Clinical trial NCT04915729
Conditions: Stroke
Sponsor: Boehringer Ingelheim
Start date: 2021-06-22; Completion date: 2023-10-08
Enrollment: 1489 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open to Chinese adults who had an ischaemic stroke, which means that blood vessels in the brain are blocked. To resolve blood clots, people in the study get either tenecteplase or alteplase within 4 hours and 30 minutes after stroke. The purpose of this study is to compare how tenecteplase and alteplase improve peoples' recovering of physical activity. Alteplase is standard of care. Tenecteplase is a modified variant of alteplase that is easier to administer and is approved to treat heart attack. This study is to find out whether tenecteplase is as good as alteplase in people with ischaemic stroke.

Participants are equally put into 2 treatment groups by chance. Participants in one group get tenecteplase as a single injection into a vein. Participants in the other group get alteplase as an injection into a vein (10% of the dose) and the remainder as an infusion over 1 hour.

Participants are in the study for about 3 months. They are in the hospital for the first week after treatment. Then they visit the study site 1 and 3 months after treatment. At these visits, peoples' ability to independently carry out daily activities is assessed. Scores for physical activity are compared between both treatment groups. The doctors also regularly check the general health of the participants.

Detailed description:

Arms: arm 1: Chinese patients with AIS were screened (visit 1) and randomised (visit 2a) when admitted. Patients received a single dose of tenecteplase, 0.25 mg/kg via intravenous (iv) bolus no later than 4.5 hours (h) after symptom onset. Visits on Day 1 consisted of two further visits (Visit 2b and Visit 2c) that were performed 1 h and 2 h after the start of the treatment. Visits 3 to 5 for continuous follow-up were performed on day 2, 8 and 30 after the start of the treatment. Treated patient performed a 90-day follow-up visit after the treatment to complete the study. arm 2: Chinese patients with AIS were screened (visit 1) and randomised (visit 2a) when admitted. Patients received a single dose of alteplase, 0.9 mg/kg, 10% via intravenous (iv) bolus and the remaining 90% of the total dose administered as an iv infusion over 1 h no later than 4.5 hours (h) after symptom onset. Visits on Day 1 consisted of two further visits (Visit 2b and Visit 2c) that were performed 1 h and 2 h after the start of the treatment. Visits 3 to 5 for continuous follow-up were performed on day 2, 8 and 30 after the start of the treatment. Treated patient performed a 90-day follow-up visit after the treatment to complete the study.
Interventions: intervention 1: tenecteplase intervention 2: alteplase
Intervention descriptions: intervention 1: tenecteplase intervention 2: alteplase

Protocol documents:
Prot_000.pdf: 


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Original Protocol date
09 Sep 2020
Revision date
23 Feb 2023
BI trial number
1123-0040
Title of trial
A phase III multi-centre, prospective, randomised, open label, 
blinded endpoint (PROBE), active-controlled parallel group trial to
assess efficacy and safety of tenecteplase versus alteplase in Chinese 
patients with acute ischaemic stroke within 4.5 hours after stroke 
onset
 investigator
Trial sites
Multi-centre study conducted in China (at neurology clinics or stroke 
units and with 24 hours [h] access to adequate imaging scanner and 
laboratory testing)
Approximately 55 sites
Clinical phase
III
Trial rationale
This trial is a phase III study to determine whether tenecteplase 
0.25 mg/kg is non-inferior to alteplase 0.9 mg/kg for thrombolysis in 
AIS patients within 4.5 h after stroke onset in the Chinese population, 
thus providing more treatment options for acute ischaemic stroke 
(AIS) patients in China.
Trial objectives
•
To assess whether tenecteplase is non-inferior to alteplase in 
favourable outcome (modified Rankin scale achieving 0 or 1
[mRS0-1]) in Chinese patients with AIS who are eligible for 
intravenous (iv) thrombolysis within 4.5 h of symptom onset
•
To assess the safety of tenecteplase in AIS patients 
•
To assess the efficacy of tenecteplase in other key functional 
outcomes
Trial endpoints
Primary Efficacy Endpoint
•
mRS score of 0 or 1 at day 90 
Secondary Efficacy Endpoint
•
Major neurological improvement at 24 h (National Institute of 
Health Stroke Scale [NIHSS] score of 0 or improvement of at 
least 4 points compared with baseline)
•
mRS score of 0-2 at day 90


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•
Change from baseline of NIHSS score at day 90
•
Distribution of mRS at day 90
•
Barthel Index score ≥95 at day 90
Secondary Safety Endpoint 
•
Symptomatic intracranial haemorrhage (sICH) per ECASS III 
definition
•
90-day mortality
•
mRS score of 5 or 6 at day 90
Trial design
Multi-centre, prospective, randomised, open label, blinded endpoint 
(PROBE), active-controlled parallel group phase III trial
Total number of patients
randomised
Approximately 1478
Number of patients on 
each treatment
Approximately 739
Diagnosis
AIS within 4.5 h after stroke onset
Main in- and exclusion 
criteria
Main inclusion criteria:
1. Age ≥18 years old
2. Diagnosis of ischaemic stroke with a measurable neurological 
deficit on NIHSS (0< NIHSS ≤25); if the total NIHSS <4,
patients have to be with at least a measurable deficit on motor 
function (upper or lower limbs ≥1).
3. Stroke symptoms should have been presented for at least 30 min
without significant improvement prior to screening
4. Thrombolytic therapy can be initiated within 4.5 h of AIS onset
5. Patients with premorbid mRS 0 or 1
6. Signed and dated written informed consent in accordance with 
good clinical practice (GCP) and local legislation prior to 
admission to the trial
Main exclusion criteria:
1. Evidence of intracranial haemorrhage
on the computed 
tomography (CT) scan or symptoms suggestive of subarachnoid 
haemorrhage, even if the CT scan is normal
2. Use restricted medications or any drug considered likely to 
interfere with the safe conduct of the trial
3. Acute bleeding diathesis
4. Bacterial endocarditis, pericarditis
5. Acute pancreatitis


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6. Significant trauma or major surgery (according to the 
investigator’s assessment) in the past 3 months (m)
7. Imaging demonstrates multi-lobar infarction
8. Severe uncontrolled arterial hypertension
9. Blood glucose <50 mg/dL at screening
10. Seizure at stroke onset
11. Known hypersensitivity to active substance alteplase
or 
tenecteplase, gentamicin or to any of the excipients
12. Currently enrolled in another investigational device or drug 
study, or <30 days since ending another investigational device or 
drug study(s), or receiving other investigational treatment(s)
13. Women who are pregnant
14. Patient has a confirmed active infection with SARS-CoV-2 in 
medical history within the prior 3 m, based on which investigator 
considers likely to interfere with the safe conduct or the trial 
evaluation, procedures, or completion
15. Any other conditions that, in the opinion of the investigator or BI 
physician, if consulted, would pose a risk to subject safety or 
interfere with the trial evaluation, procedures or completion
Test product
Metalyse®, tenecteplase (TNK-tPA)
dose
Total single dose will be 0.25 mg/kg. The upper dose limit is set to 
25 mg/patient
mode 
of 
administration
iv bolus over 5-10 seconds
Comparator product
Actilyse®, alteplase (rt-PA)
dose
Total single dose will be 0.9 mg/kg. The upper dose limit is set to 90 
mg.
mode 
of
administration
10% of the total dose administered as an initial iv bolus and 
remaining 90% of the total dose administered as an iv infusion over 
1 h
Duration of treatment
Tenecteplase: single bolus over 5-10 seconds
Alteplase: single bolus immediately followed by 1 h infusion
Statistical methods
Non-inferiority between tenecteplase and alteplase will be declared
if the relevant confidence interval (CI) for risk ratio in mRS 0-1 
response rate at day 90 is within the predefined regions of (0.937, 
+∞).
Based on the log binominal regression model, the risk ratio with 
corresponding 95% CI adjusted for the continuous covariates of 


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NIHSS at baseline, age and time to drug administration will be 
calculated as the primary analysis.
After the demonstration of non-inferiority, the superiority between 
tenecteplase and alteplase will be declared in a hierarchical manner 
with overall type I error control if the relevant CI for risk ratio in 
mRS0-1 response rate at day 90 is within the predefined regions of 
(1, +∞). 
All safety data in this study will be descriptively summarised.


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FLOW CHART
Trial periods
Screening Randomisation
Follow up
EoS9
Visit
1
2a
2b
2c
3
4
5
10
6
10
EoS
≤4.5 h
D 1
1 h after 
start 
of 
admin
2 h after 
start 
of 
admin
D 2
24 h
D 8
7 d/ discharge 
date
30 d
90 d
Time window for visits
none
none
±15 min
±30 min
±2 h
±2 d
-2 d or 
+7 d
±7 d
Informed consent1
X
IRT
X
Demographics
X
Baseline conditions/
Medical history
X
Non-contrast CT
X2
X3
(X)4
(X)4
Physical exam 
X5
X
Vital signs
X
X
X
X
X
X
X12
X12
In-/Exclusion criteria
X
Trial drug admin
X
Lab test
X6
(X)7
X
(X)7
Pregnancy test
X8
(X)7
Concomitant therapy
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
NIHSS11
X
X
X
X
X
X
Glasgow outcome score
X
Modified Rankin Scale
X
(pre-
stroke)
X
X
Barthel Index
X
X
Admin, administration; CT, computed tomography; D, day; ECG, electrocardiograms; EoS, end of study; h, hour(s); IMP, investigational 
medicinal product; NIHSS, National Institute of Health Stroke Scale
1.
Informed consent needs to be signed before start of any procedure related to the study. In case subject cannot read the ICF by 
himself/herself, an impartial witness will be needed to attest the informed consent process. 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, to be considered by investigator).
2.
Non-contrast CT is mandatory before alteplase or tenecteplase administration to exclude intracranial haemorrhage (absolute 
contraindication) or mimic stroke (e.g. cerebral tumour) and to determine whether CT hypo-density of ischaemia is present. MRI is also 
acceptable.
Investigator could make decision whether or not an imaging performed outside the site could be used for evaluation of 
inclusion/exclusion criteria. This evaluation should also include time elapsed from imaging and possible changes in clinical symptoms 
since imaging.
3.
Non-contrast CT: between 22 and 36 h after starting the trial medication. MRI is also acceptable.
4.
Optional in case of clinical deterioration (as determined by investigator)
5.
Measurement of body weight and height is only required at screening visit. If it is hard to have an actual body weight/height due to 
certain reasons, an estimated body weight/height by investigator is acceptable.
6.
For lab results used for eligibility evaluation, only the result of random glucose (POCT) is mandatory before drug administration. 
Hematology lab results including coagulation items and platelet count are necessary before drug administration only when 


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anticoagulants are used or there is suspicion of coagulopathy (as determined by investigator). Drug administration should not be delayed 
by other lab results.
7.
Optional in case of clinical deterioration or clinical demand (as determined by investigator)
8.
For women who are considered of childbearing potential (WOCBP), a urine pregnancy test is required at screening or at earliest possible; 
the test result should not delay the drug administration.
9.
Trial completion: At the end of Visit 6 (D 90) for patients who will have completed the trial on treatment and completed V6 as planned 
10.
Remote visits will be acceptable based on especial conditions:
∀
It’s hard to perform the follow up on-site visit due to subject bad condition or other situations that on-site visit is restricted/not 
doable, determined by investigator.
∀
Under pandemic of Covid-19 that the follow-up visits to the sites should be replaced with remote visits, shall be align with local 
/site related governance. 
11.
The distal motor function will be assessed when NIHSS is scored
12.
The vital sign could be an optional item in case remote visit is performed.


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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...............................................................................................14
1.1
MEDICAL BACKGROUND.............................................................................14
1.2
DRUG PROFILE................................................................................................14
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................17
1.4
BENEFIT-RISK ASSESSMENT.......................................................................18
1.4.1
Benefits.................................................................................................................18
1.4.2
Risks .....................................................................................................................18
1.4.3
Discussion.............................................................................................................20
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........22
2.1.1
Main objectives....................................................................................................22
2.1.2
Primary endpoint................................................................................................22
2.1.3
Secondary endpoints...........................................................................................22
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................24
3.1
OVERALL TRIAL DESIGN.............................................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP...........................................................................................25
3.3
SELECTION OF TRIAL POPULATION .......................................................26
3.3.1
Main diagnosis for trial entry ............................................................................26
3.3.2
Inclusion criteria .................................................................................................26
3.3.3
Exclusion criteria ................................................................................................27
3.3.4
Withdrawal of patients from treatment or assessments..................................28
3.3.4.1
Discontinuation of trial treatment .........................................................................28
3.3.4.2
Withdrawal of consent to trial participation .........................................................28
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................29
4.
TREATMENTS...................................................................................................30
4.1
INVESTIGATIONAL TREATMENT..............................................................30
4.1.1
Identity of the investigational medicinal products...........................................30
4.1.2
Selection of doses in the trial and dose modifications......................................31
4.1.3
Method of assigning patients to treatment groups...........................................32
4.1.4
Drug assignment and administration of doses for each patient......................33


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4.1.5
Blinding and procedures for unblinding...........................................................33
4.1.6
Packaging, labelling, and re-supply...................................................................33
4.1.7
Storage conditions...............................................................................................33
4.1.8
Drug accountability.............................................................................................34
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................34
4.2.1
Other treatments and emergency procedures..................................................34
4.2.1.1
Recommendation of managing bleeding...............................................................34
4.2.1.2
Recommendation of managing hypersensitivity...................................................35
4.2.1.3
Recommendation of managing other adverse events............................................36
4.2.2
Restrictions ..........................................................................................................36
4.2.2.1
Restrictions regarding concomitant treatment ......................................................36
4.2.2.2
Restrictions on diet and lifestyle...........................................................................36
4.3
TREATMENT COMPLIANCE........................................................................36
5.
ASSESSMENTS..................................................................................................37
5.1
ASSESSMENT OF EFFICACY........................................................................37
5.2
ASSESSMENT OF SAFETY.............................................................................38
5.2.1
Cerebral imaging.................................................................................................38
5.2.2
Physical examination ..........................................................................................39
5.2.3
Vital signs.............................................................................................................39
5.2.4
Safety laboratory parameters ............................................................................39
5.2.5
Electrocardiogram ..............................................................................................41
5.2.6
Other safety parameters.....................................................................................41
5.2.7
Assessment of adverse events.............................................................................41
5.2.7.1
Definitions of adverse events................................................................................41
5.2.7.2
Adverse event collection and reporting ................................................................43
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................44
5.4
ASSESSMENT OF BIOMARKER...................................................................44
5.5
BIOBANKING ....................................................................................................44
5.6
OTHER ASSESSMENTS...................................................................................45
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................45
6.
INVESTIGATIONAL PLAN.............................................................................46
6.1
VISIT SCHEDULE.............................................................................................46
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................46
6.2.1
Screening period..................................................................................................46
6.2.2
Treatment period ................................................................................................46
6.2.3
Follow-up period and trial completion..............................................................47
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................48
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................48
7.2
PLANNED ANALYSES.....................................................................................49
7.2.1
General considerations .......................................................................................49


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7.2.2
Handling of intercurrent events.........................................................................50
7.2.3
Primary endpoint analyses.................................................................................51
7.2.4
Secondary endpoint analyses .............................................................................51
7.2.6
Safety analyses.....................................................................................................52
7.2.7
Interim Analyses .................................................................................................52
7.3
HANDLING OF MISSING DATA ...................................................................52
7.4
RANDOMISATION ...........................................................................................53
7.5
DETERMINATION OF SAMPLE SIZE .........................................................53
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........55
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................55
8.2
DATA QUALITY ASSURANCE ......................................................................56
8.3
RECORDS...........................................................................................................56
8.3.1
Source documents ...............................................................................................56
8.3.2
Direct access to source data and documents.....................................................57
8.3.3
Storage period of records ...................................................................................57
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................57
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........57
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................58
8.6
TRIAL MILESTONES.......................................................................................58
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................58
9.
REFERENCES....................................................................................................60
9.1
PUBLISHED REFERENCES............................................................................60
10.
APPENDICES.....................................................................................................63
10.1
COVID-19 RELATED CONTENTS.................................................................63
10.2
SCALES OF EFFICACY ASSESSMENT .......................................................64
10.2.1
Modified Rankin Scale, MRS.............................................................................64
10.2.2
Barthel index .......................................................................................................65
10.2.3
Glasgow Outcome Scale......................................................................................66
10.2.4
National Institutes of Health Stroke Scale, NIHSS..........................................67
11.
DESCRIPTION OF GLOBAL AMENDMENTS............................................69
11.1
GLOBAL AMENDMENT 1 ..............................................................................69
11.2
GLOBAL AMENDMENT 2 ..............................................................................73
11.3
GLOBAL AMENDMENT 3 ..............................................................................80


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse event of special interest
AHA
American Health Association
AIS
Acute ischaemic stroke
ALCOA
Attributable, legible, contemporaneous, original, accurate 
ALP
Alkaline phosphatase
ALT
Alanine transaminase
AMI
Acute myocardial infarction
aPTT
Activated partial thromboplastin time
ASA
American Stroke Association
AST
Aspartate aminotransferase
BI
Boehringer Ingelheim
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CK
Creatine kinase
CRA
Clinical research associate
CRO
Contract research organisation
CT
Computed tomography
CTP
Clinical trial protocol
DBL
Database lock
DMC
Data Monitoring Committee
EAC
Endpoint Adjudication Committee
ECASS
European Cooperative Acute Stroke Study
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EMA
European Medical Agency
EoS
End of study
ES
Enrolled set


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ESMINT
European Society for Minimally Invasive Neurological Therapy
ESO
European Stroke Organisation
FAS
Full analysis set
FDA
Food and Drug Administration
GCP
Good clinical practice
GGT
Gamma-glutamyl transferase
GD
Gestational days
GMP
Good manufacturing practice
h
Hour(s)
HA
Health authority
Hb
Haemoglobin
HCT
Haematocrit
IB
Investigator’s brochure
ICE
Intercurrent Events
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
INR
International normalised Ratio
IRB
Institutional Review Board
IRT
Interactive response technology
ISF
Investigator site file
iv
Intravenous
LDH
Lactate dehydrogenase
LOCF
Last observation carried forward
LPLT
Last patient last treatment
MedDRA
Medical Dictionary for Drug Regulatory Activities
min
Minute(s)
m
Month(s)
MRI
Magnetic resonance imaging
mRS
modified Rankin Scale
NIHSS
National Institutes of Health Stroke Scale
OPU
Operative unit


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PAI-1
Plasminogen activator inhibitor 1
PK
Pharmacokinetic
POCT
Point-of-care testing 
PPS
Per-protocol set
PROBE
Prospective, randomised, open label, blinded endpoint
PT
Preferred term
PT
Prothrombin time
RA
Regulatory authority
RBC
Red blood cell
rt-PA
Recombinant tissue plasminogen activator
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
sICH
Symptomatic intracranial haemorrhage
SITS-MOST
Safety Implementation of Thrombolysis in Stroke: Monitoring Study
SS
Safety set
SOC
System organ class
SOP
STEMI
Standard operating procedure
ST Elevation Myocardial Infarction
t1/2
Half-life
t-PA
Tissue plasminogen activator
TSAP
Trial statistical analysis plan
vs
Versus
W
Week
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Stroke is one of the leading causes of death and disability worldwide. In 2016, stroke was the 
second leading cause of death globally (5.5 million deaths) and there were 13.7 million new 
stroke cases reported [R20-0900]. For more than a decade, stroke has been the leading cause 
of death in the Chinese population, responsible for an average of 1.96 million deaths/year [R19-
3903] of which acute ischaemic stroke (AIS) accounts for 80% of the cases. As the highest 
single-disease disability rate, AIS brings enormous economic and social burden to the country 
[P19-03580] which further increases with the aging Chinese population. 
Intravenous (iv) thrombolysis is of proven benefit for treatment of patients with AIS within 4.5 
hours (h) of symptom onset, and alteplase is currently the standard of care for this indication. 
Alteplase has a short half-life (t1/2) which requires a 60-minute (min) infusion.
Tenecteplase is a genetically engineered variant of alteplase. Tenecteplase is currently 
approved to treat acute myocardial infarction (AMI) in more than 90 countries around the world. 
Tenecteplase for AMI indication was approved in the United States in 2000 and in the European 
Union in 2001. 
Tenecteplase is a promising thrombolytic agent for AIS. There is no completed registration 
study of tenecteplase in AIS worldwide. Several phase II and III studies initiated by 
investigators provided information on the efficacy and safety in patients with AIS. Additionally, 
the 2018 American Heart Association/American Stroke Association (AHA/ASA) Guidelines 
for the Early Management of Patients with AIS and 2018 China Guidelines for the Diagnosis 
and Treatment of AIS recommended that tenecteplase could be considered as an alternative to 
alteplase in selected AIS patients with minor neurological impairment and no major intracranial 
occlusion (Grade II recommendation, Grade B evidence) [P19-03892, P19-10855]. The 2019
European Stroke Organisation (ESO) - European Society for Minimally Invasive Neurological 
Therapy (ESMINT) guideline stated, “In large vessel occlusion-related ischaemic stroke 
patients eligible for iv thrombolysis before mechanical thrombectomy, 7 out of 11 experts 
suggest the use of tenecteplase (0.25 mg/kg) over alteplase (0.9 mg/kg), if the decision on iv
thrombolysis is made after vessel occlusion status is known.” [P19-02504].
1.2
DRUG PROFILE
Mode of action
Tissue plasminogen activator (t-PA) is a serine protease which is pharmacologically classified 
as a thrombolytic enzyme. It converts plasminogen into plasmin, a circulating plasma protein 
that binds to and digests the solid-phase fibrin component of a thrombus, and thereby restores 
the vessel patency. The digestion of fibrin, or fibrinolysis, is regulated by the inhibitors α2-
antiplasmin and plasminogen activator inhibitor 1 (PAI-1). 




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REP is pharmacologically set to 7 days since symptoms of internal bleeds such as ICH may be 
delayed post lysis. 
Data from non-clinical studies
Single-dose toxicology studies of tenecteplase were conducted in rats, rabbits and dogs with 
no unexpected toxicities identified. In general, tenecteplase was well tolerated with findings 
mainly restricted to the expected pharmacologic effects on the blood coagulation system and 
related sequelae. Daily iv doses of tenecteplase of 0.5, 1.5, or 5 mg/kg/day did not impact 
reproductive success when administered to rabbits during gestational days (GDs) 6-10. 
However, maternal mortality was observed in nearly all rabbits at all doses tested when 
administered during GDs 11-14 or 15-18.
In sub-chronic toxicity studies of alteplase 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 iv infusion of pharmacologically 
effective doses. In rabbits, embryotoxicity (embryolethality, growth retardation) was induced 
by >3 mg/kg/day. No effects on peri-postnatal development or on fertility parameters were 
observed in rats with doses up to 10 mg/kg/day.
Data from clinical studies
Alteplase
To date, alteplase is still the only licensed thrombolytic agent for AIS; a dose of 0.9 mg/kg is 
administered starting with an iv bolus of 10% of dose, immediately followed by iv infusion of 
the remaining of the dose over 60 min, maximum 90 mg, to thrombolysis eligible patients. The 
iv alteplase is proven clinical benefit for patients with AIS within 4.5 h of the onset of 
symptoms. In China, alteplase was approved for the treatment of AIS up to 3 h after onset,
extended to within 4.5 h of the onset of symptoms on November 2019.
Tenecteplase
No prior Genentech/BI sponsored study of tenecteplase has been completed in AIS. 
A meta-analysis of head-to-head trials between tenecteplase and alteplase in AIS was 
conducted [P19-06342]. A total of 5 trials enrolling 1585 patients (828 tenecteplase and 757 
alteplase) included in the systematic analysis. For the primary endpoint, crude cumulative rates 
of disability-free (mRS score 0-1) at 3 months (m) were tenecteplase 57.9% vs alteplase 55.4%. 
The risk difference between the tenecteplase group and the alteplase group was 4% 
(95% CI -1%, 8%, 5 trials, n=1585). For the secondary efficacy endpoints, the rate of functional 
independence (mRS 0-2) at 3 months was 71.9% after tenecteplase and 70.5% after alteplase
with a risk difference of 8% (95% CI -4%, 20%; 4 trials, n=1473). For safety endpoints, 
mortality and sICH rates did not differ between tenecteplase and alteplase.


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For a more detailed description of the tenecteplase, please refer to the current investigator’s 
brochure (IB) [c30996666], and for alteplase, besides the IB [U12-2040], the approved patient 
information leaflet by National Medical Product Administration.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Ischaemic stroke is a major public health problem in the world. In China, stroke has become 
the leading fatal disease, with ischaemic stroke being the dominant type. Globally, the burden 
of stroke is still increasing. Stroke-care quality improvement should be a continuous effort. 
Intravenous thrombolysis is of proven benefit for treatment of patients with AIS within 4.5 h
of symptom onset, and alteplase is currently the standard of care for this indication. Alteplase 
has a short t1/2 which requires a 60-min infusion. 
Tenecteplase is a genetically engineered variant of alteplase. Owing to its longer t1/2, it can be 
administered as a single iv bolus, which is more convenient compared to bolus immediately 
followed by infusion. Additionally, tenecteplase demonstrates 10-14 times greater fibrin-
specificity than alteplase, which means that more fibrinogen will be available in human body 
and this potentially leads to lower risk of bleeding. The use of tenecteplase has been approved 
for the treatment of ST-elevation myocardial infarction (STEMI) in more than ninety countries. 
It has shown clinical equivalence and fewer systemic bleeding complications compared with
alteplase in STEMI patients [P99-02520].
Tenecteplase is a promising thrombolytic agent for AIS due to its modified pharmacodynamics 
properties. In recent years, several phase II and phase III trials have investigated the efficacy 
and safety of tenecteplase for the treatment of AIS [P12-03304, P18-01526].  In 2019, a meta-
analysis of 5 randomised trials was published, including 1585 patients in total
(828 
tenecteplase, 757 alteplase) [P19-06342]. It showed that the 3-m mRS 0-1 was 57.9% in the 
tenecteplase group, and 55.4% in the alteplase group, with a relative rate difference of 4% 
(95% CI -1%, 8%). In terms of safety endpoints, this meta-analysis concluded that tenecteplase
and alteplase demonstrated a risk difference of 0% in sICH (95% CI -1%, 2%) and 3-m
mortality (95% CI -3%, 2%).
The findings from the accumulated clinical trial data provide support for recent guidelines and 
recommendations. Both 2018 AHA/ASA Guidelines for the Early Management of Patients 
with AIS and 2018 China Guidelines for the Diagnosis and Treatment of AIS recommended
that tenecteplase could be considered as an alternative to alteplase in selected patients with AIS 
with minor neurological impairment and no major intracranial occlusion (Grade II 
recommendation, Grade B evidence) [P19-03892, P19-10855]. The 2019 EU ESO ESMINT 
guideline states, “In large vessel occlusion-related ischaemic stroke patients eligible for iv
thrombolysis before mechanical thrombectomy, 7 out of 11 experts suggest the use of 
tenecteplase (0.25 mg/kg) over alteplase (0.9 mg/kg), if the decision on iv thrombolysis is made 
after vessel occlusion status is known.” [P19-02504].
Although there are accumulating emerging evidence supporting the use of tenecteplase in AIS 
patients, these data are based on trials conducted in the western population. Based on the 
current available data and guidelines, this phase III study aims to demonstrate that tenecteplase 
0.25 mg/kg is non-inferior to alteplase 0.9 mg/kg for thrombolysis in AIS patients in the 


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Chinese population. The efficacy and safety results of this study will be used to register the use 
of tenecteplase to provide more treatment options for AIS patients in China.
1.4
BENEFIT-RISK ASSESSMENT
1.4.1
Benefits
Stroke-care quality improvement should be a continuous effort. This study aims to improve 
stroke-care quality by providing an alternative treatment that is at least as efficacious as the 
existing treatment that is potentially safer, and easy to administer.
Like alteplase, iv thrombolysis with tenecteplase aims at saving the ischaemic brain tissue by 
restoring blood circulation, thus reducing disability rate and potentially saving lives. A meta-
analysis of five studies have shown that tenecteplase demonstrated non-inferior efficacy 
compared with alteplase in treating AIS [P19-06342]. Additionally, tenecteplase offers the 
following potential advantages over alteplase: 
•
Longer t1/2 as demonstrated by a 4-fold slower plasma clearance compared to alteplase 
[P00-02456]. This allows tenecteplase to be administered as a single iv bolus instead of the 
traditional bolus followed by 90-min iv infusion of alteplase for the treatment of AIS
•
Higher resistance to naturally occurring PAI-1, allowing for higher initial plasma 
concentration and enabling faster restoration of vessel patency [P03-02906]
•
Evidence of faster vascular recanalization as demonstrated by several studies [P12-03304, 
P15-11262], which is correlated to excellent functional outcome
1.4.2
Risks
Table 1.4.2: 1 Summarises of the tenecteplase related risks.


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Table 1.4.2: 1
Potential clinically important risks of tenecteplase, their rationale, and 
mitigation strategies  
Possible 
or 
known risks of 
clinical 
relevance 
Summary 
of 
data, 
rationale for the risk 
Mitigation strategy 
Bleeding
During clinical trials for 
AIS, the most common 
adverse 
reaction 
associated 
with 
tenecteplase is bleeding.
The most severe bleeding 
is sICH.
A number of safety measures are defined to minimise the 
risk of sICH during this trial:
•
Patients with AIS will be excluded in the following 
situations because of increased haemorrhagic risk:
o
Known genetic predisposition to bleeding or 
significant bleeding disorder at present or within 
the past 6 m
o
Platelet count of below 100,000/mm3 at screening
o
Any history of central nervous system damage 
(i.e. neoplasm, aneurysm, intracranial or spinal 
surgery)
o
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)
o
Known 
history 
of 
suspected 
intracranial 
haemorrhage 
or 
suspected 
subarachnoid 
haemorrhage from aneurysm
o
Neoplasm with increased haemorrhagic risk
o
Documented ulcerative gastrointestinal disease 
during the last 3 m, oesophageal varices, arterial-
aneurysm, arterial/venous malformations
o
Any known disorder associated with a significant 
increased risk of bleeding
•
Clear guidance on the restricted concomitant 
medications such as heparin and anticoagulants
•
Tenecteplase 0.25 mg/kg selected in this trial has been 
supported by a number of completed studies, showing 
no increase in the risk of sICH compared to alteplase
•
Extensive safety monitoring processes will be put in 
place, including the setup of the Endpoint 
Adjudication Committee (EAC) and an independent 
DMC.
Hypersensitivit
y, 
including 
urticarial/anaph
ylactic 
reactions/
angioedema
Rare 
(<1%) 
after 
administration 
of 
tenecteplase 
(e.g., 
anaphylaxis, 
angioedema, 
laryngeal 
edema, 
rash, 
and 
urticaria)
Monitor patients treated with tenecteplase during and for 
several 
hours 
after 
infusion. 
If 
symptoms 
of 
hypersensitivity occur, appropriate therapy should be 
initiated.


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Thrombolytic therapy is associated with a risk of bleeding, which applies for both tenecteplase 
and alteplase as well. The major risk remains sICH. Although the presence of oedema or mass 
effect on baseline CT scan is associated with higher risk of sICH, patients with these findings 
are more likely to have an excellent outcome if they received thrombolytic therapy [P97-
10211]. 
Overall risks of alteplase are similar to those of tenecteplase. According to the local approved 
label dated at 15 Nov 2019, the most frequent adverse reaction associated with alteplase is 
bleeding. Hypersensitivity/anaphylactoid reactions (e.g. allergic reactions including rash, 
urticaria, bronchospasm, angio-oedema, hypotension, shock or any other symptom associated 
with hypersensitivity) are rarely reported. Serious anaphylaxis is very rarely observed. 
In addition to the above mitigation strategies, extensive safety monitoring processes will be put 
in place, including the setup of an independent DMC. The DMC assesses the progress of the 
clinical trial and evaluates the data regularly in order to provide recommendation whether the 
trial should continue as planned, continue with modification, stop, or discussed with the 
sponsor. In addition, the evaluation and adjudication of all potential sICH events in a blind 
fashion will be a critical objective to be performed by DMC. Detailed information of DMC is 
available at Section 8.7.
Given the narrow time windows of treatment of AIS, timely emergency department (ED) 
evaluation and diagnosis is of utmost significance. As such, investigational sites are selected 
based on their ability to receive, identify, evaluate, treat, and/or refer patients with suspected 
stroke, as well as obtain access to stroke expertise when necessary for diagnostic or treatment 
purposes. All centers should be able to offer 24/7 (24 h/day, 7 days/week) comprehensive 
stroke care to acute stroke patients. The hospitals must be stroke ready centers with sufficient 
capability of efficiently evaluate, diagnose, and treat acute stroke. Besides key principles, 
guideline and procedures for site selection of clinical trials, the centers should fulfil below 
elements:
•
Ability to administer iv tenecteplase and alteplase
•
Ability to perform emergency brain imaging (e.g. CT) at all times 
•
Ability to conduct emergency laboratory testing at all times
•
Availability of a system for the maintenance of stroke patient notes
In addition to the above, to minimise the risk and protect the safety of the subjects, all trial sites 
will be monitored closely and investigators will receive trainings, clear and timely updated 
supporting materials, and be notified of the availability of safety reports related to the product. 
1.4.3
Discussion
The 2019 AHA/ASA AIS guideline point out that tenecteplase is a reasonable choice over 
alteplase in patients who are eligible for iv thrombolysis and mechanical thrombectomy, and 
2018 China AIS guideline recognise tenecteplase as an alternative to alteplase. Additionally, a


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meta-analysis of five studies has shown that tenecteplase demonstrated non-inferior efficacy 
compared to alteplase in treating AIS [P19-06342].
Some PK/PD advantages of tenecteplase over alteplase include higher fibrin specificity, 
reduced binding to the physiological PAI-1 and prolonged plasma t1/2 enabling single bolus 
administration. 
The major risk of all thrombolytic therapy remains sICH. In this trial, AIS patients will receive 
either the standard of care, alteplase, or the investigational product, tenecteplase, both of which 
have a similar risk profile for sICH. The greater fibrin specificity of tenecteplase mentioned 
above suggests that it potentially has a lower risk of sICH for patients who are assigned to this 
treatment.
Alteplase is the current standard of care for thrombolysis in AIS patients. This Phase III trial 
aims to determine whether tenecteplase is non-inferior to the current standard care alteplase in 
Chinese patients with AIS within 4.5 h after symptom onset. This study will provide evidence 
and formal support to consider tenecteplase as an alternative agent to alteplase in the treatment 
of AIS.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The primary objective is to assess whether tenecteplase is non-inferior to alteplase in 
favourable outcome, i.e., modified Rankin scale achieving 0 or 1 (mRS 0 or 1) in Chinese 
patients with AIS who are eligible for iv thrombolysis within 4.5 h of symptom onset.
The secondary objectives are to assess (1) whether it is safe to use tenecteplase in patients in 
this setting as well as (2) the efficacy in other key functional outcomes. 
2.1.2
Primary endpoint
The primary efficacy endpoint is a mRS score of 0 or 1 at day 90.
2.1.3
Secondary endpoints
Secondary efficacy endpoints are defined as:
•
Major neurological improvement at 24 h (NIHSS score of 0 or improvement of at least 
4 points compared with baseline)
•
mRS score of 0-2 at day 90
•
Change from baseline of NIHSS score at day 90
•
Distribution of mRS at day 90
•
Barthel Index score ≥95 at day 90
Secondary safety endpoints are defined as:
•
Symptomatic Intracerebral Haemorrhage (sICH1) per ECASS Ⅲdefinition during on-
treatment period.
•
90-day mortality 
•
mRS score of 5 or 6 at day 90


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This trial is a multi-centre, prospective, randomised, open label, blinded endpoint (PROBE), 
active-controlled parallel group phase III trial to compare the efficacy and safety of 
tenecteplase 0.25 mg/kg vs alteplase 0.9 mg/kg in Chinese patients with AIS within 4.5 h after 
symptom onset.
A total of approximately 1478 eligible AIS patients will be randomised into either the treatment 
group of tenecteplase or alteplase at 1:1 ratio stratified by NIHSS score at baseline (<6; 6-
15; >15), and age (≤80, >80). Screening (Visit 1) will start when patients are admitted. 
Randomisation (Visit 2a) and administration of investigational medicinal products (IMPs)
should be no later than 4.5 h after symptom onset. Visits on day 1 consist of two further visits 
(Visit 2b and Visit 2c) that will be performed 1 h and 2 h after the start of IMPs. Visit 3-5 for 
continuous follow-up will be performed on day 2, 8 and 30 after the start of IMPs. The primary 
efficacy endpoint will be assessed at Visit 6 (day 90). End of study (EoS) is defined as that the 
randomised patient completes 90-day follow-up visit after the treatment.
Figure 3.1:1 Study design


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
Study design
This trial is designed to be a PROBE, active-controlled parallel group trial. EAC will be set for 
independent judgement of all sICH events described per protocol that occurred during the trial;
independent DMC will be set for safety monitor of critical safety events, e.g., sICH, death, etc.
For details, see Section 8.7.
Active-controlled and non-inferiority
Alteplase is the current standard of care for thrombolysis in eligible AIS patients within 4.5 h, 
and therefore it is chosen as the active control in this trial. Considering that there is a proven 
effective treatment, use of placebo in this case is ethically not acceptable. The objective of the 
trial is to prove that tenecteplase is non-inferior to the current standard of care in its efficacy. 
With its obvious advantage in convenience, tenecteplase, with similar or even better safety 
profile than alteplase [P12-03304, P18-01526], is expected to add value to AIS patients.
Open label
Although the double-blind design is considered optimal for phase III randomised trials, the 
double-blind and double-dummy drug administration are not considered in this trial as it will 
significantly increase the complexity of the procedure in the very urgent medical situation. 
Additionally, double-dummy designs are limited by ethical issues for AIS patients. Though the 
treatment information is available to patients and investigators, the reviewer who is responsible 
for assessing the primary efficacy endpoint must be blinded to treatment. In addition, the BI 
analysis and data cleaning team will not have access to the treatment information during the 
trial conduct phase in order to reduce the risk of bias affecting the cleaning and planning for 
analysis of the data.
Study population
The trial will include patients with AIS, who are ≥18 years of age and are eligible for standard 
iv thrombolysis therapy within 4.5 h of stroke onset. The trial population is selected based on
the current alteplase label. In addition, there are recent evidences supporting the use of iv
thrombolysis in patients aged over 80 years [P10-14128, P10-12678, P20-06029]: a pooled 
analysis of randomised trial and registry data evaluated the benefit-risk profile of alteplase for 
AIS among elderly patients (>80 years) [P20-06029]. Among patients aged >80 years, alteplase 
vs placebo was associated with a higher proportion of good stroke outcome (mRS 0-1:19.1% 
vs 13.1%, p=0.0109) and similar 90-day mortality (29.5% vs 30.2%, p=0.8382). The odds of a 
good stroke outcome following alteplase allocation were independent of age (p=0.7383). In 
conclusion, alteplase for AIS has a positive benefit-risk profile among patients aged >80 years. 
Therefore, the patients with age ≥18 years without upper age limit will be enrolled in this trial.
This is aligned with current international guidelines [P19-03892, P19-10385].


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Interim analysis
No interim analysis is planned in this trial. Futility interim is usually considered when there is 
high uncertainty on the treatment difference between two treatment arms. As all the available 
data indicate that tenecteplase is not worse than alteplase [P19-06342], the potential value of 
the futility interim is quite limited.
3.3
SELECTION OF TRIAL POPULATION
A total of approximately 1478 patients are planned to be randomised at approximately 55 sites 
in China.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all sites 
at the same time once a sufficient number of patients has been screened. Investigators will be 
notified about screening completion and will then not be allowed to screen additional patients 
for this trial.
A log of all patients enrolled into the trial at the site (i.e. who have signed informed consent
forms) will be maintained in the investigator site file (ISF) at the investigational site 
irrespective of whether they have been treated with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
3.3.1
Main diagnosis for trial entry
Patients who are clinically suspected of acute ischaemic stroke within 4.5 h after symptoms
onset will be assessed for thrombolytic treatment eligibility after CT scan of the brain.
Please refer to Section 8.3.1 for the documentation requirements pertaining to the in- and 
exclusion criteria.
3.3.2
Inclusion criteria
1. Age ≥18 years old
2. Diagnosis of ischaemic stroke with a measurable neurological deficit on NIHSS
(0< NIHSS ≤25); if NIHSS <4, patients have to be with at least a measurable deficit on 
motor power (upper or lower limbs ≥1)
3. Stroke symptoms should have been present for at least 30 min without significant 
improvement prior to randomisation
4. Thrombolytic therapy can be initiated within 4.5 h of AIS onset
5. Patients with premorbid mRS 0 or 1
6. Signed and dated written informed consent in accordance with good clinical practice (GCP)
and local legislation prior to trial admission


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3.3.3
Exclusion criteria
1. Evidence of intracranial haemorrhage on the CT scan or symptoms suggestive of 
subarachnoid haemorrhage, even if the CT scan is normal
2. Patients who must or are expected to continue the intake of restricted medications or any 
drug considered likely to interfere with the safe conduct of the trial
3. Acute bleeding diathesis, including but not limited to
1) Known genetic predisposition to bleeding or significant bleeding disorder at present or 
within the past 6 m
2) Administration of heparin within the previous 48 h and activated partial thromboplastin 
time (aPTT) exceeding the upper limit of normal for laboratory measurement
3) Current use of vitamin K based oral anticoagulants (e.g. warfarin) and a prolonged 
prothrombin time (INR >1.7 or PT >15 s) or current use of novel oral anticoagulants 
(i.e. dabigitran, rivaroxiban, or apixiban) with prolongation of aPTT and/or PT above 
the upper limit of the local laboratory reference range
4) Platelet count of below 100,000/mm3 at screening
5) Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial 
or spinal surgery)
6) Recent traumatic external heart massage, obstetrical delivery, or recent puncture of a 
non-compressive blood-vessel (e.g. subclavian or jugular vein puncture), within the 
past 10 days
7) Known history of suspected intracranial haemorrhage or suspected subarachnoid 
haemorrhage from aneurysm
8) Neoplasm with increased haemorrhagic risk
9) Documented ulcerative gastrointestinal disease during the last 3 m, oesophageal 
varices, arterial aneurysm, or arterial/venous malformations
10) Any known disorder associated with a significant increased risk of bleeding
4. Bacterial endocarditis or pericarditis at screening
5. Acute pancreatitis at screening
6. Significant trauma or major surgery (according to the investigator’s assessment) in the past 
3 m
7. Imaging demonstrates multi-lobar infarction (hypodensity >1/3 cerebral hemisphere)
8. Severe uncontrolled arterial hypertension, e.g. systolic blood pressure (BP) >185 mmHg or 
diastolic BP >110 mmHg
9. Blood glucose <50 mg/dL (2.8 mmol/L) at screening
10. Seizure at stroke onset
11. Known hypersensitivity to active substance alteplase or tenecteplase, gentamicin (a trace 
residue from the manufacturing process) or to any of the excipients.


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12. Currently enrolled in another investigational device or drug study, or <30 days since ending 
another investigational device or drug study(s), or receiving other investigational 
treatment(s) 
13. Women who are pregnant
14. Patient has a confirmed active infection with SARS-CoV-2 in medical history within the 
prior 3 m, based on which investigator considers likely to interfere with the safe conduct or
the trial evaluation, procedures, or completion 
15. Any other conditions that, in the opinion of the investigator or BI physician, if consulted, 
would pose a risk to subject safety or interfere with the trial evaluation, procedures or 
completion
3.3.4
Withdrawal of patients from treatment or assessments
Subjects may discontinue trial treatment or withdraw from trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and
3.3.4.2.
For this trial, there’s only one IMP administration, and no benefit could be expected to the 
subject withdrawing from the trial for possible reasons. Every effort should be made to keep 
the subjects in the trial, at least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and eCRF. If applicable, consider the 
requirements for AE collection reporting (please see Sections 5.2.7.2.1 and 5.2.7.2).
3.3.4.1
Discontinuation of trial treatment
If a subject is randomised but not administrated study drug due to any reason, it will be 
identified as discontinuation of trial treatment. The discontinuation of trial treatment will be 
documented, and the reason should be noted in source.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to justify 
the decision. In case of a subject elect to withdraw from consent after IMP administration, 
his/her vital/functional status at 90-day will still be collected and used for trial analysis if 
possible, which will be specified in ICF.
For all subjects the date and the reason for withdrawal should be recorded in the eCRF. These 
data will be included in the trial database and reported.
In case vital status is not yet available at Visit 6 (90-day), the follow up should be conducted 
as early as possible but within last patient last visit, and every effort should be made to obtain 
the patient vital status.


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3.3.4.3
Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
the following reasons:
•
Failure to meet expected enrolment goals overall or at a particular trial site
•
New efficacy or safety information invalidating the earlier positive benefit-risk-assessment, 
please see Section 3.3.4.1
•
Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial
Further follow up of patients affected will occur as described in Section 3.3.4.2.
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
4.1
INVESTIGATIONAL TREATMENT
4.1.1
Identity of the investigational medicinal products
Table 4.1.1:1
Test product 1: tenecteplase
Substance:
tenecteplase (TNK-tPA)
Metalyse®
Pharmaceutical formulation:
Powder and solvent for solution for injection
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
1 vial contains 40 mg tenecteplase;
1 pre-filled syringe contains 8 mL solvent (water for 
injection)
Posology:
The reconstituted solution contains 5 mg tenecteplase/mL
Single dose bolus
Mode of administration:
iv bolus over 5-10 seconds (s)
Table 4.1.1: 2
Test product 2: alteplase
Substance:
alteplase (rt-PA)
Actilyse®
Pharmaceutical formulation:
Powder and solvent for solution for injection and infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
1 vial contains 50 mg alteplase
1 vial contains 50 mL solvent (water for injection)
Posology
The reconstituted solution contains 1 mg alteplase/mL
Single dose bolus plus 1 h infusion
Mode of administration:
10% of the total dose administered as an initial iv bolus and 
remaining 90% of the total dose administered as an iv
infusion over 1 h
For detail instructions for tenecteplase using information, please refer to ISF.
The package insert of commercial product Actilyse® can be taken as the reconstitution and 
administration instruction for alteplase. Details please refer to the package insert of Actilyse®
archived in ISF.


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4.1.2
Selection of doses in the trial and dose modifications
The dose of both alteplase and tenecteplase is body weight adjusted; therefore, investigators 
will try their best to assess the actual body weight of the patient. If it is not possible to have an 
actual body weight due to any reasons, an estimated body weight by the study nurse is 
acceptable.
Alteplase will be administered as a total single dose of 0.9 mg/kg. The upper dose limit is set 
to 90 mg. Ten percent of the total dose will be administered as a bolus. The remaining 90% of 
the dose will be given by continuous iv infusion over 60 min. The alteplase dose is consistent 
with the locally approved label for AIS treatment.
Tenecteplase will be administered as a total single dose of 0.25 mg/kg. The upper total dose 
limit is set to 25 mg. The total dose will be administered as a bolus over 5-10 seconds. 
The tenecteplase dose is based on the previous studies [P19-02504, P12-03304, P18-01526]
which have demonstrated the safety and efficacy of tenecteplase 0.25 mg/kg.
The meta-analysis of five randomised trials published in 2019 [P19-06342] included 
1585 patients in total (828 in tenecteplase group, 757 in alteplase group). The proportion of 
patients in tenecteplase group at the concentration of 0.1 mg/kg, 0.25 mg/kg, and 0.4 mg/kg 
were 6.8%, 24.6%, and 68.6%, respectively. Compared with alteplase 0.9 mg/kg, tenecteplase 
0.25 mg/kg and 0.4 mg/kg groups showed equivalent efficacy in primary outcome (90-day 
mRS 0-1), and the point estimation value of tenecteplase 0.25 mg/kg was even at the further 
right side of the forest plot, which suggested better efficacy (although statistically non-
significant). See Figure 4.1.2: 1 below.


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Figure 4.1.2: 1
Comparison of primary outcome between tenecteplase at different doses 
and alteplase forest plot without disability (mRS 0-1)
Compared with alteplase 0.9 mg/kg, the point estimate of tenecteplase 0.25 mg/kg showed a 
trend of lower incidence of sICH and death. The risk difference of sICH is 0% for tenecteplase 
0.25 mg/kg compared to alteplase 0.9 mg/kg (95% CI -3%, 2%). The risk difference of 90-day 
mortality is -5% for tenecteplase 0.25 mg/kg compared to alteplase 0.9 mg/kg (95% CI -12%, 
2%).
The EXTEND-IA TNK Part 2 study published in 2020 showed a dose of 0.40 mg/kg, compared 
with 0.25 mg/kg of tenecteplase did not significantly improve cerebral reperfusion prior to 
endovascular thrombectomy in patients with large vessel occlusion ischaemic stroke, and 
provided further evidence to suggest that 0.25 mg/kg of tenecteplase may be an appropriate 
dose for ischaemic stroke [P20-01928].
4.1.3
Method of assigning patients to treatment groups
An Interactive Response Technology (IRT) will be used to screen eligible patients, perform 
drug assignment and manage initial/re-supply ordering of drug supplies. The investigator will 
receive all necessary instructions to access the IRT from the Sponsor. Detailed IRT functions 
and procedures will be documented in the user requirement specifications mutually agreed to 
by the sponsor and the IRT vendor.


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After the patient’s eligibility has been confirmed, the treatment will be assigned via IRT at 
Visit 2a. Patients will be randomised to receive tenecteplase or alteplase in a ratio of 1:1 within 
each stratum, which is stratified by NIHSS score at baseline (<6; 6-15; >15) and age (≤80, 
>80). The assignment will occur in an open label fashion via IRT.
Medication numbers will be assigned by IRT at randomization and will be entered in the eCRF. 
4.1.4
Drug assignment and administration of doses for each patient
Following the screening period, patients who qualify according to entry criteria will be
randomised to one of the two treatment groups.
The patients will receive either iv alteplase (at the standard licensed dose of 0.9 mg/kg up to a 
maximum of 90 mg, 10% as bolus and the remainder over 1 h) or iv tenecteplase (0.25 mg/kg, 
maximum 25 mg, administered as a bolus over 5-10 seconds). Alteplase and tenecteplase will be 
given as a single dose. The trial medications will be administered as iv bolus (tenecteplase) or 
iv bolus immediately followed by iv infusion (alteplase) by authorised study personnel.
4.1.5
Blinding and procedures for unblinding
The double-blind design and double-dummy designs are not applicable in the trial. Though the 
treatment information is available to patients and investigators, the reviewer who is responsible 
for assessing the primary efficacy endpoint, i.e. an mRS score of 0 or 1 must be blinded to 
treatment. Please refer to Section 3.2. In addition, the BI analysis and data cleaning team will 
not have access to the treatment information during the trial conduct phase in order to reduce 
the risk of bias affecting the cleaning and planning for analysis of the data.
4.1.6
Packaging, labelling, and re-supply
The IMPs will be provided by BI or a designated contract research organization (CRO). They 
will be packaged and labelled in accordance with the principles of good manufacturing practice 
(GMP). Re-supply to the sites will be managed via an IRT system, which will also monitor 
expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
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. A temperature 
log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research
Associate (CRA) or the Clinical Trial Manager, as provided in the list of contacts, must be 
contacted immediately.
If the storage conditions are found to be outside the specified range, the process outlined in the 
ISF should be followed.


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4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:
•
Approval of the clinical trial protocol (CTP) by the Institutional Review Board (IRB)/
Independent Ethics Committee (IEC)
•
Availability of a signed and dated trial contract between the sponsor and the investigational 
site
•
Approval/notification of the regulatory authority (RA), e.g. competent authority (CA)
•
Availability of the curriculum vitae of the Principal Investigator
•
Availability of a signed and dated CTP
•
Availability of the proof of a medical license for the Principal Investigator
Investigational drugs are not allowed to be used outside the context of this protocol. They must
not be forwarded to other investigators or clinics. 
The investigator or designee 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 to the sponsor or warehouse/drug 
distribution centre or alternative disposal of unused products. If applicable, the sponsor or 
warehouse/drug distribution centre 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 IMP and trial patients. The investigator or designee
will maintain records that document adequately that the patients were provided the doses 
specified by the CTP and reconcile all IMPs received from the sponsor. At the time of return 
to the sponsor or appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned and that no remaining supplies are in the 
investigator’s possession.
For overall drug accountability process of medication, please refer to Medication Handling 
Instruction which will be provided in ISF.
4.2
OTHER
TREATMENTS, 
EMERGENCY
PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. However, potential side effects of 
tenecteplase and alteplase were to be treated symptomatically.
4.2.1.1
Recommendation of managing bleeding
The most common complication encountered during tenecteplase and alteplase therapy is 
bleeding. The type of bleeding associated with thrombolytic therapy can be divided into two 
broad categories:


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•
Internal bleeding, involving intracranial and retroperitoneal sites, or the gastrointestinal, 
genitourinary, or respiratory tracts.
•
Superficial or surface bleeding, observed mainly at vascular puncture and access sites (e.g., 
venous cutdowns, arterial punctures) or sites of recent surgical intervention.
Standard management of AIS should be implemented concomitantly with tenecteplase/
alteplase treatment. Arterial and venous punctures should be minimized. Noncompressible 
arterial puncture must be avoided, and internal jugular and subclavian venous punctures should
be avoided to minimize bleeding from the noncompressible sites. 
Should serious bleeding occur, especially cerebral haemorrhage, concomitant heparin 
administration should be terminated 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 1g/l is desirable with cryoprecipitate infusion. Antifibrinolytic agents 
are available as a last alternative. Should an arterial puncture be necessary during the first few 
hours following tenecteplase or alteplase therapy, the use of an upper extremity vessel that is 
accessible to manual compression is preferable. Pressure should be applied for at least 30 min, 
a pressure dressing applied, and the puncture site checked frequently for evidence of bleeding.
Each patient being considered for therapy with tenecteplase and alteplase should be carefully 
evaluated and anticipated benefits weighed against potential risks associated with therapy.
4.2.1.2
Recommendation of managing hypersensitivity
Hypersensitivity, including urticarial/anaphylactic reactions, have rarely (<1%) been reported 
after administration of tenecteplase and alteplase (e.g., anaphylaxis, angioedema, laryngeal 
oedema, rash, and urticaria).
Immune-mediated hypersensitivity reactions associated with the administration of 
Actilyse/Metalyse can be caused by the active substance alteplase or tenecteplase, gentamicin 
(a trace residue from the manufacturing process), any of the excipients, or the stopper of the 
glass vial with Actilyse/Metalyse powder which contains natural rubber (a derivative of latex). 
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/Metalyse.
There is also a risk of hypersensitivity reactions mediated through a non-immunological 
mechanism.
Angio-oedema represents the most common hypersensitivity reaction reported with 
Actilyse/Metalyse. This risk may be enhanced in the indication acute ischaemic stroke and/or 
by concomitant treatment with ACE inhibitors. Patients treated for any authorised indication 
should be monitored for angio-oedema during and for up to 24h after infusion.
If a severe hypersensitivity reaction (e.g. angio-oedema) occurs, the infusion should be 
discontinued, and appropriate treatment promptly initiated. This may include intubation.


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4.2.1.3
Recommendation of managing other adverse events
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 AEs, including clinically significant 
laboratory values, related to the trial.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Additional thrombolytic medication (e.g. prolinase or streptokinase) is forbidden for either 
study group of tenecteplase or the active control group of alteplase during the whole study 
period
Heparin
Intravenous heparin at any dose is forbidden before and during the trial drug administration 
and during the initial 24 h after completion of drug administration. Thereafter iv heparin must 
not be started before the second CT is evaluated and reveals no signs of intracerebral bleeding.
In exceptional circumstances, low dose subcutaneous heparin may be given concomitantly 
during the first 24 h in order to prevent deep venous thrombosis provided that the aPTT will 
not be prolonged for >2 fold over the baseline value. The aPTT must be determined regularly 
during the administration of heparin SC. The SC heparin dose must not exceed 10,000 IU of 
sodium heparin during 24 h or equivalent doses of low molecular weight heparin. Simultaneous 
administration of heparin and other antithrombotic drugs is strongly discouraged.
Other medication
Administration of oral anticoagulants (including warfarin, dabigatran, rivaroxaban, apixaban
and edoxaban) and antiplatelet agents (including aspirin, clopidogrel, ticagrelor and cilostazol), 
is prohibited during the first 24 h after completion of the trial drug administration.
4.2.2.2
Restrictions on diet and lifestyle
Not applicable.
4.3
TREATMENT COMPLIANCE
The investigator will maintain accurate records of receipt of all trial 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 trial.
Actual weighing of the patient is preferred when it can be performed without causing delays.
The treatment effect is time-dependent; therefore, treatment must be started as early as possible 
within 4.5 h after onset of stroke symptoms.






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The brain imaging should be interpreted by a physician with expertise in reading CT. MRI is 
also acceptable.
Investigator could make decision whether or not an imaging performed outside the site could 
be used for evaluation of inclusion/exclusion criteria. This evaluation should also include time 
elapsed from imaging, possible changes in clinical symptoms since imaging.
5.2.2
Physical examination
A physical examination as per standard care will be performed at the Visit 1 and Visit 3. It 
includes at a minimum general appearance, neck, lungs, cardiovascular system, abdomen, 
extremities, and skin. Measurement of height and body weight will be performed at the 
screening visit specified in the Flow Chart.
The results must be included in the source documents available at the site. The abnormal results 
will be recorded in eCRF. 
5.2.3
Vital signs
Vital signs include blood pressure, pulse rate, respiratory rate and temperature. It should be 
measured on each visit and the result shall be noted in source.
5.2.4
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.4: 1. For the sampling time 
points please see the Flow Chart. All analyses will be performed by local laboratory, the 
respective 
reference 
ranges 
will 
be 
provided 
in 
the 
ISF. 
Patients have to be fasted for the blood sampling for the safety laboratory except for screening 
(Visit 1).


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Table 5.2.4: 1 
Safety laboratory tests
Category
Laboratory test
Point-of-care testing (POCT)
Glucose 1 (non-fasting is acceptable for Visit 1)
Haematology
Red blood cell (RBC) count 
Haemoglobin (Hb)
Haematocrit (HCT)
Mean corpuscular volume
White blood cell count including differential
Platelet count1
Biochemistry
Aspartate aminotransferase (AST)
Alanine transaminase (ALT)
Gamma-glutamyl transferase (GGT)
Alkaline phosphatase (ALP)
Creatine kinase (CK)
Lactate dehydrogenase (LDH)
Total protein
Total bilirubin
Creatinine
Glucose1 (non-fasting is acceptable for Visit 1. Fasting is 
required at the Visit 3-6)
Uric acid
Electrolytes
Sodium
Potassium
Calcium
Inorganic phosphorus
Coagulation1
International normalised ratio (INR)
Activated partial thromboplastin time (APTT)
Prothrombin time (PT)
Urinalysis2
pH, glucose, erythrocytes, leukocytes, protein, nitrite (semi 
quantitative measurements; (–, +, ++, +++), pregnancy test
1.
During screen (Visit 1) the lab values related to eligibility for the trial, only the result of random glucose (POCT) is
mandatory before drug administration. Hematology lab results including coagulation items and platelet count are
necessary before drug administration only when anticoagulants are used or there is suspicion of coagulopathy (as 
determined by investigator). Drug administration should not be delayed by other lab results.
2.
If the routine urine test during screening is not available, investigator should judge patient’s baseline condition and decide 
whether the skipping of urine test will impact the eligibility and should fully document in medical source. Urine test 
should be conducted at the earliest possible afterwards for safety consideration.
Clinically relevant abnormal findings will be reported either as baseline condition (if identified 
at the screening visit) or otherwise as AEs and will be followed up and/or treated as medically
appropriate.


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5.2.5
Electrocardiogram
The 12-lead electrocardiograms (ECGs) should be performed by a qualified personnel and 
results will be recorded as scheduled in the Flow Chart. The investigator or a designee will 
evaluate whether the ECG is normal or abnormal and assess clinical relevance. ECGs may be 
repeated for quality reasons and the repeated recording will be used. 
Clinically relevant abnormal findings will be reported either as baseline condition (if identified 
at the screening visit) or otherwise as AEs and will be followed up and/or treated as medically 
appropriate.
5.2.6
Other safety parameters
For further safety parameters, the frequency and severity of AE will be recorded and calculated 
throughout the whole trial.
5.2.7
Assessment of adverse events
5.2.7.1
Definitions of adverse events 
5.2.7.1.1
Adverse event
An 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.
The following should also be recorded as an AE in the eCRF and BI SAE form (if applicable):
•
Worsening of the underlying disease or of other pre-existing conditions 
•
Changes in imaging, vital signs, ECG, physical examination and laboratory test results, if 
they are judged clinically significant and clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected on Medical history/pages related to baseline condition in 
the eCRF only.
5.2.7.1.2
Serious adverse event
An SAE is defined as any AE, which fulfils at least one of the following criteria:
•
Results in death
•
Is life-threatening, which 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


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•
Is a congenital anomaly/birth defect
•
Is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgement 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 dyscrasias or convulsions that do not result in hospitalisation 
or development of dependency or abuse
5.2.7.1.3
AEs considered “Always Serious”
In accordance with the EMA initiative on Important Medical Events, BI has set up a list of 
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 defined above.
The latest list of “Always Serious AEs” can be found in the electronic data capture (EDC)
system. A copy of the latest list of “Always Serious AEs” will be provided upon request. These 
events should always be reported as SAEs as described in Section 5.2.7.1.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as described
in Section 5.2.7.2, subsections “AE Collection” and “AE reporting to sponsor and timelines”.
5.2.7.1.4
Adverse events of special interest (AESI)
No AESIs have been defined for this trial.
5.2.7.1.5
Intensity (severity) of adverse events
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
The intensity (severity) of AEs should be classified and recorded in the eCRF.
Causal relationship of adverse events
Medical judgement is to be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, 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. 
Claims that may suggest that there is a reasonable possibility of a causal relationship:
•
The event is consistent with the known pharmacology of the drug


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•
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 decreased)
Claims that may suggest that there is no reasonable possibility of a causal relationship:
•
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 d/w 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 t1/2)
•
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)
•
Disappearance of the event even though the trial drug treatment continues or remains
unchanged
5.2.7.2
Adverse event collection and reporting
5.2.7.2.1
Adverse event collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate eCRF by the investigator:
•
From signing the informed consent onwards until the last follow-up visit (Visit 6): all AEs 
(non-serious and serious)
•
After the individual patient’s end of the study, the investigator does not need to actively 
monitor the patient for new AEs but should report any occurrence of cancer of new 
histology and any trial treatment related SAEs of which the investigator may become aware 
of by any means of communication, e.g. phone call. Those AEs should be reported on the 
BI SAE form (see Section 5.2.7.2.2), but not on the eCRF
Vital Status Data Collection
Patients who are administrated study drugs but discontinue study prematurely, who agree to be 
contacted further but do not agree to on-site visits, should be followed up as described in 


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Section 3.3.4.2. From then on until the individual patient’s end of the study the investigator
must report all deaths/fatal and AEs regardless of relationship and trial treatment related SAEs.
5.2.7.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs and non-SAEs which are relevant for the reported SAE, on 
the BI SAE form via fax immediately (within 24 h) 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 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. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
5.2.7.2.3
Pregnancy
In rare cases, pregnancy might occur in a trial. Once a patient has been enrolled in the trial and 
has taken trial medication, the investigator must report any drug exposure during pregnancy in 
a trial participant immediately (within 24 h) by means of Part A of the Pregnancy Monitoring 
Form to the sponsor’s unique entry point.
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 Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy, an SAE form must be completed 
in addition.
5.3
DRUG 
CONCENTRATION 
MEASUREMENTS 
AND 
PHARMACOKINETICS
Not applicable.
5.4
ASSESSMENT OF BIOMARKER
Not applicable.
5.5
BIOBANKING
Not applicable.


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5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements conducted in the trial are using standard methods.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The trial will consist of six visits. The schedule for trial visits is summarised in the Flow Chart
including time windows for trial 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.
Remote visits will be acceptable under specific situations. The decision to replace a site visit 
with a remote visit will be done by the investigator based on a thorough risk assessment or after 
discussion with the sponsor. 
The procedures to be conducted at each visit are provided in the Flow Chart and further 
described below.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
All subjects should adhere to the visit schedule as specified in the Flow Chart. If any visit has 
to be rescheduled, subsequent visits should follow the original visit date schedule.
6.2.1
Screening period
Informed consent of all trial patients will be obtained in compliance with ICH and GCP 
guidelines and the principles stipulated in the Declaration of Helsinki prior to any trial related 
procedure.
After informed consent procedure, a patient may be enrolled into the trial when entering the 
clinic with acute stroke symptoms and being liable to be treated within 4.5 h after stroke onset. 
All inclusion and exclusion criteria have to be checked prior to administration of the test dose 
of trial 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 trial medication.
6.2.2
Treatment period
After the consent procedure has been completed, eligibility has been confirmed, and all 
randomisation procedures have been completed, the drug can be administered (Visit 2a). Please
refer to the Flow Chart for details.
Alteplase will be administered as a total single dose of 0.9 mg/kg. The upper dose limit is 90 
mg. Ten percent of the total dose will be administered as bolus. The remaining 90% of the dose 
will be given through continuous iv infusion over 60 min. The alteplase dose is consistent with 
the local approved label for AIS treatment.


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Tenecteplase will be administered as a total single dose of 0.25 mg/kg. The upper dose limit is 
25 mg/patient. The total dose will be administered as a bolus over 5-10 seconds. 
6.2.3
Follow-up period and trial completion
The vital signs will be measured, as well as AEs and concomitant medication will be 
documented for all patients at all predefined treatment time points (Visit 2b and Visit 2c) as of 
the administration day and Visit 3, 4, 5 and 6. For detailed assessment of the follow-up period 
and trial completion, please refer to the Flow Chart.
Subjects will complete the trial (end of study, i.e. EoS) on treatment and the follow up visit 
around day 90 as per protocol (Visit 6). Data should have been entered in eCRF when subject 
has terminated the study. In case vital status is not yet available at Visit 6, the follow up should 
be conducted as early as possible but within last patient last visit, and every effort should be 
made to obtain the patient vital status.
Based on especial conditions, remote visits will be acceptable for Visit 5 and Visit 6. It should 
be determined by investigator, and also shall keep align with the regulations from local 
governance/ site EC. E.g., when subject has a very bad condition, or under the pandemic of 
Covid-19 on-site visits are strictly limited for subject’s benefit.
If a subject is randomised but not administrated any study drug, or a subject discontinues from 
the trial after treatment, either situation will be documented and the date and reason for 
discontinuation will be recorded in the eCRFs. For any reason if a subject cannot perform a 
follow up visit to site, remote follow up visits including EoS evaluation (Visit 6, day 90) will 
be performed as complete as possible, and the data collected from these subjects will be 
included in the trial database and will be reported.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
This trial is a multi-centre, prospective, randomised, open label, blinded endpoint (PROBE), 
active-controlled parallel group phase III trial. The primary objective is to establish the non-
inferiority of in efficacy between tenecteplase and alteplase in patients with AIS based on a 
statistical comparison of the following criteria:
•
Proportion of patients achieving modified Rankin Scale 0 or 1 (mRS0-1) at day 90
Based on the meta-analysis results of historical randomised trials of intravenous alteplase for 
treatment of AIS [P14-11754], the unadjusted risk ratio for the effect of rt-PA versus placebo 
for the endpoint of mRS 0-1 was 1.24 (95% CI 1.14 to 1.36). Taking lower bound 1.14 as M1 
and f=0.5 (preserve at least 50% of the effect of alteplase), M2 will be 1.0677. Therefore, the 
non-inferiority margin (1/M2) for RR will be set as 0.937. 
Based upon these design considerations, the trial will be analysed using log binomial regression 
model with subsequent transformation of estimated parameters to risk ratio including the 
respective CI, which will include terms for NIHSS at baseline, time to drug administration and 
age as covariates. The primary treatment comparison will be as randomised, including the 
effects of performing thrombectomy. Details of the model are presented in Section 7.2.3.
The secondary objectives of this trial are to assess the safety and efficacy in other key functional 
outcomes in patients with AIS.
7.1
NULL AND ALTERNATIVE HYPOTHESES
The test will be performed with respect to tenecteplase versus alteplase. 
Based on the non-inferiority setup, the hypotheses for the non-inferiority test can be written as 
follows:
H01:  Risk ratio in mRS0-1 response rates at day 90 (tenecteplase/alteplase) is ≤0.937
versus the alternative hypothesis
H11:  Risk ratio in mRS0-1 response rates at day 90 (tenecteplase/alteplase) is > 0.937
Tests will be based on a two-sided 95% CI (using a two-sided alpha of 5%) for risk ratio 
in mRS0-1 response rates at day 90. To conclude non-inferiority, the null hypotheses
need to be rejected, which means that:
∀
the 95% CI for risk ratio in mRS0-1 response rates at day 90 has to be contained in the 
predefined non-inferiority regions (0.937, +∞)


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Once the non-inferiority hypothesis test specified above concludes non-inferiority of 
tenecteplase over alteplase, the following superiority hypotheses will be tested in risk ratio in 
mRS0-1 response rates at day 90 in a hierarchical manner with overall type I error control. 
Failure to demonstrate the non-inferiority of tenecteplase over alteplase implies that no further 
formal testing in the hierarchical sequence below will be conducted.
The hypotheses for the superiority test can be written as follows:
H02:  Risk ratio in mRS0-1 response rates at day 90 (tenecteplase/alteplase) is ≤1
         versus the alternative hypothesis
H12:  Risk ratio in mRS0-1 response rates at day 90 (tenecteplase/alteplase) is > 1
Tests will also be based on a two-sided 95% CI (using a two-sided alpha of 5%) for risk ratio
in mRS0-1 response rates at day 90. No adjustment of the alpha of 5% for constructing the 
confidence interval is necessary under the hierarchical manner. To conclude superiority, the
null hypotheses need to be rejected, which means that:
∀
the 95% CI for risk ratio in mRS0-1 response rates at day 90 has to be contained in the 
superiority regions (1, +∞)
7.2
PLANNED ANALYSES
7.2.1
General considerations
There will be 4 main patient populations in this trial for analyses: the enrolled set (ES), 
the safety set (SS), the full analysis set (FAS), and the per-protocol set (PPS).
Enrolled Set
This patient set includes all patients who signed informed consent. It will be used for analyses 
of patient disposition.
Safety Set 
This patient set includes all patients who were randomised and received any dose of treatment. 
It will be the main analysis set for presentation of safety. Patients will be analysed according 
to the actual treatment.
Full Analysis Set 
This patient set includes all randomised patients who received any dose of treatment. Treatment 
assignment will be as randomised. This is the primary analysis set for presentation of efficacy
according to the intention-to-treat principle. 


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Per-Protocol Set  
This patient set includes all patients in the FAS who adhered to the CTP without any important 
protocol deviations (IPDs) relevant for efficacy which lead to exclusion from the PPS. A 
protocol deviation (PD) will be considered important if it can be expected to have a distorting 
influence on the assessment of the primary endpoint, which will be assessed on a case-by-case 
basis.
Standard statistical parameters (number of non-missing values, mean, standard deviation (SD), 
median, quartiles, minimum and maximum) or frequency tables (including patient frequencies 
and percentages) will be calculated where appropriate.
The final trial analysis is planned to be performed at the end of the study once all randomised 
patients have completed the study (including any applicable follow-up period). The final 
analysis will include all trial data. Details of the analysis to be performed will be described in 
the trial statistical analysis plan (TSAP). 
A Clinical Trial Report will be prepared at the end of the study.
7.2.2
Handling of intercurrent events
The expected intercurrent events (ICE) of interest in this trial are listed in Table 7.2.2:1 together 
with handling strategy.
Table 7.2.2:1 Intercurrent events (ICE) and handling strategy 
ICE
Handling strategy
Comments
Perform 
thrombectomy
Treatment policy
(Include all available 
data)
This event reflects the clinical practice 
and will be included in efficacy 
evaluation
Death
Will not be considered as 
ICE for primary objective
Death event is included in mRS variable 
(death is equivalent to score 6) 
The primary estimand in evaluating the primary objective is Treatment-Regimen Estimand
which is specified as below:
1) Target population: The treatment effect will be estimated for trial patients with AIS as 
specified by the inclusion and exclusion criteria.
2) Treatment regimen under evaluation will be the randomised treatment taken (tenecteplase 
and alteplase).
3) Endpoints: Efficacy will be evaluated using endpoint “mRS score of 0 or 1 at day 90”.
4) Intercurrent events: For patients who performed thrombectomy, observed variable values
will be used for the analysis.


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5) Population-level summary: The proportion of patients with “mRS score of 0 or 1 at day 90” 
will be compared between two treatment groups in terms of risk ratio.
7.2.3
Primary endpoint analyses
Comparisons between treatment groups regarding the binary endpoint variable mRS 0-
1 at day 90 will be performed using log binomial regression model with subsequent 
transformation of the estimated parameters to risk ratio including the respective CI.
The difference in log (proportion of mRS0-1 at day90) between tenecteplase and 
alteplase will be estimated with 95% CI adjusting for continuous covariates (NIHSS at 
baseline, age and time to drug administration). The estimate and CI will be 
exponentiated to return to the ratio scale.
The analysis will be related to the defined primary estimand and performed on FAS. 
Patients will be assigned to treatment groups as randomised. Multiple imputation 
method mentioned in Section 7.3 will be used to handle the missing data of primary 
endpoint.
7.2.4
Secondary endpoint analyses
Secondary endpoints will be presented in an exploratory manner. Frequencies and percentages 
will be presented for categorical endpoints; descriptive statistics will be used for continuous 
data. If applicable, 95% CI will also be displayed. Details will be described in TSAP.


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7.2.6
Safety analyses
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA). 
Standard BI summary tables and listings will be produced. 
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of AEs will concentrate on treatment-emergent AEs. To this 
end, all AEs occurring between start of treatment and end of the residual effect period (REP) 
will be considered ‘treatment-emergent’; the REP is defined as 7 days after the end of 
treatment, will be assigned to the on-treatment period for evaluation. Adverse events that start 
before first drug intake and deteriorate under treatment will also be considered as ‘treatment-
emergent’. The frequency of all AEs collected until the end of the study will also be 
summarized.
Frequency, severity, and causal relationship of AEs will be tabulated by system organ class
(SOC) and preferred term (PT) after coding according to the current version of the MedDRA
at database lock (DBL).
Laboratory data will be analysed qualitatively and quantitatively. Treatment groups will be 
compared descriptively with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
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.
7.2.7
Interim Analyses
No interim analysis is planned.
7.3
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at all visits. However, for functional outcome 
parameters of surviving patients missing values might occur.
For primary endpoint, multiple imputation approach will be applied for the primary analysis.
Three steps will be done for multiple imputation process:


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Step 1: Multiple imputation for missing data: Fully Conditional Specification (FCS) method 
will be used for MI process. Logistic regression method will be used to impute missing values 
by using the ordering of the class level in each variable. 
Step 2: Analysis of completed datasets: The imputed complete dataset will be used to analyze 
the primary endpoint and the corresponding statistical analysis specified above will be 
performed.
Step 3: Combine the results. For risk ratio, the distribution is not expected to be approximately 
normal, before using Rubin’s rules to combine the analysis results from step 2 and generate 
valid statistical inferences by accounting for the variability introduced by MI process, normal 
transformation of the statistics estimated from step 2 will be done first.
7.4
RANDOMISATION
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-random 
number generator so that the resulting treatment will be both reproducible and non-predictable. 
Access to the codes will be controlled and documented.
Stratification for NIHSS score (<6; 6-15; >15) at baseline and age (≤80; >80) will be done in 
order to assure the balance of NIHSS score and age between the two treatment groups; these 
strata will be included into the analyses of efficacy endpoints. Within each stratum of NIHSS
at baseline and age, patients will be randomised in a 1:1 ratio (tenecteplase vs alteplase). The 
randomisation will be done in blocks to achieve balanced allocation. The block size of the 
randomisation will be documented in the CTR.
The process of randomisation is done via an IRT. Practical aspects of the treatment allocation 
process are detailed in Section 4.1.3.
7.5
DETERMINATION OF SAMPLE SIZE
In NORTEST study [P17-08885], which had a similar enrolment criteria with this trial, the 
proportion of patients with mRS 0 or 1 at 90 days was 63% in alteplase group. In the China 


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single arm 3-4.5 h alteplase study [P20-04860], the proportion of patients with mRS 0 or 1 at
90 days was 63%. Thus, it is assumed that 63% of patients in alteplase group will achieve mRS 
0 or 1 at day 90. Recent ACT study results showed that the proportion of patients with mRS 0 
or 1 at 90-120 days in Canadian was 36.9% in tenecteplase group and 34.8% in alteplase group
[P22-05053]. The unadjusted absolute relative risk was 1.06. Based on the absolute relative 
risk 1.06, proportion of patients with mRS 0 or 1 at day 90 in tenecteplase group will be 66.8%.
For conservative consideration, it is assumed as 65.8%.
The power estimates for detecting the non-inferiority were performed using R (Version 4.01). 
With an expected response rate of 65.8% in tenecteplase group, 63% in alteplase group for the 
primary endpoint, a type I error of 0.025(1-sided) and a non-inferiority margin of 0.937, for a 
total sample size of 1478 patients, there is an 80% power to demonstrate non-inferiority.
Approximately 739 patients will be randomised in either group.


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8.
INFORMED 
CONSENT, 
TRIAL
RECORDS, 
DATA 
PROTECTION, 
PUBLICATION 
POLICY, 
AND
ADMINISTRATIVE STRUCTURE
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 Guideline for GCP,
relevant BI standard operating procedures (SOPs), and other relevant regulations. Investigators 
and site staff must adhere to these principles. Deviation from the protocol, the principles of 
ICH GCP or applicable regulations as will be treated as “protocol deviation”.Standard medical 
care (prophylactic, diagnostic and therapeutic procedures) remains 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 patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The BI 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 finalisation 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.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB/IEC and 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 patient must be given sufficient time to consider participation in the trial. The investigator
or delegate 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 or 
 delegate
must sign (or place a seal on) and date the informed consent form. If a trial 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.


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8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment of 
critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk Management 
Plan documents the rationale and strategies for risk management during trial conduct including 
monitoring approaches, vendor management and other processes focusing on areas of greatest 
risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB/IEC or by RAs. 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 trial.
8.3
RECORDS
The eCRFs for individual patients will be provided by the sponsor. For drug accountability, 
refer to Section 4.1.8.
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 patient. Source data as well as reported 
data should follow the “Attributable, Legible, Contemporaneous, Original, Accurate (ALCOA)
principles” and be attributable, legible, contemporaneous, original and accurate. Changes to 
the data should be traceable (audit trail).
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient 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 at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient would be 
acceptable if applicable. It will be determined by the investigator whether the patient is eligible 
to participate the trial according to all the available information which should be documented 
in source.
If the patient is not compliant with the protocol, any corrective action such as re-training must 
be documented in the patient file.
For the eCRF, data must be derived from source documents, for example:
•
Patient identification: gender, 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


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•
Medical history (including trial indication and concomitant diseases, if applicable)
•
Medical history
•
AEs (onset date (mandatory), and end date (if available))
•
SAEs (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 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 trial
8.3.2
Direct access to source data and documents
The investigator/institution will allow site trial-related monitoring, audits, IRB/IEC review and 
regulatory inspections. Direct access must be provided to the eCRF 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 CRAs, auditor and regulatory inspector 
(e.g. FDA). They may review all eCRFs 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 GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whichever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.


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Individual patient data obtained as a result of this trial is considered confidential and disclosure 
to third parties is prohibited with the following exceptions:
Personalised 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 at the site
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 RAs.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Not applicable.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs informed 
consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”). The “Last Patient Last Treatment” (LPLT) date is defined as the 
date on which the last patient in the whole trial is administered the last dose of trial treatment
(as scheduled per protocol or prematurely). Individual investigators will be notified of 
suspected unexpected serious adverse reactions occurring with the trial medication until 30 
days after LPLT 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.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority
(HA) request.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by BI.
In order to ensure the patient’s safety during the trial, fully external EAC and DMC will be set
up respectively, independent of the trial and project teams. The EAC will be responsible to 
provide consistent independent judgement of all sICH events described per protocol that 
occurred during the trial. Events will be blinded, adjudicated on an ongoing basis and EAC 
meetings will be scheduled approximately after every 15 - 18 events reported since first-
patient-in or at a frequency determined by the EAC.
The DMC will review all available un-blinded safety data (group tenecteplase and group 
alteplase not disclosing the actual treatment) based on EAC review outcome report at a similar 
frequency and provide review recommendation. A DMC statistical analysis plan (SAP) which 
describes the analyses required for assessment by the DMC will be produced. Further details 
will be provided in a DMC charter.
The two committees, EAC and DMC, each consist of members independent of BI.


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•
The EAC members will be specialists with proven expertise in pertaining therapeutic areas.
•
The DMC members include physicians experienced in the treatment of the disease under 
investigation and a statistician.
The DMC will assess the progress of the 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. The DMC will also receive urgent significant safety 
concerns for immediate evaluation. DMC meetings will be held at a frequency determined by 
the DMC or with regular intervals. The DMC will recommend continuation, modification or 
termination of the trial as detailed in the DMC charter. DMC recommendations as well as the 
final BI decision (if needed) will be reported to the appropriate RAs/HAs, IRBs/ECs, and to 
investigators as requested by local law. The tasks and responsibilities of the DMC are specified 
in DMC charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula vitae)
will be filed in the ISF. The investigators will have access to the BI web portal Clinergize to 
access documents provided by the sponsor.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required activities, in 
order to 
•
Manage the trial in accordance with applicable regulations and internal SOPs,
•
Direct the trial team in the preparation, conduct, and reporting of the trial,
•
Ensure appropriate training and information of Clinical Trial Managers, CRAs, and 
investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a CRO with which the responsibilities and tasks will have been 
agreed and a written contract filed before initiation of the trial.
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.
Local laboratories and an IRT vendor will be used in this trial. Details will be provided in the 
IRT Manual and Local Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P00-02456
Modi NB, Fox NL, Clow FW, et al. Pharmacokinetics and pharmacodynamics 
of tenecteplase: results from a phase II study in patients with acute myocardial 
infarction. J Clin Pharmacol 2000. 40: 508-515.
P03-02906
Tanswell P, Modi N, Combs D, Danays T. Pharmacokinetics and 
pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial 
infarction. Clin Pharmacokinet 2002; 41(15):1229 – 1245.
P05-02918
Haley EC, Lyden PD, Johnston KC, Hemmen TM. A pilot dose-escalation 
safety study of tenecteplase in acute ischemic stroke. Stroke 2005; 36 (3): 607-
612.
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
P12-03304
Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus 
alteplase for acute ischemic stroke. N Engl J Med 2012. 366 (12):1099-1107.
P13-10973
Hage A ver. The NIH Stroke Scale: a window into neurological status. 
https://ce.nurse.com/PrintTopic.aspx?TopicId=5975 (access date: 5 September 
2013) (2013).
P14-11754
Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke 
severity on the effects of intravenous thrombolysis with alteplase for acute 
ischaemic stroke: a meta-analysis of individual patient data from randomised 
trials. Lancet. 2014 Nov 29;384(9958):1929-35. 
P15-11262
Coutts SB, Dubuc V, Mandzia J, et al. ESOC 2015, 1st Ann Conf of the 
European Stroke Organisation (ESO), Glasgow, 17 - 19 Apr 2015. Int J Stroke 
2015; 10:79-80.
P17-08885
Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase for 
management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, 
open-label, blinded endpoint trial. Lancet Neurol 2017; 16(10): 781-788.
P18-01526
Kate M, Wannamaker R, Kamble H, et al. Penumbral imaging-based 
thrombolysis with tenecteplase is feasible up to 24 hours after symptom onset. 
J Stroke 2018; 20 (1): 122-130.
P19-02504
Turc G, Bhogal P, Fischer U, et al. European Stroke Organisation (ESO) -
European Society for Minimally Invasive Neurological Therapy (ESMINT) 
guidelines on mechanical thrombectomy in acute ischaemic stroke: endorsed by 
Stroke Alliance for Europe (SAFE). Eur Stroke J 2019; 4 (1): 6-12.


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P19-03580 
Liu L, Liu J, Wang Y, Wang D, Wang Y. Substantial improvement of stroke 
care in China. Stroke 2018; 49(12):3085-3091.
P19-03892
Powers WJ, Rabinstein AA, Ackerson T, et al. American Heart Association 
Stroke Council 2018 Guidelines for the early management of patients with acute 
ischemic stroke: a guideline for healthcare professionals from the American 
Heart Association/American Stroke Association. Stroke 2018; 49(3):e46-e99.
P19-06342
Burgos AM, Saver JL. Evidence that tenecteplase is noninferior to alteplase for 
acute ischemic stroke: meta-analysis of 5 randomized trials. Stroke 2019; 50: 
2156-2162.
P19-10385
Powers W J, Rabinstein A A, Ackerson T, et al. Guidelines for the early 
management of patients with acute ischemic stroke: 2019 update to the 2018 
guidelines for the early management of acute ischemic stroke: a guideline for 
healthcare professionals from the American Heart Association/American 
Stroke Association. Stroke, 2019, 50(12): e344-e418. P19-10855 Peng B, Liu 
M, Cui L. Chinese guidelines for diagnosis and treatment of acute ischemic 
stroke 2018.Original in Chinese.Chin J Neurol 2018; 51 (9):666 – 682.
P19-10855
Peng B, Liu M, Cui L. Chinese guidelines for diagnosis and treatment of acute 
ischemic stroke 2018. Original in Chinese. Chin J Neurol 2018; 51 (9): 666 –
682.
P20-01928
Effect of intravenous tenecteplase dose on cerebral reperfusion before 
thrombectomy in patients with large vessel occlusion ischemic stroke: the 
EXTEND-IA TNK part 2 randomized clinical trial. JAMA. 2020; 
323(13):1257-1265.
P20-04860
Zheng H, Yang Y, Chen H, et al. Thrombolysis with alteplase 3-4.5 hours after 
acute ischaemic stroke: the first multicentre, phase III trial in China. Stroke 
Vasc Neurol. 2020 Sep;5(3):285-290. 
P20-06029
Bluhmki E, Danays T, Biegert G, et al. Alteplase for acute ischemic stroke in 
patients aged >80 years: pooled analyses of individual patient data. Stroke 2020.
P22-05053
Menon BK, Buck BH, Singh N, et al. Intravenous tenecteplase compared with 
alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, 
open-label, registry-linked, randomised, controlled, non-inferiority trial. 
Lancet. 2022 Jul 16;400(10347):161-169.
P89-49823
Tanswell P, Seifried E, Su CAPF, Feuerer W, Rijken DC. Pharmacokinetics 
and systemic effects of tissue-type plasminogen activator in normal subjects. 
Clin Pharmacol Ther 1989; 46 (2):155-162.
P97-0977
Cannon CP, McCabe CH, Gibson CM, et al. TNK-tissue plasminogen activator 
in acute myocardial infarction: results of the thrombolysis in myocardial 
infarction (TIMI) 10A dose-ranging trial. Circulation 1997; 95(2):351-356
P97-9851
Cannon CP, McCabe CH, Gibson CM, et al. TNK-tissue plasminogen activator 
compared with front-loaded tissue plasminogen activator in acute myocardial 
infarction: primary results of the TIMI 10B trial. 70th Sci Sess of the American 




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10.
APPENDICES
10.1
COVID-19 RELATED CONTENTS
Potential risks for trial participants due to the COVID-19 pandemic have been evaluated 
together with the principal investigator. 
Both IMPs, tenecteplase and alteplase, are classified as tissue plasminogen activators (t-PA). 
The t-PA is a serine protease which is pharmacologically classified as a thrombolytic enzyme. 
It converts plasminogen into plasmin, a circulating plasma protein that binds to and digests the 
solid-phase fibrin component of a thrombus, and thereby restores the vessel patency. Based on 
the mode of action, the trial treatment is not expected to impose an increased susceptibility to 
infections or immune suppression. According to previous clinical trials no impaired lung 
function is observed or reported.  
Patients have confirmed active infection with SARS-CoV-2 within the prior 3 months, as 
recorded in medical histories, will be excluded during screening visit.
In case of a confirmed infection after study drug treatment, appropriate measures for 
monitoring, treatment and quarantine will be implemented. Remote follow-up visits will be 
performed to replace any visits to site. 
Due to local travel restrictions or lock down policy caused by COVID-19 pandemic, the trial 
conduct may need to be adjusted and remote visits could be performed as follows:
∀
For Visit 5 and Visit 6, if a patient is not able to come to the site for the visit(s), a remote 
visit (by video call or telephone, video call is highly recommended) should be 
performed within time window instead. The following assessment can be done 
remotely: Adverse Events, concomitant therapy, mRS, Barthel Index, Glasgow 
outcome score. The remote assessment of NIHSS may not be completely reliable on 
certain criteria, e.g., the assessment of motor function: some/no effort against gravity.
The remote assessment of NIHSS is not judged by the investigator to be reliable unless, 
for example, the patient did not have motor function score during the previous NIHSS 
assessments, and the patient did not report an associated AE. The remote NIHSS should 
be clearly documented in case the investigator judges the result could be reliable.
∀
Safety lab tests during the following visit of Visit 6
If by investigator’s determination, any local safety lab analyses are necessary, the blood 
sample should be collected with every effort to reduce the risk virus infection. The 
results of the lab tests must be transferred to the investigator who ensures medical 
review and proper documentation in the eCRF. 


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10.2
SCALES OF EFFICACY ASSESSMENT
10.2.1
Modified Rankin Scale, MRS
Score
Description
0
No symptoms at all
1
No significant disability despite symptoms; able to carry out all usual duties 
and activities
2
Slight disability; unable to carry out all previous activities, but able to look 
after own affairs without assistance
3
Moderate disability; requiring some help, but able to walk without 
assistance
4
Moderately severe disability; unable to walk without assistance and unable 
to attend own bodily needs without assistance
5
Severe disability; bedridden, incontinent and requiring constant nursing 
care and attention
6
Dead
Total (0-6): ________


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10.2.2
Barthel index 
Item
Score
Categories
Bowels
0
Incontinent or needs enemas
5
Occasional incontinence (<once/week)
10
Continent
Bladder
0
Incontinent/unable to manage catheter
5
Occasional accident (<once/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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10.2.3
Glasgow Outcome Scale
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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10.2.4
National Institutes of Health Stroke Scale, NIHSS
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
Obeys one correctly
2
Both incorrect
2.Best gaze (only horizontal 
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 (absence 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)


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10.2.4        National Institutes of Health Stroke Scale, NIHSS (continued)
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
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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11.
DESCRIPTION OF GLOBAL AMENDMENTS
11.1
GLOBAL AMENDMENT 1
Date of amendment
17 May 2021
BI trial number
1123-0040
BI Investigational Medicinal
Product
Metalyse®, tenecteplase
Title of protocol
A phase III multi-centre, prospective, randomised, open 
label, blinded endpoint (PROBE), active-controlled 
parallel group trial to assess efficacy and safety of 
tenecteplase versus alteplase in Chinese patients with 
acute ischaemic stroke within 4.5 hours after stroke 
onset
Global Amendment due to 
urgent safety reasons
Global Amendment
X
Section to be changed
  Lay Title
Description of change
 Replaced “improve long-term physical activity” 
with “improve recovering of physical activity”.
Rationale for change
 Updated the wording to describe the drug effect and 
objective with better accuracy.
Section to be changed
FLOW CHART
Description of change
 Updated the 2nd footnote. Added “This evaluation 
should also include time elapsed from imaging and 
possible changes in clinical symptoms since 
imaging.”
Rationale for change
 Clarified that the investigator should fully evaluate 
whether to use the imaging performed in the transfer 
hospital, including time elapsed from imaging and 
possible changes in clinical symptoms since 
imaging.
Description of change
 Removed the description of pregnancy test
Rationale for change
 Pregnancy test (blood) takes a long time for the 
testing result, not suitable for eligibility evaluation 
in this trial.


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Description of change
 Updated the footnote 6
Rationale for change
 Clarified only the result of random glucose (POCT) 
is 
mandatory 
before 
drug 
administration. 
Hematology lab results including coagulation items 
and platelet count are necessary before drug 
administration only when anticoagulants are used or 
there is suspicion of coagulopathy. Therefore, drug 
administration should not be delayed by other lab 
results.
Description of change
 Updated the footnote 8
Rationale for change
 Clarified a urine pregnancy test is required for 
WOCBP at screening or at earliest possible; the test 
result should not delay the drug administration. 
Description of change
 Added the footnote 11 to NIHSS
“The distal motor function will be assessed when 
NIHSS is scored.”
Rationale for change
 Data on distal motor function improvement will be 
collected.
Section to be changed
ABBREVIATIONS
Description of change
 Added the abbreviation of POCT: Point - of- care 
testing
Rationale for change
 The random blood glucose test during screening was 
updated, to be performed via POCT. 
Section to be changed
2.1.3 Secondary endpoints
Description of change
 Added footnote to sICH:
“Both investigator and DMC will evaluate and 
report the sICH events. The conclusion on endpoints 
will rely on the adjudication outcome by DMC.”
Rationale for change
 Clarified that the DMC’s adjudication of sICH 
events should play the primary role in the endpoint 
conclusion.
Section to be changed
Description of change


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Rationale for change
Section to be changed
3.3.3 Exclusion criteria
Description of change
 Added “Current use of vitamin K based oral 
anticoagulants (e.g. warfarin) and a prolonged 
prothrombin time (INR >1.7 or PT >15 s) or current 
use of novel oral anticoagulants (i.e. dabigitran, 
rivaroxiban, or apixiban) with prolongation of aPTT
and/or PT above the upper limit of the local 
laboratory reference range” under “Acute bleeding 
diathesis”
Rationale for change
 To 
exclude 
patient 
currently 
using 
oral 
anticoagulants to lower the risk of bleeding might 
occur after IMP administration.
Section to be changed
5.1
ASSESSMENT OF EFFICACY
Description of change
 Added the assessment of distal motor function 
together with NIHSS
Rationale for change
 Data on distal motor function improvement will be 
collected.
Section to be changed
5.2.1   Cerebral imaging
Description of change
 Added “This evaluation should also include time 
elapsed from imaging and possible changes in 
clinical symptoms since imaging.”
Rationale for change
 Clarified that the investigator should fully evaluate 
whether to use the imaging performed in the transfer 
hospital, including time elapsed from imaging and 
possible changes in clinical symptoms since 
imaging.
Section to be changed
  Table 5.2.4:1   Safety laboratory tests
Description of change
 Added the category of Point-of- care testing for 
glucose test for eligibility
Rationale for change
 The POCT of random glucose will benefit a rapid 
analysis outcome, which is proper and preferred for 
the eligibility evaluation for this trial
Description of change
 Updated the note 1
Rationale for change
 Clarified in screen only the result of random glucose 
(POCT) is mandatory before drug administration.


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Hematology lab results including coagulation items 
and platelet count are necessary before drug 
administration only when anticoagulants are used or 
there is suspicion of coagulopathy (as determined by 
investigator). Drug administration should not be 
delayed by other lab results
Description of change
 Updated the note 2
Rationale for change
 Editorial change to improve the wording.
Section to be changed
5.2.5 Electrocardiogram
Description of change

Revised “administered” to “performed”.
Rationale for change

Updated wording for better expression.
Section to be changed
7.1   NULL AND ALTERNATIVE HYPOTHESES
Description of change
 Changed “H02” to “H11”and “H11” to “H02”
Rationale for change
 Corrected the typo error.


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11.2
GLOBAL AMENDMENT 2  
Date of amendment
29 Sep 2022
BI trial number
1123-0040
BI Investigational Medicinal 
Product
Metalyse®, tenecteplase
Title of protocol
A phase III multi-centre, prospective, randomised, open 
label, blinded endpoint (PROBE), active-controlled 
parallel group trial to assess efficacy and safety of 
tenecteplase versus alteplase in Chinese patients with 
acute ischaemic stroke within 4.5 hours after stroke 
onset
Global Amendment due to 
urgent safety reasons
Global Amendment
X
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Updated the site amount
Rationale for change
 Adjust according to the actual situation
Description of change
Updated total number of patients randomised, number 
of patients on each treatment and non-inferiority 
margin for risk difference for pre-defined regions
Rationale for change
 See rationale in Sections 7 and 7.5
Description of change
Updated the criteria for Covid-19 infected subjects
Rationale for change
 As the virus evolves, the impact to patient safety and 
study evaluation/completion will change. It’ll be up 
to the investigator.
Section to be changed
FLOW CHART
Description of change
Added footnote 2 “MRI is also acceptable”
Rationale for change
 In very rare cases, MRI at screening will happen, 
which is also acceptable.
Description of change
Added footnote 12 to vital sign during V5 and V6
Rationale for change
 The vital sign could be an optional item in case 
remote visit is performed.


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Section to be changed
ABBREVIATIONS
Description of change
Added 
the 
abbreviation 
of 
EAC: 
Endpoint 
Adjudication Committee
Rationale for change
 Responsibility of independent adjudication of all 
potential sICH events is picked out from DMC and 
to be conducted by Endpoint Adjudication 
Committee (EAC) 
Section to be changed
1.4.2 Risks
Description of change
Added “Endpoint Adjudication Committee (EAC)” for 
extensive safety monitoring processes 
Rationale for change
 Clarified the responsibility will be conducted by 
EAC
Section to be changed
2.
TRIAL OBJECTIVES AND ENDPOINTS
Description of change
The footnote was changed/added for sICH in Sections 
2.1.3 
Rationale for change
 To keep the consistence with EAC responsibility 
Section to be changed
3.1 OVERALL TRIAL DESIGN
Description of change
Updated total number of eligible AIS patients in 
context and Figure 3.1.1
Rationale for change
 See rationale in Section 7 and Section 7.5
Section to be changed
3.2 
DISCUSSION 
OF 
TRIAL 
DESIGN, 
INCLUDING THE CHOICE OF CONTROL 
GROUP
Description of change
Added EAC for sICH events adjudication
Rationale for change
 Responsibility of independent adjudication of all 
potential sICH events was picked out from DMC 
and to be conducted by EAC
Description of change
Replaced the wording ‘some local site staffs may be 
aware of the treatment’ to ‘the treatment information is 
available to patients and investigators’
Rationale for change
 Small adaptation for accurate expression
Description of change
The following new text was added: In addition, the BI 
analysis and data cleaning team will not have access to 
the treatment information during the trial conduct phase 
in order to reduce the risk of bias affecting the cleaning 
and planning for analysis of the data.


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Rationale for change
 Explained that the BI BDS team will conduct a blind 
review to ensure that the PROBE design is well 
implemented.
Section to be changed
3.3 SELECTION OF TRIAL POPULATION
Description of change
Updated total number of patients randomised
Rationale for change
 See rationale in Section 7 and Section 7.5
Section to be changed
3.3.3 Exclusion criteria
Description of change
Updated the criteria for Covid-19 infected subjects
Rationale for change
 As the virus evolves, the impact to patient safety and 
study evaluation/completion will change. It’ll be up 
to the investigator.
Section to be changed
3.3.4.2 Withdrawal of consent to trial participation
Description of change
The following new text was added: In case vital status 
is not yet available at Visit 6 (90-day), the follow up 
should be conducted as early as possible but within last 
patient last visit, and every effort should be made to 
obtain the patient vital status.
Rationale for change
 To mitigate the risk of endpoint missing for V6
Section to be changed
4.1.5 Blinding and procedures for unblinding
Description of change
Replaced the wording ‘some local site staffs may be 
aware of the treatment’ to ‘the treatment information is 
available to patients and investigators’
Rationale for change
 Small adaptation for accurate expression
Description of change
The following new text was added: In addition, the BI 
analysis and data cleaning team will not have access to 
the treatment information during the trial conduct phase 
in order to reduce the risk of bias affecting the cleaning 
and planning for analysis of the data.
Rationale for change
 Explained that the BI BDS team will conduct a blind 
review to ensure that the PROBE design is well 
implemented.
Section to be changed
4.2.2.1
Restrictions 
regarding 
concomitant 
treatment
Description of change
Added the specific drug names for oral anticoagulants
and antiplatelet agents
Rationale for change
 Clarified the restricted medication in detail




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Description of change
Removed the description of pregnancy test at screening
is mandatory for WOCBP and the identification of
WOCBP
Rationale for change

Pregnancy
test should not delay the
drug 
administration. For women who are considered of 
childbearing 
potential 
(WOCBP), 
a 
urine 
pregnancy test is required at screening or at earliest 
possible.
Section to be changed
6.2.3 Follow-up period and trial completion
Description of change
Added “In case vital status is not yet available at Visit 
6, the follow up should be conducted as early as 
possible but within last patient last visit, and every 
effort should be made to obtain the patient vital status”
Rationale for change

To emphasis the important of vital status and 
mitigate the risk of endpoint missing for V6
Section to be changed
7
STATISTICAL
METHODS 
AND 
DETERMINATION OF SAMPLE SIZE
Description of change
Based on the meta-analysis results of historical 
randomised trials of intravenous alteplase for treatment 
of AIS [P14-11754], the unadjusted risk ratio for the 
effect of rt-PA versus placebo for the endpoint of mRS 
0-1 was 1.24 (95% CI 1.14 to 1.36). Taking lower 
bound 1.14 for RR and assumed the response rate for 
alteplase group was 63%, the corresponding M1 for risk 
difference will be 7.7%; Taking f=0.35 (preserve 35% 
of M1), M2 will be 5.0%. Therefore, the non-inferiority 
margin (-M2) for risk difference will be -5.0%. 
Rationale for change
 In accordance with CDE guideline of non-inferiority 
trials design, update of the non-inferiority margin
Section to be changed
7.1 NULL AND ALTERNATIVE HYPOTHESES
Description of change
Changed the non-inferiority margin (from -9.5% to -
5.0%)
Rationale for change
 See rationale to Sections 7 
Section to be changed
7.2.2 Primary endpoint analyses
Description of change
Added the fold words in sentence ‘Secondary analysis 
of the primary endpoint will include but not limited 
to:’
Rationale for change

To improve the accuracy




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Section to be changed
8.7 ADMINISTRATIVE STRUCTURE OF THE 
TRIAL
Description of change
Added Endpoint Adjudication Committee (EAC) for 
the independent adjudication of all potential sICH 
events after randomisation 
Rationale for change
 To clarify the responsibility of adjudication is 
independently performed by EAC
to keep a 
complete blind adjudication on safety data (sICH 
events)
Section to be changed
9
REFERENCES
Description of change
Added published references P14-11754, P22-05053, 
and P20-04860 in Section 9.1, and deleted unpublished 
reference c21624583 in Section 9.2
Rationale for change
 To keep consistent with statistical changes in 
Section 7.
Section to be changed
10.1 COVID-19 RELATED CONTENTS
Description of change
Added the instruction on remote assessment of NIHSS
Rationale for change
 To ensure high-quality data, helping investigators to
get reliable conclusions from remote NIHSS 
assessment.
Section to be changed
Throughout the protocol
Description of change
Small adaptations and corrections throughout the 
document 
Rationale for change
 Minor corrections and/or clarifications that have no 
effect on the way the study is to be conducted was
done to keep consistency and/ or improve the
accuracy.


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11.3
GLOBAL AMENDMENT 3  
Date of amendment
23 Feb 2023
BI trial number
1123-0040
BI Investigational Medicinal 
Product
Metalyse®, tenecteplase
Title of protocol
A phase III multi-centre, prospective, randomised, open 
label, blinded endpoint (PROBE), active-controlled 
parallel group trial to assess efficacy and safety of 
tenecteplase versus alteplase in Chinese patients with 
acute ischaemic stroke within 4.5 hours after stroke 
onset
Global Amendment due to 
urgent safety reasons
Global Amendment
X
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Updated total number of patients randomised, number 
of patients on each treatment, statistical methods part 
including non-inferiority margin for risk ratio for pre-
defined regions, analysis model and superiority margin 
for risk ratio for predefined regions.
Rationale for change
 See rationale to Sections 7 and 7.5
Section to be changed
2.1.3 Secondary endpoints
Description of change
Added the bold text in the endpoint definition: 
•
Symptomatic Intracerebral Haemorrhage (sICH) 
per ECASS Ⅲdefinition during on-treatment 
period
Rationale for change
 Clarify the timepoints for endpoint definition
Section to be changed
Description of change
 
Rationale for change


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Section to be changed
3.1 OVERALL TRIAL DESIGN
Description of change
Updated total number of eligible AIS patients in context 
and Figure 3.1.1
Rationale for change
 See rationale to Section 7.5
Section to be changed
3.3 SELECTION OF TRIAL POPULATION
Description of change
Updated the number of patients planned to be 
randomised.
Rationale for change
 See rationale to Section 7.5
Section to be changed
5.2 ASSESSMENT OF SAFETY
Description of change
Changed ‘An ECASS III-defined sICH were assess’ to: 
‘An ECASS III-defined sICH were assessed’
Rationale for change
 Correction
Section to be changed
7 STATISTICAL METHODS AND 
DETERMINATION OF SAMPLE SIZE
Description of change
Updated
the non-inferiority margin
determination 
paragraph: Based on the meta-analysis results of 
historical randomised trials of intravenous alteplase for 
treatment of AIS [P14-11754], the unadjusted risk ratio 
for the effect of rt-PA versus placebo for the endpoint of 
mRS 0-1 was 1.24 (95% CI 1.14 to 1.36). Taking lower 
bound 1.14 as M1 and f=0.5 (preserve at least 50% of 
the effect of alteplase), M2 will be 1.0677. Therefore, 
the non-inferiority margin (1/M2) for RR will be set as 
0.937.
Rationale for change
 In accordance with CDE guideline of non-inferiority 
trials design, the non-inferiority margin was reset 
based on risk ratio and consider f≥0.5.
 It was believed that risk ratio met ‘constancy’, then 
risk ratio was chosen as the statistics for primary 
endpoint analysis.
Description of change
The following bold text was revised, “Based upon these 
design considerations, the trial will be analysed using 
log binomial regression model with subsequent 
transformation of estimated parameters to risk ratio 
including the respective CI, which will include terms 
for NIHSS at baseline, time to drug administration and 
age as covariates”. 


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Rationale for change
 Considering that the statistics revised from risk 
difference to risk ratio, the primary analysis model 
was revised accordingly.
Description of change
Added the sentence “The primary treatment comparison 
will be as randomised, including the effects of 
performing thrombectomy.”
Rationale for change
 Clarify details related to the primary estimand.
Section to be changed
7.1 NULL AND ALTERNATIVE HYPOTHESES
Description of change
Updated non-inferiority margin for risk ratio for pre-
defined regions and superiority margin for risk ratio for 
predefined regions.
Rationale for change
 See rationale to Section 7
Section to be changed
7.2.1 General considerations
Description of change
Changed ‘all randomised patients received any dose of 
treatment’ to ‘all randomised patients who received any 
dose of treatment’
Rationale for change
 Correction
Section to be changed
7.2.2 Handling of intercurrent events
Description of change
Added definition for primary estimand and specified the 
handling strategy for intercurrent events.
Rationale for change
 Re-consider the trial design from the perspective of 
estimand with reference to ICH E9 (R1) and present 
the attributes for the primary estimand.
Section to be changed
7.2.3 Primary endpoint analyses
Description of change
Primary endpoint analysis model was revised to log 
binomial regression model.
Rationale for change
 Considering the statistics for primary endpoint 
change from risk difference to risk ratio, the analysis 
model was revised accordingly.
Description of change
Added the sentence “The analysis will be related to the 
defined primary estimand and performed on FAS. 
Patients will be assigned to treatment groups as 
randomised. Multiple imputation method mentioned in 
Section 7.3 will be used to handle the missing data of 
primary endpoint”.
Rationale for change
 Clarify the imputation approach used for the primary 
analysis.




 
 
 
APPROVAL / SIGNATURE PAGE 
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Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
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Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
ABCD
BI-VQD-12681_50-415_AD-01 (4.0)
TRIAL STATISTICAL ANALYSIS PLAN
 
Document No.:
c42514142-02
BI Trial No.:
1123-0040
Title:
A phase III multi-centre, prospective, randomised, open label, 
blinded endpoint (PROBE), active-controlled parallel group trial 
to assess efficacy and safety of tenecteplase versus alteplase in 
Chinese patients with acute ischaemic stroke within 4.5 hours after 
stroke onset
Investigational
Product(s):
Metalyse®, tenecteplase
Responsible trial 
statistician(s):
Phone:
Date of statistical 
analysis plan:
6 SEP 2023 REVISED
Version:
2.0
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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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.
ENDPOINTS(S) ....................................................................................................8
5.1
PRIMARY ENDPOINT(S) ..................................................................................9
5.2
SECONDARY ENDPOINT(S) ............................................................................9
5.2.1
Key secondary endpoint(s)...................................................................................9
5.2.2
Secondary endpoint(s) ..........................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENT(S)................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
INTERCURRENT EVENTS .............................................................................15
6.4
SUBJECT SETS ANALYSED...........................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................17
6.6.1
Efficacy data........................................................................................................18
6.6.1.1
Binary efficacy endpoints .....................................................................................18
6.6.1.2
Continuous efficacy endpoints..............................................................................21
6.6.2
Safety data ...........................................................................................................21
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................21
7.
PLANNED ANALYSIS......................................................................................24
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........24
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................25
7.3
TREATMENT COMPLIANCE........................................................................25
7.4
PRIMARY OBJECTIVE ANALYSIS..............................................................25
7.4.1
Main analysis.......................................................................................................26
7.5
SECONDARY OBJECTIVE ANALYSIS........................................................28




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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AIS
Acute ischaemic stroke
AME
Average Marginal Effects
ATC3
Anatomical-Therapeutic-Chemical classification level 3
BI
Boehringer Ingelheim
BMI
Body Mass Index
CI
Confidence interval
CM
Concomitant medication
CTP
Clinical trial protocol
DBL
Database lock
DBP
Diastolic blood pressure
ECASS
European Cooperative Acute Stroke Study
ECG
Electrocardiogram
EDMS
Electronic Document Management System
EOS
End of Study
EOT
End of Text
eCRF
Electronic case report form
ES
Enrolled set
FAS
Full analysis set
FCS
Fully Conditional Specification
H
Hour(s)
ICH
International Council for Harmonisation
IRT
Interactive Response Technology
iPD
Important Protocol deviations 
iv
Intravenous
LOCF
Last observation carried forward
MAR
Missing at random
MedDRA
Medical Dictionary for Drug Regulatory Activities
min
Minute(s)
m
Month(s)


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Term
Definition / description
MI
Multiple imputation
MMRM
Mixed model repeated measures
mRS
Modified Rankin Scale
NIHSS
National Institutes of Health Stroke Scale
OC
Observed Case
PPS
Per-protocol set
PROBE
Prospective, randomised, open label, blinded endpoint
REML
Restricted Maximum Likelihood
RS
Randomised Set
REP
Residual effect period
PN
Preferred Name
PT
Preferred Term
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SD
Standard deviation
sICH
Symptomatic intracerebral haemorrhage
SITS-MOST
Safety Implementation of Thrombolysis in Stroke: Monitoring Study
SS
Safety set
SOC
System organ class
TSAP
Trial statistical analysis plan
TMF
Trial Mater Files


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3.
INTRODUCTION
As per International Council on Harmonisation (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 “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.
The statistical analyses will be performed using SAS® Version 9.4. 








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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on treatments to be administered, assignment of treatment groups, 
and selection of doses, refer to CTP Section 4. There will be four treatment study phases in this 
trial: screening, on-treatment, post-treatment and post-study. For detailed information, see 
Table 6.1: 1.
Table 6.1: 1
Treatment regimens / study intervals
Label
Interval
Start date 
Start time
Screening
Screening
Date of informed consent
Time of informed 
consent
On-treatment
On-treatment
Date 
of 
start
bolus 
administration 
of 
study 
medication
Time of start bolus 
administration 
of 
study medication
Post-treatment 
Post-treatment
Date of end administration of 
study medication +7 +1
00:00
Post-study
Post-study
Trial completion date +1
00:00 
The purpose of the definitions above is to describe all the different study/treatment intervals, to 
which a patient can be assigned during the course of the trial. Note that the term “treatment 
regimen” can also cover time periods with no active treatment.
In general, for safety analyses, data up to 7 days (Residual effect period, REP) after the end of 
study drug administration will be considered as on-treatment for Adverse events (AE), which 
will be summarized as primary interest. The frequency of all AEs collected from signing 
informed consent until study completion will also be summarized. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
Each protocol deviation must be assessed to determine whether it is an important protocol 
deviation(iPD). For definition of iPDs, and for the process of identification of these, refer to the 
BI reference document "Identify and Manage Important Protocol Deviations (iPD)[2]".
Handling of iPDs in analysis is included in the DV domain specifications and stored within the 
Trial Master File (TMF) in Electronic Document Management System (EDMS). Not all iPDs 
will lead exclusion from the Per-Protocol set (PPS). Deviations that lead to exclusion from 
analysis populations are indicated in Table 6.2:1.


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Table 6.2: 1
Important protocol deviations
IPD 
Code
IPD Category & brief 
description
Example/Comment
Exclude 
from 
which 
analysis 
set
A
Eligibility criteria not met
A1
Inclusion criteria not met
A 1.01
Age <18 years old
Inclusion criterion #1 not met
None
A 1.02
No diagnosis of ischemic stroke 
with a measurable neurological 
deficit on NIHSS (0<NIHSS≤25; 
if NIHSS<4, patients have to be 
with at least a measurable deficit 
on motor power (upper or lower 
limbs ≥ 1))
Inclusion criterion #2 not met
PPS
A 1.03
Stroke symptoms present for less 
than 30 minutes or with significant 
improvement prior to 
randomisation
Inclusion criterion #3 not met
PPS
A 1.04
Thrombolytic therapy cannot be 
initiated within 4.5 h of acute 
ischaemic stroke (AIS) onset
Inclusion criterion #4 not met
PPS
A 1.05
Modified Rankin Scale (mRS) > 1 
prior to the stroke
Inclusion criterion #5 not met
PPS
A2
Exclusion criteria met
A 2.01
Evidence of intracranial 
haemorrhage (ICH) or symptoms 
suggestive of subarachnoid 
haemorrhage
Exclusion criterion #1 met
PPS
A 2.02
Patients who must or are expected 
to continue the intake of restricted 
medications or any drug 
considered likely to interfere with 
the safe conduct of the trial
Exclusion criterion #2 met
None
A 2.03
Acute bleeding diathesis
Exclusion criterion #3 met
None
A 2.04
Bacterial endocarditis, or 
pericarditis at screening
Exclusion criterion #4 met
None
A 2.05
Acute pancreatitis at screening
Exclusion criterion #5 met
None


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IPD 
Code
IPD Category & brief 
description
Example/Comment
Exclude 
from 
which 
analysis 
set
A 2.06
Significant trauma or major 
surgery (according to the 
investigator’s assessment) in the 
past 3 months
Exclusion criterion #6 met
None
A 2.07
Imaging demonstrates multi-lobar 
infarction (hypodensity >1/3 
cerebral hemisphere)
Exclusion criterion #7 met
PPS
A 2.08
Severe uncontrolled arterial 
hypertension, e.g. systolic blood 
pressure (BP) >185 mmHg or 
diastolic BP >110 mmHg
Exclusion criterion #8 met
None 
A 2.09
Blood glucose <50 mg/dL(2.8 
mmol/L) at screening
Exclusion criterion #9 met
PPS
A 2.10
Seizure at stroke onset
Exclusion criterion #10 met
None
A 2.11
Known hypersensitivity to active 
substance alteplase or tenecteplase, 
gentamicin or to any of the 
excipients
Exclusion criterion #11 met
None
B
Informed Consent
B1 
Informed consent not available/not 
done
Inclusion criterion #6 not met
All
B2 
Informed consent too late, i.e., 
after randomization
Date of informed consent not 
obtained prior to any study 
related procedure.
None
C
Trial medication and 
randomisation
C1.01
Incorrect medication received by 
patients
Wrong medication taken, i.e. 
Electronic case report form 
(eCRF) kit number does not 
match kit number assigned by 
interactive response technology 
(IRT) [Needs unblinding to 
determine if kit is same 
medication as assigned or not –
so, will be finally judged after 
database lock(DBL)]
PPS


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IPD 
Code
IPD Category & brief 
description
Example/Comment
Exclude 
from 
which 
analysis 
set
C2.01
Non-compliance with study drug 
intake not due to AE
Administration dose less than 
planned dose 67% or over 
planned dose 10%
PPS
C3.01
Treated without randomisation
Patient treated according to 
eCRF, but not randomised 
according to IRT
FAS, PPS
D
Concomitant medication (CM)
D2.01
Use of prohibited therapy
Review of eCRF for prohibited 
medication 
None
E
Critical study 
procedure/assessment
E1
Improper unblinded primary 
endpoint assessment
PPS
6.3
INTERCURRENT EVENTS
The expected intercurrent events (ICE) of interest in this trial are listed in Table 6.3:1 together
with handling strategy.
Table 6.3: 1
Intercurrent events (ICE) and handling strategy
ICE
Handling strategy
Comments
Perform
thrombectomy
Treatment policy (Include 
all available data)
This event reflects the clinical 
practice and will be included in 
efficacy evaluation
Death
Will not be considered as
ICE for primary objective
Death event is included in mRS 
variable (death is equivalent to 
score 6)
Composite 
strategy 
for 
secondary 
and 
further 
functional 
score 
related 
objective
Missing data due to death will be 
replaced to corresponding worst 
score


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6.4
SUBJECT SETS ANALYSED
The following analysis sets will be defined for this trial.
Enrolled Set (ES)
This subject set includes all patients who signed informed consent. It will be used for analysis 
of disposition.
Randomised Set (RS)
This subject set includes all randomised patients, whether treated or not.
Safety Set (SS)
This subject set includes all patients who are randomised and received any dose of treatment. 
It will be the basis for safety analysis. The assignment of patients to treatment groups will be 
based on the initial actual study medication administration in the treatment period.
Full Analysis Set (FAS)
This subject set includes all randomised patients received any dose of treatment. The 
assignment of patients to treatment groups will be based on the planned randomised study 
medication at the time of randomisation. It will be the basis for efficacy analysis according to 
the intention-to-treat principle. 
Per-Protocol Set (PPS)
This subject set includes all patients in the FAS who adhered to the CTP without any iPDs 
relevant for efficacy which lead to exclusion from the PPS. A protocol deviation will be 
considered important if it can be expected to have a distorting influence on the assessment of 
the primary endpoint, which will be assessed on a case-by-case basis. This set will be used for 
sensitivity analysis for the primary efficacy endpoint.
The summary of which data sets will be used for which class of endpoints is illustrated in Table 
6.4: 1.






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Use data observed at day30 and day 90, impute mRS as ordinal variables with values 0, 1, 2, 3, 
4, 5 and 6. The imputation will be done using OC data as the input dataset and will follow the 
steps outlined below:
Step 1: Multiple imputation of missing data: The SAS procedure PROC MI with the Fully 
Conditional Specification (FCS) method will be used. Logistic regression method is used to 
impute missing values by using the ordering of the class level in each variable.
The variables mRS_day30 and mRS_day90 represent the mRS score in Visit 5 and Visit 6. 
These two variables are treated as ordinal variable from 0 (best) to 6 (worst). For each mRS 
imputed at specific visit, the mRS at the other visit are used as covariates together with the 
treatment and other continuous factors (NIHSS score at baseline, age and time to 
administration). Example SAS code is as follows:
PROC MI DATA= data_input seed= 112340 nimpute=1000 out=mi_fcs;
CLASS mRS_day30 mRS_day90 trt; 
FCS logistic (mRS_day30  mRS_day90 /details); 
VAR mRS_day30 mRS_day90 trt factors;  
RUN;
Note that the seed 112340 will be used throughout. The imputation process will be conducted 
1000 times to produce 1000 complete datasets.
Step 2: Analysis of completed datasets: For each imputed complete dataset, the statistical 
analysis specified in Section 7.4.1 will be performed to produce risk ratio. This will then result 
in 1000 sets of results, from the analysis on each of the 1000 completed datasets. 
The 1000 completed datasets will be saved and directly used for other analysis which also uses 
MI approach and is based on the same analysis set.
Step 3: Combine results: 
For the response rate of each arm, the point estimate will be calculated as the mean of each 
response rate from each imputation and the 95% confidence interval (CI) for each arm 
calculation will implement the MIWilson approach [3]. Algorithms to calculate 95% CI for 
each arm are provided in Section 10.1.
For the risk ratio, Rubin’s rules will be applied on the log-transformed estimates to get the final
combined estimate of RR and CI in log scale, which will then be back-transformed to the 
original scale. Example SAS code is as follows:
PROC MIANALYZE DATA=Estimates (where=(label="beta"));
ODS OUTPUT PARAMETERESTIMATES=mian_lgrr_t;
MODELEFFECTS LBETAESTIMATE;


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STDERR STDERR;
RUN;
DATA mian_lgrr_bt; 
SET mian_lgrr_t;
Estimate_back = EXP(ESTIMATE); 
LCL_back=EXP(LCLMEAN); 
UCL_back=EXP(UCLMEAN); 
RUN;
For risk difference in the supplementary analysis for primary endpoint, the distributions are 
approximately normal, so Rubin’s rules will be implemented directly using PROC 
MIANALYZE.
Observed case (OC) approach: include all collected data with no imputation performed on the 
missing data except that the missing data due to death will be replaced as the worst value 6. 
This approach will be used for endpoints below:
mRS score 0-1 at day 90;
Major neurological improvement at 24 h (NIHSS score of 0 or improvement of at least
4 points compared with baseline); 
Barthel Index score ≥95 at day 90;
Barthel Index score ≥85 at day 90;


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6.6.1.2
Continuous efficacy endpoints
1) For continuous endpoint “Change from baseline of NIHSS score at day 90”, missing data 
will be handled implicitly by the statistical model MMRM under the assumption of MAR; 
2) For continuous endpoint “NIHSS score at 
 24 h, 
”, missing data 
handling approach will be OC approach. 
6.6.2
Safety data
Missing or incomplete AE onset dates and time are imputed according to BI standards [4].
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 not be 
imputed.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
With regard to efficacy and safety endpoints, the term “baseline” refers to the last observed 
measurement prior to administration of any randomised treatments.
Table 6.7: 1 presents the visit structure according to the study flowchart depending on the time 
window scheduled in the CTP. Table 6.7: 2 presents the extended time windows around the 
planned visit dates.
Table 6.7: 1
Visit structure
Period
Baselin
e
Randomisatio
n 
and 
drug 
administration
On-treatment & Post-treatment
Visit 
number per 
protocol
V1
V2a
V2b
V2c
V3
V4
V5
V6/En
d 
of 
study
(EOS)
Planned 
study 
window
none
none
1 
hour 
! 15 
2 hrs 
! 30
min
s
24 
hrs 
!
2hr
7 
days 
! 2 d
30 
days -
2d or 
+7 d
90 days 
! 7 d




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7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics of concomitant disease and therapy (medication and non-drug 
therapy) by treatment group are planned based on RS.
Concomitant disease (i.e. baseline conditions) will be coded according to the most recent 
version of Medical Dictionary for Drug Regulatory Activities (MedDRA). All concomitant 
disease will be summarised by treatment, System Organ Class (SOC) and Preferred Term (PT).
Concomitant therapy will be coded according to the World Health Organisation – Drug 
Dictionary (current version at the time of analysis), sorted by the Anatomical-Therapeutic-
Chemical classification level 3(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 that started on or before study drug bolus administration and is stopped after end of 
infusion and therapies with new onset after treatment start until Visit 6 (EOS) will be 
summarized by treatment groups. 
Concomitant non-drug therapy will be coded according to the most recent version of MedDRA 
and will be summarised by treatment, SOC and PT.
7.3
TREATMENT COMPLIANCE
Descriptive statistics are planned for this section of the report. The number and percentage of
patients with overall compliance will be reported on SS. Treatment administration including 
planned dose, actual dose and reason for administration altered or stopped prematurely will be 
listed by each patient. 
7.4
PRIMARY OBJECTIVE ANALYSIS
The primary endpoint in this trial is mRS score of 0 or 1 at day 90. An overview table of analysis 
approach for primary endpoint is listed in Table 7.4: 1.


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7.4.1
Main analysis 
Comparisons between treatment groups regarding the binary endpoint mRS 0-1 at day 90 will 
be performed on FAS using Log-binomial regression model with subsequent transformation for 
the estimated parameters to risk ratio including the respective CI. The difference in log 
(proportion of mRS0-1 at day90) between tenecteplase and alteplase will be estimated with 95% 
CI adjusting for continuous covariates (NIHSS at baseline, age and time to drug administration). 
The estimate and CI will be exponentiated to return to the ratio scale. The statistical model will 
be described as follows:
(M1) Log (E{proportion of mRS0-1 at day90}) = treatment + NIHSS at baseline + age + time 
to drug administration.
The analysis will be related to the defined primary estimand and performed on FAS. All data 
collected after performing thrombectomy will be used for the analysis. Patients will be assigned 
to treatment groups as randomised. Multiple imputation method mentioned in Section 6.6 will 
be used to handle the missing data of primary endpoint.


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Example SAS code for Log-binomial regresson model is as follows:
proc genmod data = indata descending;
class trtVar (ref = ‘trtref’ param=ref);
model resp = trtVar &covar. / dist = binomial link = log;
estimate ‘beta’ trtVar 1 /exp;
run;
If the Log-binomial model fails to converge and thus the model fails to provide valid risk ratio 
estimate, then the modified Poisson regression model will be adopted to provide the risk ratio 
estimate and confidence interval.
Example SAS code for Modified Poisson regression model is as follows:
proc genmod data = indata descending;
class usubjid trtVar (ref = ‘trtref’ param=ref);
model resp = trtVar &covar. / dist = poisson link = log;
repeated subject = usubjid / type = unstr;
estimate ‘beta’ trtVar 1 /exp;
run;
Distribution of mRS at day 90 before dichotomization for primary analysis will be plotted using 
Grotta bars.


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7.5
SECONDARY OBJECTIVE ANALYSIS
7.5.1
Key secondary objective analysis
Not applicable as no key secondary endpoints have been specified in CTP.


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7.5.2
Secondary objective analysis
Secondary endpoints will be analysed in an exploratory manner.
7.5.2.1
Responder analysis 
The responder analysis includes the analysis of secondary efficacy endpoints of major 
neurological improvement at 24 h (NIHSS score of 0 or improvement of at least 4 points 
compared with baseline), mRS score of 0-2 at day 90 and Barthel Index score ≥95 at day 90. 
The responder analysis will be performed on FAS by determining the percentage of patients 
that fulfill responder criteria. The corresponding imputation approach for each endpoint 
mentioned in Section 6.6 will be used to handle the missing data. The analysis will consist of a 
tabulation by treatment of the percentage of responders along with 95% confidence intervals. 
Same Log-binomial regression model used for primary analysis of primary endpoint with 
categorical treatment and continuous NIHSS at baseline, age and time to drug administration
since onset of stroke symptoms will be fitted on the corresponding binary response variable to 
calculate the estimate of the risk ratio of treatment to active control group. Estimate of risk ratio
and 95% confidence intervals will be presented along with the p-values for the comparison.
If the Log-binomial model fails to converge and thus the model fails to provide valid risk ratio 
estimate, then the modified Poisson regression model will be adopted.
7.5.2.2
Change from baseline of NIHSS score at day 90
A restricted maximum likelihood (REML) based MMRM approach will be used to compare the 
change from baseline in NIHSS score at day 90. The analysis will be based on FAS. If a patient 
misses a visit, the missing data will not be imputed. The mixed effect model will handle missing 
data based on a likelihood method under the MAR assumption.
The statistical model will be:
Change in NIHSS score from baseline = overall mean + treatment + visit + baseline NIHSS + 
age + time to drug administration since onset of stroke symptoms + treatment by visit 
interaction + baseline NIHSS by visit interaction + random error.
For each patient, the error terms from all visits represent the within-patient variability and are 
assumed to follow a multivariate normal distribution with an unstructured covariance matrix. 
The Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom and adjust standard errors.
7.5.2.3
Distribution of mRS at day 90
Distribution of mRS at day 90 will be summarised. Comparisons between treatment groups 


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regarding the ordinal variable mRS at day90 will be performed using the ordinal logistic 
regression model including continuous covariates NIHSS at baseline, age and time to drug 
administration since onset of stroke symptoms. If the proportional-odds assumptions are not 
met, alternative assumption-free ordinal analysis [7, 8, 9] on the mRS score will be used. 
Grotta bars will be presented as well.
A forest plot showing odds ratio of a good stroke outcome, for each alternative definition of 
‘good’ outcome (mRS 0; 0-1; 0-2; 0-3; 0-4; 0-5) will also be presented.
7.5.2.4
Symptomatic Intracerebral Haemorrhage (sICH) per European Cooperative Acute 
Stroke Study (ECASS) Ⅲdefinition
Number of patients with sICH occurred during on-treatment period per ECASS Ⅲdefinition
will be tabulated in frequency tables by treatment groups based on SS. Comparisons between 
treatment groups regarding the binary endpoint variable will be performed using Suissa-Shuster 
test. The unadjusted risk ratio together with 95% confidence interval will be used to quantify 
the treatment effect for the following pair-wise comparisons of interest: tenecteplase vs 
alteplase. No imputation is planned for the analysis. Wilson method [10] will be used to provide 
confidence intervals for single proportions. Chan and Zhang [11] method will be used to 
provide confidence interval for unadjusted risk ratio.
Number of patients with investigator reported Intracranial Haemorrhage(ICH) events identified 
by MedDRA PTs during on-treatment period will be tabulated in frequency tables by treatment 
groups based on SS. The MedDRA PTs are shown in Section 10.2. Comparisons between 
treatment groups regarding the binary endpoint variable will be performed using Suissa-Shuster 
test.
Number of patients with ICH events by cerebral imaging as well as the haemorrhage 
clarification (HI1, HI2, PH1 and PH2) during on-treatment period will be tabulated in frequency 
tables by treatment groups based on SS. Comparisons between treatment groups regarding the 
binary endpoint variable patients with Intracranial hemorrhage clarification PH2 by CT image
will be performed using Suissa-Shuster test.
7.5.2.5
90-day mortality
Frequency of death by each time interval (day 0-7, day 8-30, day 31-90 and day >90) will be 
tabulated by treatment groups based on SS. The 90-day mortality cut-off date will be day 90. 
Comparisons between treatment groups regarding the binary endpoint variable will be
performed using Chi-square (X2) test. The unadjusted risk ratio between two treatment group 
and corresponding 95% confidence interval will be calculated to quantify the treatment effect 
for the following pair-wise comparisons of interest: tenecteplase vs alteplase. Wilson method
[10] will be used to provide confidence intervals for single proportions. Wald method will be 
used to provide confidence interval for unadjusted risk ratio. No imputation is planned for the 
analysis.


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7.5.2.6
mRS score of 5 or 6 at day90
Number of patients with mRS score of 5 or 6 at day90 will be tabulated in frequency tables by 
treatment groups based on FAS. The adjusted risk ratio between two treatment group and 
corresponding 95% confidence interval will be estimated using Log-binomial regression model 
including categorical treatment and continuous NIHSS at baseline, age and time to drug 
administration since onset of stroke symptoms as covariates.
Note that though it is defined as safety endpoint in CTP, all related analysis outputs will be 
presented in Section 15.2 together with other mRS score related efficacy endpoints.


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7.7
EXTENT OF EXPOSURE
Only descriptive analyses are planned for this section. Total duration will be presented only for 
alteplase group. Actual dose received and actual dose received per kg will be presented by 
treatment group. The analysis will be performed on the SS.
In addition, time in study will be analysed descriptively on SS. 
7.8
SAFETY ANALYSIS
All safety analyses will be performed on SS. The secondary and further safety endpoints are 
mentioned in Section 7.5 and 7.6.
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. For further details on summarization of AE data, please refer to the guidance [12].
The primary interest analysis of AEs will be based on the concept of treatment emergent (on-
treatment period) AEs, i.e. AEs occurring between start of treatment and end of the REP. 
AEs stopped before the start of bolus treatment administration will be assigned to ‘screening’ 
and AEs occurring after the end of REP to Visit 6 will be assigned to ‘post-treatment’. For 
details on the treatment definition, see Section 6.1. The frequency of all AEs collected from 
signing informed consent until study completion will also be summarized.
According to ICH E3, AEs classified as ‘other significant’ needs to be reported and will include 
those non-serious AEs with ‘action taken = discontinuation’ or ‘action taken = reduced’.
An overall summary of AEs will be presented.
The frequency of patients with AEs will be summarised by primary SOC and 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 (SAE)
∃
Drug-related AEs
∃
Drug-related SAEs
∃
AEs leading to treatment discontinuation
∃
AEs leading to death
∃
Other significant AEs (according to ICH E3 [13])
∃
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.


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The above tables will be presented for both on-treatment period and the overall period (from 
inform consent to study completion).
7.8.2
Laboratory data
For continuous safety laboratory parameters original and standardized values will be 
summarised as well as the change from baseline. Frequency of patients with possible clinically 
significant abnormalities will also be summarised by treatment groups.
7.8.3
Vital signs
Descriptive statistics of vital sign will be presented over all measured time points for absolute 
value and change from baseline. Figures may be presented over specified time points if 
appropriate.
7.8.4
ECG
Electrocardiogram (ECG) data will not be analysed. Any clinically significant relevant changes 
in the ECG will be reported as AEs.
7.9
OTHER ANALYSIS
Not applicable.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
This trial is an open-label trial but the database is handled in blinded way. The treatment 
information will be released to unblind the trial database after the last patient has completed 
their End-of-Study/Follow-up visit and all data has been entered and cleaned as defined in the 
“Data Ready to be Unblinded and/or Final Trial Closure Notification” (RUN) form.


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9.
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
001-MCS-40-413: " Identify and Manage Important Protocol Deviations (iPD)", 
current version; IDEA for CON
3
Anne Lott & Jerome P. Reiter. Wilson Confidence Intervals for Binomial Proportions 
With Multiple Imputation for Missing Data. The American Statistician 2020; 74:2, 109-
115
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
Ge, Miaomiao & Durham, L. & Meyer, Dan & Xie, Wangang & Thomas, Neal. (2011). 
Covariate-Adjusted Difference in Proportions from Clinical Trials Using Logistic 
Regression and Weighted Risk Differences. Drug Information Journal - DRUG INF J. 
45. 481-493.
7
Agresti A. Generalized odds ratios for ordinal data. Biometrics 1980; 36:59-67.
8
Howard G, Waller JL, Voeks JH. A simple, assumption-free, and clinically interpretable
approach for analysis of modified Rankin outcomes. Stroke 2012; 43:664-669.
9
Churilov L, Amup S, Johns H, et al. An improved method for simple, assumption-free
ordinal analysis of the modified Rankin Scale using generalized odds ratios. Int J
Stroke 2014; 9(8):999-1005.
10 Brown LD, Cai TT, DasGupta A. Confidence intervals for a binomial proportion and 
asymptotic expansions. Ann Stat 30 (1), 160 – 201 (2002). 
11 Chan I S F, Zhang Z. “Test‐based exact confidence intervals for the difference of two 
binomial proportions”[J]. Biometrics, 1999, 55(4): 1202-1209.
12 001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", version 8.0; IDEA for CON.
13 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.
14 FDA: Guideline Adjusting for covariates in RCT for drugs and biological products.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1.0
10-JUL-23
None
This is the final TSAP.
2.0
6-SEP-23