute stroke: an updated analysis from SITS-ISTR. Lancet 
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4422(10)70165-4 Lancet Neurol 2010. 9(9):866-874.  
P10-12678
Ford GA, Ahmed N, Azevedo E, Grond M, Larrue V, Toni D. Intravenous 
alteplase for stroke in those older than 80 years old. Stroke 2010. 
41(11):2568-2574. 
P10-14128
Mishra NK, Ahmed N, Andersen G, Egido JA, Wahlgren NG,VISTA and 
SITS Collaborators. Thrombolysis in very elderly people: controlled 
comparison of SITS International Stroke Thrombolysis Registry and 
Virtual International Stroke Trials Archive. Br Med J 2010. 341:c6046
P11-00417
Mishra NK, Davis SM, Kaste M, Lees KR, VISTA Collaboration. 
Comparison of Outcomes Following Thrombolytic Therapy Among 


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Patients With Prior Stroke and Diabetes in the Virtual International Stroke 
Trials Archive (VISTA). Diabetes Care 2010. 33(12):2531-2537.  
P11-00579
Nakagawara J, Minematsu K, Okada Y, Tanahashi N, Mori E, The post-
Marketing Alteplase Registration Study J-MARS investigators. 
Thrombolysis with 0.6 mg/kg intravenous alteplase for acute ischemic 
stroke in routine clinical practice: the japan post-marketing alteplase
registration study (J-MARS). 7th World Stroke Cong, Seoul, 13 - 16 Oct 
2010 Int J Stroke 2010. 5(Suppl 2):12 Abstr FC10001
P11-02890
Parsons MW. Treating as early as possible with thrombolysis is crucial, 
but can we do better in the sub-4.5-hour time window? Cerebrovasc Dis 
2011. 31(3):229  
P11-02891
Shobha N, Buchan AM, Hill MD, Canadian Alteplase for Stroke 
Effectiveness Study (CASES) Investigators. Thrombolysis at 3 - 4.5 hours 
after acute ischemic stroke onset - evidence from the Canadian Alteplase 
for Stroke Effectiveness Study (CASES) Registry. Cerebrovasc Dis 2011. 
31(3):223-228.  
P11-05168
Centers for Disease Control and Prevention (CDC). Use of a registry to 
improve acute stroke care - seven states, 2005 - 2009. MMWR 2011. 
60(7):206-210.  
P11-07866
Wang Y, Liao X, Zhao X, Wang DZ, Wang C, China National Stroke 
Registry (CNSR) Investigators. Using recombinant tissue plasminogen 
activator to treat acute ischemic stroke in China: analysis of the results 
from the Chinese National Stroke Registry (CNSR). Stroke 2011. 
42(6):1658-1664.
P11-09116
Tung CE, Win SS, Lansberg MG. Cost-effectiveness of tissue-type 
plasminogen activator in the 3- to 4.5-hour time window for acute 
ischemic stroke. Stroke 2011. 42(8):2257-2262.
P11-09575
Kim AS, Nguyen-Huynh M, Johnston SC. A cost-utility analysis of 
mechanical thrombectomy as an adjunct to intravenous tissue-type 
plasminogen activator for acute large-vessel ischemic stroke. Stroke 2011. 
42(7):2013-2018.
P12-07668
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(9834):2352-2363.
P13-09520
Boudreau DM, Guzauskas G, Villa KF, Fagan SC, Veenstra DL. A model 
of cost-effectiveness of tissue plasminogen activator in patient subgroups 
3 to 4.5 hours after onset of acute ischemic stroke. Ann Emerg Med 2013. 
61(1):46-55.
P13-12586
Xu AD, Wang YJ, Wang DZ, Chinese Stroke Therapy Expert Panel for 
Intravenous Recombinant Tissue Plasminogen Activator. Consensus 


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statement on the use of intravenous recombinant tissue plasminogen 
activator to treat acute ischemic stroke by the Chinese Stroke Therapy 
Expert Panel. CNS Neurosci Ther 2013. 19(8):543-548.
P14-10421
P14-16668
Liao X, Wang Y, Pan Y, Wang C, Zhao X, Wang Y, Thrombolysis 
Implementation and Monitor of Acute Ischemic Stroke in China 
Investigators. Standard-dose intravenous tissue-type plasminogen 
activator for stroke is better than low doses. Stroke, published online July 
10, 2014, doi: 10.1161/STROKEAHA.114.005989 Stroke 2014. 
45(8):2354-2358.  
Yen TL, Ong ET, Lin KH, Chang CC, Jayakumar T, Lin SC, Fong TH, 
Sheu JR. Potential advantages of Chinese medicine Taohong Siwu 
Decoction (term depicted in Chinese) combined with tissue-plasminogen 
activator for alleviating middle cerebral artery occlusion-induced embolic 
stroke in rats. Chinese Journal of Integrative Medicine, Online First, Date 
of Publication: 24 Sep 2014, DOI 10.1007/s11655-014-1847-x Chin J 
Integr Med 2014.
P15-10504
Asuzu D, Nystrom K, Amin H, Schindler J, Wira C, Sheth KN. TURN: a 
simple predictor of symptomatic intracerebral hemorrhage after iv 
thrombolysis. Neurocrit Care 2015. 23(2):166-171.  
P15-11922
Mazya MV, Lees KR, Collas D, Rand VM, Mikulik R, Ahmed N. IV 
thrombolysis in very severe and severe ischemic stroke: results from the 
SITS-ISTR registry. Neurology, Published Ahead of Print on November 
6, 2015, doi: 10.1212/WNL.0000000000002199 Neurology 2015. 85  
P84-97880
Rijken DC, Collen D. Purification and characterization of the 
plasminogen activator secreted by human melanoma cells in culture. J 
Biol Chem 1981. 256:7035-7041. 
P87-31520
Papadopoulos SM, Chandler WF, Salamat MS, Topol EJ, Sackellares JC. 
Recombinant human tissue-type plasminogen activator therapy in acute 
thromboembolic stroke. J Neurosurg 1987. 67:394-398.
P95-3793
Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, Hennerici M. 
Intravenous thrombolysis with recombinant tissue plasminogen activator 
for acute hemispheric stroke: the European Cooperative Acute Stroke 
Study (ECASS). JAMA 1995. 274(13):1017-1025.
P95-4908
Marler JR, rtPA Study Group. Tissue plasminogen activator for acute 
ischemic stroke. N Engl J Med 1995. 333(24):1581-1587.
P97-10211
Broderick JP. Intracerebral hemorrhage after intravenous t-PA therapy for 
ischemic stroke. Stroke 1997. 28(11):2109-2118. 
P98-10052
Hacke W, Kaste M, Fieschi C, Kummer R von, Trouillas P. Randomised
double-blind placebo-controlled trial of thrombolytic therapy with 
intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998. 
352(9136):1245-1251.


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UNPUBLISHED REFERENCES
9.2
R09-0863
Global burden of stroke. 
www.who.int/cardiovascular_diseases/resources/atlas/en/; In: WHO Atlas 
of Heart Disease and Stroke. Geneva 2004:50-51.
R09-0864
Deaths from stroke. 
www.who.int/cardiovascular_diseases/resources/atlas/en/ ; In: WHO 
Atlas of Heart Disease and Stroke. Geneva 2004:52-53.
R12-4499
. Global variation in the relative burden of stroke 
and ischemic heart disease. Circulation 2011. 124(3):314-323.  
Other 
Reference
. Current status of diagnosis and treatment on acute 
ischemic stroke in China (improvements and gaps) Beijing Tian tan 
Hospital, Capital Medical University. China Stroke Committee 2014


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10.
APPENDICES
NATIONAL INSTITIUE OF HEALTH STROKE SCOR, NIHSS
10.1
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 hemianopsia
2
Complete hemianopsia
3
Bilateral hemianopsia (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
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 90º or 45º 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 90º or 45º 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 30º 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 30º 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


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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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MODIFIED RANKIN SCALE, MRS
10.2
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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BARTHEL INDEX
10.3
Item
Score
Categories
Bowels
0
Incontinent or needs enemas
5
Occasional incontinence (< once per week)
10
Continent
Bladder
0
Incontinent / unable to manage catheter
5
Occasional accident (< once per day)
10
Continent
Grooming
0
Needs help with shaving, washing, hair or teeth
5
Independent
Toilet use
0
Dependent
5
Needs some help
10
Independent on, off, dressing and cleaning
Feeding
0
Dependent
5
Needs some help (e.g. with cutting, spreading)
10
Independent if food provided within reach
Transfer (e.g. bed to 
chair)
0
Unable and no sitting balance
5
Needs major help
10
Needs minor help
15
Independent
Mobility
0
Unable
5
Wheelchair independent indoors
10
Walks with help or supervision
15
Independent (but may use aid)
Dressing
0
Dependent
5
Needs some help
10
Independent including fasteners
Stairs
0
Unable
5
Needs some help or supervision
10
Independent up and down
Bathing
0
Dependent
5
Independent in bath or shower
Total
100


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GLASGOW OUTCOME SCALE
10.4
Grade
Description
Definition
1
Good recovery
Patient can lead an independent life, with or
without minimal neurological deficit
2
Moderately disabled
Patient has neurological or intellectual
impairment but is independent
3
Severely disabled
Patient conscious but totally dependent on others
to get through daily activities
4
Vegetative survival
Patient is unresponsive, but alive; a "vegetable" in
lay language
5
Dead


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ACCORDING TO THE LOCAL APPROVED LABEL, EFFECTIVE 
10.6
DATE: 29 DEC 2014
Adverse reactions listed below are classified according to frequency and system organ class. 
Frequency groupings are defined according to the following convention: Very common (≥
1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to 
<1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data). 
Except for intracerebral/intracranial haemorrhage as adverse reaction in the indication stroke 
as well as for reperfusion arrhythmias in the indication myocardial infarction, there is no 
medical reason to assume that the qualitative and quantitative adverse reaction profile of 
Actilyse in the indications pulmonary embolism and acute ischaemic stroke is different from 
the profile in the indication myocardial infarction. 


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Haemorrhage    
The most frequent adverse reaction associated with Actilyse is bleeding in different forms 
resulting in a fall in haematocrit and/or haemoglobin values. 
very common
intracerebral haemorrhage represents the major adverse reaction in the 
treatment of acute ischaemic stroke (up to 15 % of patients without any 
increase of overall mortality and without any relevant increase in overall 
mortality and severe disability combined, i.e. mRS of 5 and 6).
bleeding from damaged blood vessels (such as haematoma)
common
intracerebral haemorrhage (such as cerebral haemorrhage, cerebral 
haematoma, 
haemorrhagic stroke, haemorrhagic transformation of stroke, intracranial 
haematoma, subarachnoid haemorrhage) in the treatment of acute 
myocardial infarction and acute pulmonary embolism 
pharyngeal haemorrhage
gastrointestinal haemorrhage (such as gastric haemorrhage, gastric ulcer 
haemorrhage, rectal haemorrhage, haematemesis, melaena, mouth 
haemorrhage, gingival bleeding)
ecchymosis
urogenital haemorrhage (such as haematuria, haemorrhage urinary tract)
injection site haemorrhage (puncture site haemorrhage, catheter site 
haematoma, catheter site haemorrhage)
uncommon
pulmonary haemorrhage (such as haemoptysis, hemothorax, respiratory 
tract haemorrhage)
epistaxis 
ear haemorrhage
rare
eye haemorrhage 
pericardial haemorrhage
retroperitoneal bleeding (such as retroperitoneal haematoma)
not known***
bleeding in parenchymatous organs (such as hepatic haemorrhage)


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Death and permanent disability are reported in patients who have experienced stroke 
(including intracranial bleeding) and other serious bleeding episodes.
If a potentially dangerous haemorrhage occurs in particular cerebral haemorrhage, the 
fibrinolytic therapy must be discontinued. In general, however, it is not necessary to replace 
the coagulation factors because of the short half-life and the minimal effect on the systemic 
coagulation factors. Most patients who have bleeding can be managed by interruption of 
thrombolytic and anticoagulant therapy, volume replacement, and manual pressure applied to 
an incompetent vessel. Protamine should be considered if heparin has been administered 
within 4 hours of the onset of bleeding. In the few patients who fail to respond to these 
conservative measures, judicious use of transfusion products may be indicated. Transfusion 
of cryoprecipitate, fresh frozen plasma, and platelets should be considered with clinical and 
laboratory reassessment after each administration. A target fibrinogen level of 1 g/l is 
desirable with cryoprecipitate infusion. Antifibrinolytic agents are available as a last 
alternative.
Immune system disorders*
rare
hypersensitivity / anaphylactoid reactions (e.g. allergic reactions including 
rash, urticaria, bronchospasm, angio-oedema, hypotension, shock or any 
other symptom associated with hypersensitivity)
very rare 
serious anaphylaxis
If they occur, conventional anti-allergic therapy should be initiated. In such cases a relatively 
larger proportion of patients were receiving concomitant Angiotensin Converting Enzymes 
inhibitors. No definite anaphylactic (IgE mediated) reactions to ACTILYSEare known. 
Transient antibody formation to ACTILYSEhas been observed in rare cases and with low 
titres, but a clinical relevance of this finding could not be established.
Nervous system disorders
very rare
events related to the nervous system (e.g. epileptic seizure, convulsion, 
aphasia, speech disorder, delirium, acute brain syndrome, agitation, 
confusion, depression, psychosis) often in association with concurrent 
ischaemic or haemorrhagic cerebrovascular events 
Cardiac disorders**
As with other thrombolytic agents, the events described above under the respective section 
have been reported as sequelae of myocardial infarction and / or thrombolytic administration.
very common
recurrent ischaemia / angina pectoris, hypotension and heart failure / 
pulmonary oedema, 
common
cardiogenic shock, cardiac arrest and reinfarction


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uncommon
reperfusion arrhythmias (such as arrhythmia, extrasystoles, AV block first 
degree to atrioventricular block complete, atrial fibrillation / flutter, 
bradycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia / 
fibrillation, electromechanical dissociation [EMD])
mitral regurgitation, pulmonary embolism, other systemic embolism / 
cerebral embolism, ventricular septal defect 
These cardiac events can be life-threatening and may lead to death.
Reperfusion arrhythmias may lead to cardiac arrest, can be life threatening and may require 
the use of conventional antiarrhythmic therapies.
Vascular disorders
rare
Embolism, which may lead to corresponding consequences in the organs 
concerned
Gastrointestinal disorders
rare
Nausea (can also occur as symptoms of myocardial infarction)
not known***
Vomiting (can also occur as symptoms of myocardial infarction)
Investigations
uncommon
blood pressure decreased
not known***
body temperature increased
Injury and poisoning and procedural complications
not known***
fat embolism (cholesterol crystal embolisation), which may lead to 
corresponding consequences in the organs concerned
Surgical and medicinal procedures
not known***
Blood transfusions (necessary)
***This adverse reaction has been observed in post-marketing experience. With 95 % 
certainty, the frequency category is not greater than “rare”, but might be lower. Precise 
frequency estimation is not possible as the adverse drug reaction did not occur in a clinical 
trial database of 8299 patients.


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APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08776773
3.0
clinical-trial-protocol-revision-02
An open label, multicentre, single-arm trial to assess safety and efficacy of alteplase
(rt-PA) in Chinese patients with acute ischemic hemispheric stroke where
thrombolysis is initiated between 3 and 4.5 hours after stroke onset
Approval–Clinical Monitor
17 Feb 2017 08:47 CET
Approval-Biostatistics
17 Feb 2017 08:48 CET
Approval-Therapeutic Area 
19 Feb 2017 11:34 CET
Approval-Team Member Medicine
24 Feb 2017 11:55 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08776773
3.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c13465372-02
BI Trial No.:
135.331
Title:
An open label, multicenter, single-arm trial to assess safety and 
efficacy of alteplase (rt-PA) in Chinese patients with acute ischemic 
hemispheric stroke where thrombolysis is initiated between 3 and 4.5 
hours after stroke onset
Including Protocol Amendment 02 <135.331>-protocol-amendment-
x [include c08776773]
Investigational
Product(s):
Actilyse®, Alteplase (rt-PA) 
Responsible trial 
statistician(s):
Phone: 
Date of statistical 
analysis plan:
23 Aug 2017 SIGNED
Version:
Final
Page 1 of 29
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2017 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.


Boehringer Ingelheim
TSAP for BI Trial No: 135.331
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................3
2.
LIST OF ABBREVIATIONS ..............................................................................4
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................7
5.
ENDPOINT(S).......................................................................................................8
5.1
PRIMARY ENDPOINT(S) ..............................................................................8
5.2
SECONDARY ENDPOINT(S) ........................................................................8
5.2.1      Key secondary endpoint(s)............................................................................8
5.2.2      (Other) Secondary endpoint(s) .....................................................................8
8
9
6.
GENERAL ANALYSIS DEFINITIONS ............................................................9
6.1
TREATMENT(S)............................................................................................11
6.2
IMPORTANT PROTOCOL VIOLATIONS ...............................................11
6.3
PATIENT SETS ANALYSED.......................................................................13
13
6.5
POOLING OF CENTRES .............................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...............19
7.
PLANNED ANALYSIS......................................................................................21
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.....21
7.2
CONCOMITANT DISEASES AND MEDICATION .................................21
7.3
TREATMENT COMPLIANCE....................................................................22
7.4
PRIMARY ENDPOINT(S) ............................................................................22
7.5
SECONDARY ENDPOINT(S) ......................................................................22
7.5.1          Key secondary endpoint(s) .......................................................................22
7.5.2           (Other) Secondary endpoint(s).................................................................22
23
7.7
EXTENT OF EXPOSURE.............................................................................24
7.8
SAFETY ANALYSIS......................................................................................24
7.8.1           Adverse events ...........................................................................................24
7.8.2         Laboratory data ........................................................................................25
7.8.3        Vital signs...................................................................................................25
7.8.4         ECG............................................................................................................26
7.8.5         Others.........................................................................................................26
8.
REFERENCES....................................................................................................27
28
10.
HISTORY TABLE..............................................................................................29


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LIST OF TABLES
Table 6.2: 1
Important protocol violations ...........................................................................12
Table 6.6:1     Handling of missing data ..................................................................................16
Table 6.7: 1
Visit structure ...................................................................................................19
Table 10: 1
History table .....................................................................................................29


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
ATC
Anatomical Therapeutic Chemical
BI
Boehringer Ingelheim
BP
Blood Pressure
BMI
Body Mass Index
BRPM
Blinded Report Planning Meeting
CRF
Case Report File
CT
Computer Tomography
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DMC
Data Monitoring Committee
ECG
Electrocardiogram
EoT
End-of-Text
EX
Exclusion Criteria
FAS
Full Analysis Set
ICH
International Conference on Harmonisation
sICH
symptomatic Intracranial Haemorrhage
IN
Inclusion Criteria
IPV
Important Protocol Violation
LOCF
Last Observation Carried Forward
IV
Intravenous 
MAC
Meta-Analytic-Combined
Max
Maximum
MedDRA
Medical Dictionary for Drug Regulatory Activities
Min
Minimum
MQRM
Medical Quality Review Meeting
MRI
Magnetic Resonance Imaging
mRS
Modified Rankin Scale
N
Number of Patients
NIHSS
National Institute of Health Stroke Scale
PN
Preferred Name


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Term
Definition / description
PR
Pulse Rate
PT
Preferred Term
PV
Protocol Violation
Q1
Lower Quartile
Q3
Upper Quartile
REP
Residual Effect Period
SAE
Serious Adverse Event
SAS
Statistical Analysis Software
SD
Standard Deviation
sICH
symptomatic Intracranial Haemorrhage
SOC
System Organ Class
TCM
Trial Clinical Monitor
ToC
Table of Contents
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
WHO-DD
World Health Organization’s Drug Dictionary
WLOCF
Worst and Last Observation Carried Forward


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3.
INTRODUCTION
As per ICH E9 [1], the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary
variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in Section 7 of the CTP [2] “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomisation.
This TSAP is also used as the interim TSAP. The interim analysis will be performed when 60 
patients enter and complete the study. The safety and efficacy will be evaluated on the first 60 
patients who complete the study.
SAS® Version 9.2 versions will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
There has been no change in the planned analyses from the statistical methods described in 
the CTP.


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5.
ENDPOINT(S)
Please refer to Section 5.1 in CTP [2].
5.1
PRIMARY ENDPOINT(S)
The primary efficacy endpoint is the percentage of patients with mRS 0-1 (favourable 
outcome) at Visit 5 (i.e., Day 90) after stroke onset by face-to-face interview with patient. A 
patient is considered to be a mRS 0-1 responder (response value set to 1) if he/she obtained a 
response of 0 or 1 on the modified Rankin scale otherwise the response value will be set to 0.
The primary safety endpoint is the percentage of patients with symptomatic intracranial 
haemorrhage (sICH) centrally evaluated by DMC consultants according to ECASS III 
definition within the whole study period. ECASSIII definition is any apparently extravascular 
blood in the brain or within the cranium that was associated with clinical deterioration 
(defined by an increase in the National Institute of Health Stroke Scale (NIHSS) score of 4 or 
more points), or that led to death and that was identified as the predominant cause of the 
neurological deterioration.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable.
5.2.2
(Other) Secondary endpoint(s)
The percentage of global outcome responder at Visit 5 (i.e. Day 90) if he/she obtains the 
following results at Visit 5 (i.e. Day 90) (for all of the 4 endpoints)
              mRS score of 0 to 1
              Barthel Indext score≥95
              NIHSS score of 0 to 1
              Glasgow Outcome Scale score of 1
The secondary safety endpoints are:
-
Patient’s survival at Visit 5 (censoring at day 90)
-
Frequency of deaths related to stroke or of neurological causes
-
Frequency and severity of adverse events
-
Incidence of cerebral herniation and symptomatic edema


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
This is a single dose study. The treatment periods are defined as below:
-
Screening: from the time of signing informed consent to the start time of bolus 
treatment administration
-
On-treatment: through the drug treatment administration and residual effect period 
(REP, is defined as 7 days after finishing the drug medication)
-
Post-treatment: after end of the REP to the Visit 5 (i.e. Day 90)
-
Post-study: after Visit 5 (i.e. Day90)
Adverse events (AEs) in on-treatment period will be summarized as primary interest. The 
frequency of all AEs collected from signing informed consent until to Visit 5 (i.e. Day 90)
will also be summarized.
6.2
IMPORTANT PROTOCOL VIOLATIONS
No per protocol analysis will be performed for this study; however patients with potential 
important protocol violations (IPVs) will be documented. The following list of potential IPVs 
will be used; note that this is a working list and may not be finalised until the final Blinded 
Report Planning Meeting (BRPM) prior to database lock. Inclusion criteria/exclusion criteria 
numbers refer to the definition given in the protocol or case report file (CRF).


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Table 6.2: 1
Important protocol violations
Category /
Code
Description
Comment/Example
Exclude
d from
A
Entrance criteria not met
A1
Inclusion Criteria Not Met
A1.1*
Age is greater than 80 or lower than 18
Inclusion criterion IN1 not met
None
A1.2
Women pregnant, nursing or with 
childbearing potential do not use highly 
effective methods of birth control
Inclusion criterion IN2 not met
Exclusion criterion EX17 met
None
A1.3
Diagnosis of ischemic stroke without a 
measureable neurological deficit 
Inclusion criterion IN4 not met
None
A1.4.1*
Thrombolytic therapy initiated within 3 
hours of stroke onset.
Inclusion criterion IN5 not met or
Exclusion criterion EX1 met
None
A1.4.2*
Thrombolytic therapy initiated beyond
4.5 hours of stroke onset.
Inclusion criterion IN5 not met or
Exclusion criterion EX1 met
None
A2 
Exclusion Criteria Met
A2.1*
The time of symptom onset is unknown
Exclusion criterion EX1 met
None
A2.2
Evidence of intracranial haemorrhage 
on the CT/MRI-scan or symptoms 
suggestive of subarachnoid 
haemorrhage, even if the CT/MRI-scan 
is normal
Exclusion criterion EX2 met
None
A2.3
Patients who must or wish to continue 
the intake of restricted medications (see 
protocol section 4.2.2.1) or any drug 
considered likely to interfere with the 
safe conduct of the trial
Exclusion criterion EX3 met
None
A2.4
Acute bleeding diathesis (detailed 
items can be found in CRF)
Exclusion criterion EX4 met
None
A2.5
Bacterial endocarditis, pericarditis, 
acute pancreatitis, or severe hepatic 
dysfunction, including hepatic failure, 
cirrhosis, portal hypertension 
(oesophageal varices) and active 
hepatitis
Exclusion criterion EX5, EX6 or EX7 met
None
A2.6
Significant trauma or major surgery 
(according to the investigator's 
assessment) in past 3 months
Exclusion criterion EX8 met
None
A2.7
Severe stroke as assessed clinically 
(e.g. NIHSS>25) and/ or imaging 
demonstrates multi-lobar infarction 
(hypodensity >1/3 cerebral 
hemisphere)
Exclusion criterion EX9 met
None
A2.8
Symptoms rapidly improved
significantly before start of study drug
Exclusion criterion EX10 met
None
A2.9
Severe uncontrolled arterial 
hypertension 
Exclusion criterion EX11 met
None
A2.10*
Serious abnormal blood glucose
Exclusion criterion EX12 met
None
A2.11*
Any history of prior stroke in previous 
3 months, or any history of prior stroke 
with concomitant diabetes
Exclusion criterion EX13 met
None
A2.12
Seizure at stroke onset
Exclusion criterion EX14 met
None


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A2.13
Known hypersensitivity to active 
substance alteplase, gentamicin (a trace 
residue from the manufacturing
process) or to any of the excipients
Exclusion criterion EX15 met
None
A2.14
Currently enrolled in another 
investigational device or drug study, or 
less than 30 days since ending another 
investigational device or drug study(s), 
or receiving other investigational 
treatment(s)
Exclusion criterion EX16 met
None
B
Informed consent
B1
Informed consent not available /not 
done
e.g. date of informed consent  missing
No signature on ICF
Detected automatically/manually
All
B2
Informed consent too late
e.g. date of informed consent for the study not 
obtained prior to any study related procedure
None
C
Non compliance
C1
Patients not treated as label instructed
e.g. bolus date missing
None
D
Concomitant medication
D1
Prohibited medication use
Concomitant medications for prohibited 
medication use. Refer to
Section 4.2.2 of the CTP.
None
E
Trial specific
E1
Non-stroke patient
e.g. Lyme disease
None
* IPVs will be identified programmatically; others will be manually recorded.
6.3
PATIENT SETS ANALYSED
The treated set (TS) includes all enrolled patients who received alteplase (rt-PA) treatment at 
any dose. The full analysis set (FAS) is the same as TS since all treated patients will be 
evaluated. 
All safety and efficacy analysis will be performed on the TS.


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6.5
POOLING OF CENTRES
Not applicable.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
According to CTP, all efforts should be made to collect complete CRF information referring 
to all patients with drug administration. No missing values regarding vital status and 
intracranial bleeds are expected. 
The missing values related to efficacy outcome parameters will be imputed according to the 
rules described below and listed in Table 6.6:1.
Baseline imputation
In case of missing data for baseline NIHSS, the baseline NIHSS will be imputed to the best 
possible score (0).
Post baseline imputations
WLOCF: Worst and last observation carried forward
-
any missing data that it is not due to death will be replaced by the last observation carried 
forward (LOCF) i.e., either Visit 4, Visit 3, Visit 2, Visit 1C, Visit 1B.
-
if the missing data is due to death, the data will be replaced by the worst score: the highest 
possible score (42) for the NIHSS, the score of 6 (i.e. Dead) for the modified Rankin scale, 
the score of 5 (i.e. Dead) for the Glasgow outcome, the lowest score (0) for the Barthel 
index.


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-
if the patient status (i.e. alive yes/no) is missing, the data will be replaced by the worst score 
excluding death: the highest possible score (42) for the NIHSS, the score of 5 for the 
modified Rankin scale, the score of 4 for the Glasgow outcome, the lowest possible score (0)
for the Barthel index.
When all post baseline measurements are missing, the imputation across visits will depend on 
survival status (dead/missing/alive, alive will be handled the same as missing in this scenario) as 
per definition above. These imputations will be used for the derived endpoints (e.g. 
dichotomized endpoint) as defined in Section 5.
For multi items scales (NIHSS, Barthel index): Imputation will be performed in two steps: 
1.) Individual items will be imputed following the LOCF or worst score
2.) Total score is calculated
When all post baseline measurements are missing, the individual values for post baseline 
measurements will stay missing and the imputation across visits will depend on survival status 
(dead/missing/alive, alive will be handled the same as missing in this scenario) as per definition 
above.
In case of NIHSS missing at baseline and at all post baseline time points, then the individual 
values for post baseline measurements will stay missing and the total NIHSS score for all post 
baseline data will be imputed depending on survival status (dead/missing/alive, alive will be 
handled the same as missing in this scenario).
Barthel index is present only at Visit 4 and Visit 5. In case of missing items for the Barthel index 
at Visit 4, the worst value will be imputed for these items.
Furthermore, in cases where one of more individual items is missing, the total score must be set 
to missing for the observed case type of analysis.


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Table 6.6:1                   Handling of missing data
Endpoint
Baseline 
value
Baseline 
imputation value
Post-baseline 
value at visit
Patient 
dead/alive 
at visit
Post baseline 
imputation value 
at visit
modified 
Rankin scale
Available
Alive
NA
Missing
Alive
LOCF or worst 
excluding death
(5) if missing at 
Visit 4
Missing
Dead
Worst (6)
Missing
Missing
Worst excluding 
death (5)
Barthel Index
Available
Alive
NA
Missing
Alive
LOCF or worst if 
missing at Visit 4
Missing
Dead
Worst (0)
Missing
Missing
Worst (0)
Glasgow 
outcome
Available
Alive
NA
Missing
Alive
Worst excluding 
death (4)
Missing
Dead
Worst (5)
Missing
Missing
Worst excluding 
death (4)
NIHSS total 
score
Available 
or 
missing
If missing impute 
best value (0)
Available
Alive
NA
Available 
or 
missing
If missing impute 
best value (0)
Missing
Alive
LOCF or worst 
(42) if all post-
baseline were 
missing
Available 
or 
missing
If missing impute 
best value (0)
Missing
Dead
Worst (42)
Available 
or 
missing
If missing impute 
best value (0)
Missing
Missing
Worst (42)


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NIHSS Total score:
The total score of the NIHSS is the sum of the 15 individual item scores: level of 
consciousness (1), LOC questions (2), LOC commands (3), best gaze (4), visual (5), facial 
paresis (6), motor arm right (7), motor arm left (8), motor leg right (9), motor leg left (10), 
limb ataxia (11), sensory (12), best language (13), dysarthria (14), extension and inattention 
(15). 
For the calculation of the total score: 
The scores of ‘9’ on motor (7-10) indicating amputation or joint fusion on motor arm right or
left, motor leg right or left will be replaced by (4) for post baseline value and by best case (0) 
at baseline.
A score of ‘9’ on dysarthria (14) will be replaced by the worst case value (2) for post baseline 
value and by best case (0) at baseline.
This rule is to be applied for observed cases and WLOCF.
The censoring rules for time to death (survival time, [day]) at Day 90 and censoring flag will 
be calculated as following manner:

for a dead patient:
death=yes
censoring flag=0
survival time=date of death – date of start bolus +1
if survival time >90 (patient alive at Visit5) 
then death=no, censoring flag=1, survival time=90

for patient alive at Visit 5:
death=no
censoring flag=1
survival time= date of last contact – date of start bolus +1
if survival time>90 then survival time=90

for a lost to follow up patient:
death = no
censoring flag=1
if « last date patient known to be alive » is known
then survival time= last date patient known to be alive – date of start bolus +1
  if « last date patient known to be alive » is unknown
then survival time= date of last contact – date of start bolus +1
if survival time>90 then survival time=90


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Date of last contact is the maximum of {date of last measurement or visit, date of trial 
completion, last available date from AE and last available date from CM}.
The censoring rules for time to death (survival time, [day]) overall study and censoring flag 
will be calculated as following manner:
All deaths are taken into account whatever their time of occurrence, and even if they occurred 
after the 97 days (90 days +7).

for a dead patient:
death=yes
censoring flag=0
survival time=date of death – date of start bolus +1

for patient alive at Visit 5:
death=no
censoring flag=1
survival time= date of last contact – date of start bolus +1

for a lost to follow up patient:
death = no
censoring flag=1
if « last date patient known to be alive » is known
then survival time= last date patient known to be alive – date of start bolus +1
  if « last date patient known to be alive » is unknown
then survival time= date of last contact – date of start bolus +1
Date of last contact is the maximum of {date of last measurement or visit, date of trial 
completion, last available date from AE and last available date from CM}.
The length of stay in hospital will be calculated as follows:
The length of stay in hospital is expressed in days and is equal to the date of discharge date 
and time is approximated to 23h O’clock for the end of day minus the date and time of the 
start of bolus. Because the date in SAS are expressed in seconds, the results will be divided by 
86400 (24*60*60) in order to obtain a results expressed in number of days. The exact time of 
day of when the discharge time occurred is fixed at 23H59 PM for all patients (exact time not 
recorded in CRF).
Example: Start of bolus: 23/01/03 12H00 and date of discharge: 30/01/03 
The length of stay in hospital will be: date of discharge (30/01/03, 23H59) - date of bolus 
(23/01/03, 12H00) / 86400 = 7.5 days.
Missing or incomplete AE onset dates are imputed according to BI standards [27, 27]. 


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Missing or incomplete concomitant therapy onset dates are also imputed referring to AE 
standards. The end dates of missing or incomplete AE and concomitant therapy will be not 
imputed.
Trial completion is defined as the patients who are treated and completed Day 90 visit (i.e 
Visit 5).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The table below presents the visit structure according to the study flowchart depending on the 
time window scheduled in the CTP.
Table 6.7: 1
Visit structure
Period
Baseline
Trial 
drug 
admin.
On-treatment & Post-treatment
Visit 
number per 
protocol
V1A
V1B#
V1C#
V2
V3
V4
V5
Planned 
study 
window
-4.5-0 
hour
x
60 
mins
1 
hour 
15 
mins
2 hrs 
30
mins
24 
hrs 
2hr
7 
days 
3
day
30 days 
3 days
90 days 
7 days
Study Day
   D0   
D1
D7
D30
D90
Visit 
description*
Baseline
Day0
(1H)
Day0
(2 H)
Day1
Day7
Day30
Day90
*label to be used in tables.
‘Baseline’ is defined as from enrolled in this study to the start time of bolus treatment 
administration.
‘Study Day’ is calculated from the date & time of starting bolus treatment administration.
# date & time is calculated from the date & time of starting infusion treatment administration.
Start of treatment:
The start of treatment (used for survival start time, length of stay in hospital, treatment at 
onset for adverse event) will be the start of bolus treatment administration; end of 
treatment is the end of infusion/drug/treatment administration.
Baseline value:
The baseline value will be the value recorded at V1A (last available value before the start of 
bolus treatment).


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Change from baseline:
The change from baseline for any efficacy or safety endpoints (Vital signs) will be calculated 
as: value after baseline – value at baseline (V1A).
All efficacy analyses will be based on ‘nominal visits’ (CRF raw data visit) which will be 
labelled as indicated in the ‘Visit description’ row in tables, listings and graphs.


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7.
PLANNED ANALYSIS
Unless otherwise specified, the following general conventions for End-of-Text (EoT) [5] 
tables should be used regarding all descriptive statistical analysis and result presentations.
The set of summary statistics: N / Mean / SD / Min / Median / Max are for continuous data
with one more decimal place compared to the original data in the subject data listing. For 
tables that are provided for endpoints with some extreme data, Q1 and Q3 would be preferred 
to Min and Max.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) ( unless
otherwise specified, all patients in the respective patient set whether they have non-missing 
values or not). Percentages will be rounded to one decimal place. The category missing will 
be displayed only if there are actually missing values. All the confidence interval calculations
for proportions will use the Wilson score method.
The visit will be analysed as calculated visit and should be named ‘Baseline’, ‘Day0(1H)’, 
‘Day0(2H)’, ‘Day1’, ‘Day7’, ‘Day30’ and ‘Day90’ as described in Section 6.7. The units of 
variables should be given in the titles or column/row descriptors in square brackets (e.g. 
[mmHg]), unless the variable does not have a unit (e.g. scores). And the imputation rules for 
missing data will be applied as in Section 6.6.
An independent data monitoring committee (DMC) will oversee the trial conduct, monitor
safety data monthly, and review the interim analysis results when 60 patients complete the
study. As for details please refer to DMC SAP. [6]
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics of concomitant therapy (medication and other treatment) are 
planned for this section of the report based on TS.
Concomitant therapy will be coded according to the WHO-DD (current version at the time of 
analysis), sorted by the ATC3 class and the preferred name (PN). PNs that belong to different 
ATC3 classes will be shown under all applicable ATC3 classes.
All concomitant therapies after the start of bolus until Visit 5 will be summarized. 
Antithrombotic therapies (e.g, aspirin, heparin, etc.) within 24 hours after the start of bolus 
will be summarized separately.
Concomitant therapy without end date will be considered as ongoing.


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7.3
TREATMENT COMPLIANCE
Not applicable.
7.4
PRIMARY ENDPOINT(S)
Primary analysis
The primary efficacy endpoint is the percentage of mRS 0-1 (favourable outcome) responder 
at Visit 5 after stroke onset by face-to-face interview with patient. The proportion of patients 
with mRS 0-1 will be presented with corresponding 95% confidence intervals (CIs). The 
imputation rules described in Section 6.6 will be applied for the primary analysis. The 
observed case analysis, that is the proportion of patients with mRS 0-1 observed at Visit 5, 
will be performed as sensitivity analysis.
The null hypothesis of p ≤40% versus the alternative hypothesis of p > 40% will be tested 
using a one sample t-test at two-sided significance level of 0.05. The horizontal stacked bar 
graphs of each level in the ordinal mRS will be presented.
The primary safety endpoint is the proportion of patients with symptomatic intracranial 
haemorrhage (sICH) evaluated by DMC consultants within whole study period. The 
proportion of patients with sICH will also be presented along with corresponding 95% CIs. 
 
 
 
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
Not applicable.
7.5.2
(Other) Secondary endpoint(s)
The secondary efficacy endpoint is the percentage of global outcome at Visit 5. A global 
outcome responder is defined as patient with outcomes at Visit 5 of a score of 0 or 1 on the 
mRS, a score of 95 or higher on the Barthel Index, a score of 0 or 1 on the NIHSS, and a 


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score of 1 on the Glasgow Outcome Scale. The proportion of global outcome responders will 
be displayed along with corresponding 95% CIs. Each item of the composite criteria global 
outcome responder (refer to Section 5.2.2) will be evaluated separately as well. Its observed
result will also be summarized. The imputation rules described in Section 6.6 will be applied 
for the primary analysis. 
 
The secondary safety endpoints are:
-
Patient’s survival at Day 90 (censoring at 90 days)
The cumulative probability (Kaplan-Meier estimate) of death from bolus treatment
administration to Day 90 will be analysed and plotted by a Kaplan-Meier survival with the 
median survival along with 95% confidence interval, using Greenwood’s standard error 
estimate. The Kaplan-Meier estimates will also be analysed over the observation period of 90 
days.
-
Frequency of deaths related to stroke or of neurological causes will be analysed 
descriptively.
-
Incidence of cerebral herniation and symptomatic edema will be analyzed descriptively.
-
Frequency and severity of adverse events refer to Section 7.8.1.


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7.7
EXTENT OF EXPOSURE
Only descriptive statistics are planned for this section of the report.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set (TS).
7.8.1
Adverse events
Unless otherwise specified, the analyses of adverse events (AEs) will be descriptive in nature. 
All analyses of AEs will be based on the number of patients with AEs and NOT on the 
number of AEs.
Multiple AE occurrence data on the CRF will be collapsed into an AE provided that all of the 
following applies:
•
All AE attributes are identical (LLT, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, and outcome).
•
The occurrences were time-overlapping or time-adjacent (time-adjacency of 2
occurrences is given if the second occurrence started on the same day or on the day after 
the end of the first occurrence).
For further details on summarization of AE data, please refer to the guidance [3, 4].
The primary interest analysis of AEs will be based on the concept of treatment emergent (on-
treatment period) AEs, i.e. AEs which occurred through the single dose treatment phase and 
throughout the REP (i.e. exactly day 7). AEs stopped before the start of bolus treatment
administration will be assigned to ‘screening’ and AEs occurring after the end of REP to Visit
5 will be assigned to ‘post-treatment’. The frequency of all AEs collected after Visit 5 until 
the end of the study (i.e. Visit5) defined as ‘post study’ will also be summarized. For details 
on the treatment definition, see Section 6.1.
According to ICH E3 [7], AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant AEs with
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or


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(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality Review 
Meeting.
An overall summary of AEs will be presented.
The frequency of patients with AEs will be summarised by primary system organ class (SOC)
and preferred term (PT) of MedDRA (using the version that is current at the time of analysis).
Frequency tables will be created for the following AEs:

All AEs

Serious AEs

Drug-related AEs

AEs leading to treatment discontinuation

AEs leading to death

Other significant AEs (according to ICH E3) [7]

AEs with incidence in preferred term greater than 2%
The system organ classes will be sorted alphabetically, and preferred terms will be sorted by 
descending frequency within system organ class.
The above tables will be repeated within the on-treatment period and the overall period from 
Inform consent to Visit 5.
7.8.2
Laboratory data
Laboratory data will not be analysed. Any clinical significant abnormalities in laboratory will 
be reported as AEs.
7.8.3
Vital signs
Blood pressure (BP, systolic and diastolic) and pulse rate (PR) are measured at baseline (prior 
to administration of trial medication i.e. Visit 1A). Further BP/PR monitoring take place in 
the following order: every 30 minutes for 6 hours, then hourly until 24 hours after IV rt-PA 
treatment, thereafter on Visit 2, Visit 3, Visit 4, and Visit 5 (seated and rested for a minimum 
of 5 minutes).
Descriptive tables of the following variables will be presented in the  time points of Visit 1A, 
Visit 1B: 0.5H, Visit 1C: 1h,4h, 6h,12h, Visit 2, Visit 3, Visit 4, and Visit 5. 
-
Systolic blood pressure [N(%)]: ≤185 mmHG, and >185 mmHG 
-
Diastolic blood pressure [N(%)]:≤110 mmHG, and >110 mmHG
-
Pulse rate [beats/min]
In addition, descriptive tables of blood pressure will be presented over all measured time
points. Figures of blood pressure will be presented over specified time points.


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7.8.4
ECG
ECG data will not be analysed. Any clinically significant relevant changes in the ECG will be 
reported as AEs.
7.8.5
Others
Not applicable.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
"Clinical Trial Protocol (CTP) of Boehringer Ingelheim Trial 135.331", current version, 
BIRDS.
3
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", version 8.0; IDEA for CON.
4
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", version 3.0; 
IDEA for CON.
5
001-MCG-159_RD-03: "Standard table shells for inferential and descriptive End-of-
Text tables (EoT-Catalogue) ", current version; IDEA for CON.
6
"DMC SAP of Boehringer Ingelheim Trial 135.331", current version.
7
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH Guideline 
Topic E3, Note For Guidance on Structure and Content of Clinical Study Reports, 
current version.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
10-Jan-17
None
This is the initial TSAP without any 
modification.
Final
23-Aug-17
None
This is the final TSAP without any 
modification.