STrategic Reperfusion in Elderly Patients Early After Myocardial Infarction
Phase: PHASE4
Conditions: Myocardial Infarction
Sponsor: KU Leuven

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Version 
Version 5, 19 April 2021 
Title 
STREAM-2 (STrategic Reperfusion in elderly patients Early After 
Myocardial Infarction) 
Phase 
IV 
 
Sponsor 
 
Leuven Research & Development (LRD) at University of Leuven, 
Belgium 
 
Supported by 
 
- Boehringer Ingelheim 
- Life Sciences Research Partners (LSRP) 
- Fund for Clinical Cardiovascular Research at LRD 
EudraCT 
Sponsor trial code 
2016-001642-26 
LRD.2016.STREAM2 
 
 
 
 

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CLINICAL TRIAL SYNOPSIS 
Name of sponsor 
Leuven Research & Development (LRD) at University of Leuven, Belgium 
 
Supported by: 
- 
Boehringer Ingelheim 
- 
Life Sciences Research Partners (LSRP) 
- 
Fund for Clinical Cardiovascular Research at LRD 
Planned trial period 
September 2016 – June 2022 
Protocol version and date 
Version 5, 19 April 2021 
Title of trial 
STREAM-2 (STrategic Reperfusion in elderly patients Early After Myocardial 
Infarction) 
Investigators 
Executive Committee and the National Coordinators of the participating countries 
Trial sites 
Multi-national multi-centre trial 
Clinical phase 
IV 
Objectives 
In patients ≥ 60 years with acute ST-elevation myocardial infarction randomised 
within 3 hours of onset of symptoms the efficacy and safety of a strategy of early 
fibrinolytic treatment with half-dose tenecteplase and additional antiplatelet therapy 
with a loading dose of 300 mg clopidogrel, aspirin and coupled with antithrombin 
therapy followed by catheterisation within 6-24 hours or rescue coronary 
intervention as required, will be compared to a strategy of primary PCI with a P2Y12 
antagonist and antithrombin treatment according to local standards. 
Methodology 
Open-label, prospective, randomised, parallel, comparative international multi-
centre trial 
No. of patients 
Total: Approximately 600 
Each treatment: Approximately 400 Pharmaco-invasive (PhI) and 200 Primary PCI 
(PPCI) 
Diagnosis and main 
criteria for inclusion 
Patients (≥ 60 years) with acute ST-segment elevation myocardial infarction 
(STEMI) randomised within 3 hours of symptom onset in a pre-hospital 
setting/emergency room (ER) of community hospital that cannot reliably undergo 
primary PCI (PPCI) within 60 min of ECG diagnosis 
Inclusion criteria 
1. Age equal or greater than 60 years 
2. Onset of symptoms < 3 hours prior to randomisation 
3. 12-lead ECG indicative of an acute STEMI (ST-elevation will be measured from 

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the J point; scale: 1 mm per 0.1 mV): 
 2 mm ST-elevation across 2 contiguous precordial leads (V1-V6) or leads I 
and aVL for a minimum combined total of  4 mm ST-elevation  
or 
 2 mm ST-elevation in 2 contiguous inferior leads (II, III, aVF) for a minimum 
combined total of  4 mm ST-elevation 
4. Informed consent received  
Exclusion criteria 
1. 
Expected performance of PCI < 60 minutes from diagnosis (qualifying ECG) 
or inability to arrive at the catheterisation laboratory within 3 hours  
2. 
Previous CABG 
3. 
Left bundle branch block or ventricular pacing  
4. 
Patients with cardiogenic shock - Killip Class 4  
5. 
Patients with a body weight < 55 kg (known or estimated) 
6. 
Uncontrolled hypertension, defined as sustained blood pressure  180/110 mm 
Hg (systolic BP  180 mm Hg and/or diastolic BP  110 mm Hg) prior to 
randomisation  
7. 
Known prior stroke or TIA 
8. 
Recent administration of any i.v. or s.c. anticoagulation within 12 hours, 
including unfractionated heparin, enoxaparin, and/or bivalirudin or current use 
of oral anticoagulation (i.e. warfarin or a NOACs) 
9. 
Active bleeding or known bleeding disorder/diathesis 
10. Known history of central nervous system damage (i.e. neoplasm, aneurysm, 
intracranial or spinal surgery) or recent trauma to the head or cranium (i.e. < 3 
months) 
11. Major surgery, biopsy of a parenchymal organ, or significant trauma within the 
past 2 months (this includes any trauma associated with the current myocardial 
infarction) 
12. Clinical diagnosis associated with increased risk of bleeding including known 
active peptic ulceration and/or neoplasm with increased bleeding risk 
13. Known severe renal insufficiency  
14. Prolonged cardiopulmonary resuscitation (> 2 minutes) within the past 2 weeks 
15. Known acute pericarditis and/or subacute bacterial endocarditis 
16. Known acute pancreatitis or known severe hepatic dysfunction, including hepatic 
failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis  
17. Dementia 
18. Previous enrolment in this study or treatment with an investigational drug or 
device under another study protocol in the past 7 days 

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19. Known allergic reactions to tenecteplase, clopidogrel, enoxaparin and aspirin 
20. Inability to follow the protocol and comply with follow-up requirements or any 
other reason that the investigator feels would place the patient at increased risk if 
the investigational therapy is initiated 
Test products  
½ dose tenecteplase with concomitant antithrombotic therapy including 300 mg 
clopidogrel  
Dose and mode of 
administration 
Pre-PCI hospital/ER community hospital  treatment: 
Tenecteplase 
50 or 40 mg of drug reconstituted in 10 or 8 ml sterile water for injection given as single 
weight-adjusted i.v. bolus over 5 - 10 seconds 
Weight (kg) 
   Dose (mg)                              Dose (ml) 
55 to <60 
15.0 mg 
  3.0 ml 
60 to <70 
17.5 mg 
  3.5 ml 
70 to <80 
20.0 mg 
  4.0 ml 
80 to <90 
22.5 mg 
  4.5 ml 
90                                                     25.0 mg 
  5.0 ml 
 
Clopidogrel 
300 mg p.o. initial loading dose 
Maintenance dose of 75 mg p.o. once daily 
The maintenance dose of Clopidogrel (75 mg p.o. per day) should be continued for 1 year 
 
In-hospital treatment: 
Assessment of reperfusion (by ECG and evaluation of clinical symptoms) 90 min after  
injection of tenecteplase or earlier if clinically indicated 
Catheterisation: 
- 
 If ST-segment resolution is  50 % in the qualifying lead (i.e. with maximum initial ST-
segment elevation in the baseline ECG), diagnostic coronary angiography (followed by 
elective PCI +/- stenting, if indicated) should be performed no sooner than 6 hours but within 
24 hours after administration of tenecteplase (considered as planned catheterisation according 
to protocol) 
- 
 If ST-segment resolution is < 50 % in the qualifying lead, irrespective of the presence or 
absence of clinical symptoms, rescue coronary intervention should be performed promptly 
- 
In case of haemodynamic or electrical instability or worsening ischaemia requiring 
coronary intervention, urgent coronary intervention is indicated at any time (irrespective of 
previous ST-segment resolution) 
 

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Reference therapy 
Standard primary PCI (PPCI) 
Dose and mode of 
administration 
Pre-hospital treatment: 
In agreement with international guidelines, upfront antithrombin treatment, aspirin 
and a P2Y12 antagonist according to local standards and at the discretion of the 
investigator (e.g., unfractionated heparin/ enoxaparin or bivalirudin, clopidogrel or 
ticagrelor). Prasugrel is not recommended (cfr bleeding risk in elderly patients). 
In-hospital treatment:  
Maintenance dose of aspirin and a P2Y12 antagonist. Additional GP IIb/IIIa 
antagonists during PCI are at the investigator’s discretion (eg for bail-out). 
Criteria for efficacy 
Pharmaco-invasive strategy compared with primary PCI 
Number of patients achieving ≥ 50 % ST-segment resolution before and after PCI in 
lead with maximal ST elevation at baseline; % rescue PCI; TIMI flow grades  
 
Clinical events of interest i.e. death, shock, heart failure, recurrent MI, rescue PCI 
and aborted MI will be recorded and assessed as single or composite endpoints for 
evaluation.  
Criteria for safety 
- 
Total stroke, intracranial haemorrhage (ICH), ischaemic stroke, haemorrhagic 
conversion up to 30 days 
- 
Non-intracranial bleeds (total, major, minor, and blood transfusions) up to 30 
days 
- 
Serious cardiac events (e.g. death , congestive heart failure, reinfarction, 
resuscitated ventricular fibrillation, repeat target vessel recanalization, stent 
thrombosis, total AV block etc) up to 30 days 
Statistical methods 
The trial is a hypothesis-generating study to examine the medical question whether 
half-dose tenecteplase plus 300 mg clopidogrel in STEMI patients 60 years of age or 
older who cannot undergo PPCI within 1 hour after first medical contact is as 
effective and safe as PPCI according to local practice. A minimum of 100 patients ≥ 
70 years will be randomized to the PhI arm. No confirmatory statistical hypothesis is 
pre-specified. All statistical tests are of exploratory nature based on descriptive 
statistics for formal statistical hypotheses generation. An intent-to-treat analysis of 
all patients randomized will be carried out. After 50 % of the planned recruitment a 
formal interim analysis will be performed by the DSMB to evaluate and advise the 
Executive Committee on the feasibility and justification of enlarging the sample size 
with provision to proceed to a confirmatory trial. For this analysis the available data 
from STREAM 2 and similar data from STREAM 1 will be used. 
 In order to ensure adequate balance between the representation of ambulance and 
community hospital patients their relative proportions will be monitored and an 
adjustment in their numbers considered. 
 

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FLOW CHART 
Trial Periods 
Screening/ 
Baseline 
Randomised 
period 
End of trial 
Follow-up 
period 
Period 
 
Days 
Pre-PCI 
hospital 
 
 
In PCI- 
Hospital 
Hospital 
discharge 
or Day 30 
Day 30j 
 
30 (to 37) 
1-year Fk 
 
365 (to 395) 
Informed consent 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
Medical history/current diseases 
X 
 
 
 
 
Physical assessmenta 
X 
 
 
 
 
Vital signs 
X 
 
 
 
 
Concomitant therapy 
X 
X 
X 
 
 
Haematologyb 
Xb 
 
Xb 
 
 
Renal functionc 
Xc 
 
 
 
 
Troponin I/T (CK/CK-MB)d 
Xd 
Xd 
 
 
 
Twelve-lead ECGe 
X 
Xe 
Xe 
 
 
Killip classf 
Xf 
 
Xf 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
Randomisation 
X 
 
 
 
 
Administration of  medicationg 
Xg 
Xg 
 
 
 
Catheterisation/PCIh 
 
X 
 
 
 
TIMI flow grade 
 
X 
 
 
 
Check for rehospitalisation 
 
 
 
X 
X 
Check for clinical events 
X 
 
Check for vital status 
X 
X 
Check for SAEs/serious clinical eventsi 
Xi 
 
 
a Physical assessments can be performed by paramedics. 
 
b According to hospital practice; but it is required to include at least haemoglobin, haematocrit, platelets pre-hospital 
or, if not possible, on hospital arrival and before hospital discharge. 
 
c Renal function: A laboratory test of serum creatinine clearance (as per Cockcroft-Gault formula) should be done at 
the first occasion to rule out renal insufficiency or, if applicable, to adapt the dose of subcutaneous enoxaparin 
according to protocol in Group PhI patients with low creatinine clearance. 
 
d Cardiac biomarkers : The first available value (pre-hospital or upon arrival at hospital) should be recorded. Additional 
values should be taken 8-12 hours and 24 hours after randomisation. Cardiac biomarkers should also be taken in case 
of signs and symptoms suggestive of recurrent myocardial ischaemia or reinfarction until day 30. 
 
e Twelve-lead ECG in Group PhI: In the receiving hospital an ECG will be recorded 90 min after injection of 
tenecteplase or earlier, if clinically indicated, for assessment of ST resolution. If planned catheterization or rescue or 

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urgent PCI is done, ECGs will be taken immediately before the procedure and 30 min after the end of the procedure, 
respectively.  
Twelve-lead ECG in Group PPCI: In the receiving hospital an ECG will be taken prior to the PCI procedure and 30 
min after the end of the procedure.  
In all patients, in addition to baseline and possible in-hospital ECGs, an ECG will be recorded before hospital 
discharge. Serial in-hospital ECGs should be taken in case of symptoms of recurrent ischaemia or reinfarction. ECGs 
will be centrally adjudicated. 
 
f  Killip class will be determined prior to randomization (or, if this is not possible, immediately on hospital arrival). 
 
g Patients randomized to Group PhI will receive the trial medication in the ambulance/ER community hospital 
immediately after randomization. Patients randomized to PPCI will receive medication in the ambulance/ER 
community hospital and/or prior to PPCI according to the local hospital standards. 
 
h In Group PhI catheterization and PCI should be delayed for at least 6 hours, but no longer than 24 hours after 
randomization, if ST resolution is  50% and no rescue or urgent PCI is indicated (for details refer to section 6.2.2.1); 
whereas in Group PPCI all patients are expected to receive catheterization and PCI according to local standards. 
Catheterization and PCI data will be recorded in the eCRF (cf. section 6.2.2.2). 
 
i Serious clinical events will be recorded until and including day 30. 
 
j Visit at 30 days either at outpatient clinic or via phone. 
k Visit at 1 year either at outpatient clinic, via phone or from medical records. 
 
 

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TABLE OF CONTENTS 
CLINICAL TRIAL SYNOPSIS .................................................................................................. 2 
FLOW CHART ............................................................................................................................. 6 
TABLE OF CONTENTS ............................................................................................................. 8 
ABBREVIATIONS ..................................................................................................................... 11 
1. 
INTRODUCTION ............................................................................................................... 13 
1.1 
MEDICAL BACKGROUND ........................................................................................ 13 
1.2 
PHARMACOLOGIC THERAPY.................................................................................. 14 
1.3 
RATIONALE FOR PERFORMING THE TRIAL ........................................................ 16 
1.4 
BENEFIT / RISK ASSESSMENT ................................................................................. 20 
2. 
TRIAL OBJECTIVES ........................................................................................................ 21 
2.1 
GENERAL AIM ............................................................................................................ 21 
2.2 
EFFICACY ENDPOINT................................................................................................ 22 
3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION.......................................... 22 
3.1 
OVERALL TRIAL DESIGN AND PLAN - DESCRIPTION ...................................... 22 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL 
GROUPS ................................................................................................................................... 23 
3.3 
SELECTION OF TRIAL POPULATION ..................................................................... 24 
3.3.1 
Inclusion criteria ..................................................................................................... 24 
3.3.2 
Exclusion criteria .................................................................................................... 24 
4. 
TREATMENTS ................................................................................................................... 25 
4.1 
TREATMENTS TO BE ADMINISTERED .................................................................. 25 
4.1.1 
Identity of investigational products ........................................................................ 25 
4.1.2 
Methods of assigning patients to treatment groups................................................. 25 
4.1.3 
Selection of doses in the trial .................................................................................. 26 
4.1.4 
Selection and timing of doses for each patient ....................................................... 27 
4.1.4.1 
Group PI .......................................................................................................... 27 
4.1.4.2 
Group PPCI...................................................................................................... 29 
4.1.5 
Blinding................................................................................................................... 30 
4.1.6 
Study medication .................................................................................................... 30 
4.2 
ADDITIONAL THERAPIES ........................................................................................ 30 
4.2.1 
Rescue medication and additional treatments ......................................................... 30 

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4.2.2 
Restrictions ............................................................................................................. 30 
4.3 
TREATMENT COMPLIANCE ..................................................................................... 31 
5. 
OBSERVATIONS ............................................................................................................... 31 
5.1 
EVALUATION OF EFFICACY ................................................................................... 31 
5.1.1 
ECGs to be taken/analysed ..................................................................................... 31 
5.1.2. 
Clinical events ......................................................................................................... 32 
5.2 
SAFETY RECORDING ................................................................................................ 32 
5.2.1 
General assessment of safety .................................................................................. 32 
5.2.2 
Specific safety recording within 30 days ................................................................ 35 
5.3 
OTHER RECORDINGS ................................................................................................ 36 
5.3.1 
Duration of hospitalization ..................................................................................... 36 
5.3.2 
Evaluations at 1 year ............................................................................................... 36 
5.3.3 
Evaluations specific for group PI ............................................................................ 37 
5.4 
APPROPRIATENESS OF MEASUREMENTS ........................................................... 37 
5.5 
DATA QUALITY ASSURANCE ................................................................................. 37 
6. 
INVESTIGATIONAL PLAN ............................................................................................. 38 
6.1 
VISIT SCHEDULE ........................................................................................................ 39 
6.2 
TRIAL PROCEDURES AT EACH VISIT .................................................................... 39 
6.2.1 
Pre-PCI hospital period ........................................................................................... 39 
6.2.2 
In-PCI hospital period (including day of discharge) ............................................... 40 
6.2.2.1 
Group PI .......................................................................................................... 40 
6.2.2.2 
Group PPCI...................................................................................................... 42 
6.2.3 
End of trial and follow-up period ............................................................................ 43 
6.2.3.1 
End of trial (day 30) ......................................................................................... 43 
6.2.3.2 
Follow-up......................................................................................................... 43 
6.3 
REMOVAL OF PATIENTS FROM THERAPY ASSESSMENT ................................ 43 
7. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ............... 44 
7.1 
STATISTICAL DESIGN/MODEL ............................................................................... 44 
7.2 
PLANNED ANALYSES ............................................................................................... 44 
7.2.1 
Interim analyses ...................................................................................................... 44 
7.3 
HANDLING OF MISSING DATA ............................................................................... 44 
7.4 
RANDOMISATION ...................................................................................................... 45 

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7.5 
DETERMINATION OF SAMPLE SIZE ...................................................................... 45 
8. 
ADMINISTRATIVE MATTERS ...................................................................................... 45 
8.1 
ETHICS .......................................................................................................................... 45 
8.1.1 
Institutional Review Board or Independent Ethics Committee .............................. 45 
8.1.2 
Informed Consent and Patient Information ............................................................. 46 
8.2 
RECORDS ..................................................................................................................... 47 
8.2.1 
Drug accountability ................................................................................................. 47 
8.2.2 
Case Report Forms (CRFs) ..................................................................................... 47 
8.2.3 
Source documents ................................................................................................... 47 
8.2.4 
Direct access to source data / documents ................................................................ 47 
8.3 
QUALITY ASSURANCE AUDIT ................................................................................ 48 
8.4 
PROCEDURES .............................................................................................................. 48 
8.4.1 
Adverse events ........................................................................................................ 48 
8.5 
RULES FOR AMENDING PROTOCOL...................................................................... 49 
8.6 
DISCONTINUATION OF THE TRIAL ....................................................................... 49 
8.7 
STATEMENT OF CONFIDENTIALITY ..................................................................... 50 
8.8 
PUBLICATION POLICY .............................................................................................. 50 
8.9 
COMPLETION OF TRIAL ........................................................................................... 50 
8.10 STUDY COMMITTEES................................................................................................ 50 
APPENDIX A: CLINICAL EVENTS TO BE RECORDED IN ECRF ................................ 53 
APPENDIX B: DEFINITIONS OF CLINICAL EVENTS ..................................................... 54 
B1. 
Bleeds ............................................................................................................................. 54 
B2. 
Major cardiac events ...................................................................................................... 54 
APPENDIX C .............................................................................................................................. 58 
9. 
REFERENCES .................................................................................................................... 60 
 
 

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ABBREVIATIONS 
ACC 
American College of Cardiology 
AE 
Adverse Event 
AHA 
American Heart Association 
ARO 
AUC 
Academic Research Organisation 
Area Under The Curve 
CA 
Competent Authority 
CABG 
Coronary Artery Bypass Graft 
CCU 
Coronary Care Unit 
CHF 
Congestive Heart Failure 
CI  
Confidence Interval 
CK 
Creatine Kinase 
CK-MB 
Creatine Kinase Muscle Band 
CRA 
Clinical Research Associate 
CRF/eCRF 
Case Report Form / electronic Case Report Form 
CRO 
Clinical Research Organisation 
CTP 
Clinical Trial Protocol 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ER 
ESC 
Emergency room 
European Society of Cardiology 
EU 
European Union 
EC/IEC 
(Independent) Ethics Committee 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
Intracranial Haemorrhage 
ICU 
Intensive Care Unit 
IEC 
IRA 
Independent Ethics Committee 
Infarct-Related Artery 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
i.v. 
Intravenous(ly) 
IVRS 
Interactive Voice Response System 
LMWH 
Low Molecular Weight Heparin 
LRD 
Leuven Research & Development 
LSRP 
Life Sciences Research Partners 
 
 

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mg 
Milligram(s) 
min 
Minute(s) 
ml 
Millilitre(s) 
No. 
Number 
PCI                     Percutaneous Coronary Intervention 
PhI 
Pharmaco-invasive 
PPCI 
Primary Percutaneous Coronary Intervention 
p.o. 
per os (latin); oral(ly) 
PTCA 
Percutaneous transluminal coronary angioplasty 
SAE 
Serious Adverse Event 
s.c. 
Subcutaneous(ly) 
SOP 
Standard Operating Procedure 
STEMI 
ST-Segment Elevation Myocardial Infarction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TIA 
Trans-ischaemic Attack 
TIMI 
Thrombolysis in Myocardial Infarction 
TNK 
Tenecteplase 
UFH 
Unfractionated Heparin 
ULN 
Upper Limit of Normal  
 
 
 

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1. 
INTRODUCTION 
1.1 
MEDICAL BACKGROUND 
The use of timely primary percutaneous coronary intervention (PPCI) in patients with ST-segment 
elevation myocardial infarction (STEMI) is recommended by guidelines of the European Society 
of Cardiology (ESC)1 and American College of Cardiology (ACC)/American Heart Association 
(AHA)2 and has steadily increased during recent years. There is strong evidence that PPCI is a 
very effective therapy for STEMI.3, 4 
To be efficacious PPCI must be provided in an expert and timely fashion. This capacity is not 
equally accessible for all STEMI patients; moreover the frequency of PPCI use differs between 
countries and even between and within hospitals in the same country.  
Fibrinolysis is a well-accepted, evidence-based and guideline-supported strategy, especially in 
patients presenting soon after symptom onset, i.e. within 3 hours.5-8 
Pre-hospital fibrinolysis has proven to be feasible in various countries and patient’s management 
organisations, to increase the proportion of patients treated early and improve outcome.5, 6, 9-12 
 
In contemporary practice patients receiving fibrinolytic therapy may subsequently be treated with 
PCI either as part of a routine angiographic assessment before hospital discharge, as a rescue 
strategy based on inadequate pharmacologic reperfusion, or because of spontaneous or provoked 
recurrent ischaemia. Fibrinolysis combined with subsequent PCI has therefore been investigated 
in several contexts in recent trials.7, 10, 13, 14 
 
The STREAM-1 trial15, 16 demonstrated that in STEMI patients presenting within 3 hours of 
symptom onset (who could not undergo PPCI within 60 minutes), a pharmaco-invasive strategy 
that includes tenecteplase , urgent PCI for failed reperfusion and angiography within 24 hours in 
the remaining fibrinolytic-treated patients, achieved a comparable 30-day composite endpoint of 
all-cause death, cardiogenic shock, congestive heart failure (CHF), and re-infarction when 
compared to timely, contemporary PPCI. Mortality was also similar in both treatment groups at 1 
year.17 Importantly the original trial protocol was amended after 21% (n=379) of the intended 
enrolment because of an excess of intracranial haemorrhage (ICH) in patients ≥75 years. Thereafter 
there was a 50% reduction in the dose of tenecteplase in these patients. When concluded, the 
overall primary composite endpoint of death, cardiogenic shock, CHF and re-MI occurred in 
12.4% of the PhI group versus 14.3% of the PPCI patients (relative risk (RR) 0.86; 95% confidence 
interval (CI) 0.68-1.09; P=0.21) in 1892 patients. Whereas no further ICH occurred in the 
subsequent 97 patients ≥75 years randomised to the PhI strategy, the relationship between the dose 
reduction and efficacy remains uncertain. Preliminary data indicates that the extent of ST-segment 
resolution 60 to 90 minutes after ½ dose tenecteplase was comparable to full dose but this requires 
confirmation in a larger data set.18  
Importantly at least one third of PhI- treated patients required urgent coronary intervention because 
of failed fibrinolysis or early recurrent ischemia after initially successful reperfusion.19 The role of 

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platelet aggregation as it relates to this issue is unclear, but has been postulated to be significant 
and is known to be ameliorated by administration of P2Y12 antagonists. In STREAM-1 no 
additional loading dose of clopidogrel was given because when designing the study no reliable 
data were available in patients ≥ 60 years. Hence the role of a more effective dosing of clopidogrel 
(a loading dose of 300 mg vs 75 mg used in STREAM-1) in patients ≥ 60 years is worthy of further 
exploration and will be incorporated in STREAM-2. Such a dose has been used safely in the elderly 
as reported by Larson et al.20. 
 
Recognizing  the continuing challenges in achieving timely expert PPCI,  the need to acquire 
greater confidence in the efficacy and safety of ½ dose tenecteplase in patients ≥ 60 years  and  the 
gap in knowledge on both the safety and efficacy of new and adequately-dosed conventional 
P2Y12 platelet inhibitors, the STREAM-2 study has the following main objectives; 
 
1. Compare the efficacy and safety of a PhI reperfusion strategy with PPCI in STEMI patients 
≥ 60 years. 
2. Compare the incidence of intracranial and non-ICH major systemic bleeding in  STEMI 
patients ≥ 60 years receiving pre-hospital clopidogrel 300 mg as adjunct to ½ dose 
tenecteplase. 
1.2 
PHARMACOLOGIC THERAPY 
Tenecteplase 
Tenecteplase is a derivative of the wild-type tissue type plasminogen activator, tPA (identical to 
the recombinant marketed agent, rtPA, alteplase) with three amino acid site substitutions:  
a threonine (T) replaced by an asparagine, which adds a glycosylation site to position 103;  
an asparagine (N) replaced by a glutamine, thereby removing a glycosylation site from position 
117; and four amino acids, lysine (K), histidine (H), arginine (R), and arginine (R), replaced by 
four alanines at the third site.  
These substitutions prolong half-life, increase fibrin specificity, and increase resistance to 
inhibition by plasminogen activator inhibitor-1 (PAI-1).21 In pharmacokinetic studies in patients 
with acute myocardial infarction, tenecteplase was shown to exhibit biphasic disposition kinetics 
with an initial half-life of 17-24 min and a terminal half-life of 65-132 min. The initial half-life 
accounted for approximately 70 % of the AUC (area under the curve).22 
ASSENT-3, a large international phase III study with 6095 patients, compared the efficacy and 
safety of various treatment regimens combining tenecteplase with different antithrombin agents: 
unfractionated heparin (UFH) or enoxaparin or UFH plus abciximab.23 Tenecteplase combined 
with body weight-adjusted UFH showed the same 30-day mortality as in ASSENT-2 (6.0 % and 
6.2 %, respectively), whereas major bleeds (other than ICH) were reduced by half compared to 
ASSENT-2 (2.2 % and 4.7 %, respectively).23, 24 The reduced bleeding rate, without reducing 
efficacy was probably related to the use of a lower body weight-adjusted dose of UFH in ASSENT-

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3 in accordance with the ACC/AHA and ESC guidelines of that time. Although there was no 
difference in mortality between the three treatment groups in ASSENT-3, adjunctive therapy with 
abciximab or enoxaparin with half-dose tenecteplase reduced ischaemic complications (in-hospital 
reinfarction or ischaemia) as compared to adjunctive treatment with UFH. Particularly for 
abciximab and to a lesser extent for enoxaparin, these benefits were obtained at the cost of an 
increased rate of extracranial and intracranial bleeding complications particularly in female and 
the elderly patients.23 
As noted above the STREAM-1 trial used a pharmaco-invasive strategy of tenecteplase, ASA, 
enoxaparin followed by an invasive strategy urgent PCI for failed reperfusion and angiography 
within 24 hours in the remaining fibrinolytic-treated patients. This strategy achieved a comparable 
30-day composite endpoint of all-cause death, cardiogenic shock, congestive heart failure (CHF), 
and re-infarction when compared to timely, contemporary PPCI. In the patients ≥ 75 years a change 
from full to half dose tenecteplase proved to be safer without evidence of reduced efficacy based 
on the extent of ST resolution and rate of rescue PCI.16 Based on these results the new ESC 
guidelines for the treatment of STEMI patients recommend administration of half-dose 
tenecteplase to patients ≥ 75 years of age.1 This recommendation is based on the data from 97 
patients ≥ 75 years from the STREAM-1 study randomized to half-dose tenecteplase after the 
amendment. They had a favourable clinical outcome and, importantly,  no ICH was observed.18  
Enoxaparin 
Addition of unfractionated or low molecular weight heparin (LMWH) to fibrinolytic therapy has 
been shown to reduce mortality and the rate of recurrent myocardial infarction.23, 25 Enoxaparin is 
a low molecular weight heparin used for anticoagulation that – in contrast to heparin which 
requires intravenous use – can be administered subcutaneously.  
In the ExTRACT-TIMI 25 trial enoxaparin and UFH were compared as adjunctive therapies to 
fibrinolytic treatment in 20506 patients with STEMI.25 This trial used reduced enoxaparin doses 
in the elderly and the renal insufficiency patient as compared to ASSENT-3 and ASSENT-3 
PLUS26. In the enoxaparin group the primary end point, death or nonfatal myocardial infarction 
within 30 days, was significantly reduced by 2.1 percentage points (17% relative change) as 
compared to unfractionated heparin. However, the rate of major bleedings was significantly 
increased in the enoxaparin group (2.1% vs. 1.4%), whereas the rate of intracranial haemorrhage 
did not differ significantly at 30 days.25, 27 The magnitude of excess of bleeding tended to lower in 
the elderly assigned to reduced-dose enoxaparin, however.  
Clopidogrel 
Addition of clopidogrel, a thienopyridine acting as adenosine diphosphate receptor antagonist, to 
a regimen of fibrinolytic agent, heparin (if indicated), and acetylsalicylic acid lead to a highly 
significant reduction (15.0 % vs. 21.7 % as compared to placebo) in the composite endpoint (TIMI 
flow 0-1 on angiogram, death and recurrent myocardial infarction prior to angiography) in the 

Version 5, 19 April 2021 
 
 
16 
 
CLARITY study with 3491 patients presenting with STEMI within 12 hours from symptom onset. 
Although mortality was not reduced by addition of clopidogrel as compared to placebo, consistent 
effects of clopidogrel in improving angiographic outcomes and reduction of ischaemic events as 
well as a near-significant (p = 0.052) reduction of the stroke risk were observed.28 In addition, the 
dose used (300 mg loading dose, followed by 75 mg daily) did not increase the risk of bleeding 
and was therefore considered safe for patients up to 75 years. Additional observational data from 
Larson et al supports the safety and efficacy of 300 mg clopidogrel in elderly patients receiving 
half dose fibrinolysis.20 
These results are supported by the COMMIT trial, a large study with 45852 patients admitted 
within 24 hours of symptom onset of myocardial infarction, which showed a highly significant 
proportional reduction of the composite of death, reinfarction, or stroke.29 Although, in contrast to 
CLARITY, no loading dose was given, the mortality rate was reduced significantly as compared 
to placebo. Furthermore, the daily dose of 75 mg neither led to increased bleeding rates in elderly 
patients (> 70 years of age) nor in patients who received additional fibrinolytic treatment 
(approximately 54 %).29 
1.3 
RATIONALE FOR PERFORMING A NEW TRIAL COMPARING A 
PHARMACO-INVASIVE THERAPY WITH PRIMARY PCI 
Substantial data indicate that the patient baseline characteristics30 and the ‘PCI-related delay30, 31, 
32 are key factors for the selection of optimal treatment for STEMI patients , i.e. whether a PhI 
strategy or PPCI is the more favourable treatment  for the patient. Local and logistic factors, such 
as the availability and distance to catheterisation laboratories, have a major impact on the PCI-
related delay33 and also modulate  selection of reperfusion strategies. A flexible approach, which 
retains the ability to employ either strategy, is therefore desirable and is supported by current 
ACC/AHA/ESC guidelines.1, 2 
As compared to PPCI, fibrinolytic treatment is a therapy that is immediately available and requires 
much less technical effort and equipment. It has been shown to be beneficial and most effective, 
when it is administered early after onset of symptoms.5, 6, 30, 34 Initiation of fibrinolytic treatment 
within the first three hours after onset of symptoms was shown to result in a lower or at least 
equivalent mortality rate for patients receiving fibrinolytic therapy as compared to PPCI.5, 6, 17, 30, 
34 The use of early fibrinolytic treatment in the pre-hospital setting led to reduced mortality as 
demonstrated in different national registries.6, 8, 11 Further combination with subsequent routine or 
rescue coronary intervention as required has also been supported by recent studies.7, 10, 13, 14, 35 
In the French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction (FAST-
MI) 1492 STEMI patients with a first call ≤ 12 hours from onset, 447 (30%)  received fibrinolysis 
(66% prehospital; 97% with subsequent angiography, 84% with subsequent PCI).36 583 (39%) had 
PPCI, and 462 (31%) received no reperfusion. Crude 5-year survival was 88% for the fibrinolytic 
based strategy, 83% for PPCI, and 59% for no reperfusion. Adjusted hazard ratios for 5-year death 
were 0.73 (95% confidence interval, 0.50–1.06) for fibrinolysis versus PPCI, 0.57 (95% 

Version 5, 19 April 2021 
 
 
17 
 
confidence interval, 0.36–0.88) for prehospital fibrinolysis versus PPCI, and 0.63 (95% confidence 
interval, 0.34–0.91) for fibrinolysis versus PPCI beyond 90 minutes of call in patients having 
called ≤180 minutes from onset. In propensity score–matched populations, however, survival rates 
were not significantly different for fibrinolysis and PPCI, both in the whole population (88% lysis, 
85% PPCI) and in the population seen early (87% fibrinolysis, 85% PPCI beyond 90 minutes from 
call). The authors concluded that in a real-world setting, on a nationwide scale, a pharmaco-
invasive strategy constitutes a valid alternative to PPCI, with 5-year survival at least equivalent to 
PPCI.36 Recent registry data from Belgium and the US similarly supports this supposition.37, 38 
More recent publications provide additional support for PhI strategy in STEMI. A randomized 
clinical trial [Circulation  2017]  showed that in 171 patients < 76 years half-dose alteplase given 
as a PhI strategy when there was an expected PCI delay of  > 1 hour was safe (no ICH) and 
associated with more complete epicardial and myocardial reperfusion (tissue reperfusion) 
compared with standard PPCI.39 The accompanying editorial highlights the role of a PhI strategy 
in a broad range of settings and references the STREAM2 study.40 Another registry study of over 
12000 STEMI patients from Germany  [European Heart Journal 2018] re-emphasizes the 
importance of timely  PCI (reperfusion) when this is the sole reperfusion strategy.41 In patients 
with or without hemodynamic instability who had their first balloon inflation within 1 to 3 hours 
after first medical contact (exactly the same time window for PCI as in STREAM there was a 
nearly linear relationship between PCI delay and mortality. In cardiogenic shock patients, every 
10 min delay resulted in an excess of 3.3 deaths per 100 PCI-treated patients. It is likely that 
earlier reperfusion with pre-hospital administration of a fibrinolytic agent would have prevented 
a significant amount of cardiogenic shock and death in this population. The 1.5 % absolute 
reduction in the incidence of shock observed in the STREAM-1 study supports this conjecture. 
       Against this background the bleeding risk of full dose tenecteplase was evaluated according 
to age by using all the data from studies using the current recommended full weight-adjusted 
dose of tenecteplase. These data are drawn from the following trials: Assessment of the Safety 
and Efficacy of a New Thrombolytic (ASSENT)-2, ASSENT-3, ASSENT-3 Plus, ASSENT- 4 
PCI and STREAM-1.9, 16, 23, 24, 42 Major bleeding complications and ICH were assessed from 
almost 24 000 patients treated with full weight-adjusted dose tenecteplase. The results are 
compelling and are shown in the 3 figures below.  
 
Figure 1: ICH  

Version 5, 19 April 2021 
 
 
18 
 
 
 
N=
Age (yrs)
Assent 2 TNK+Activase & 3 (full dose TNK only) & 3+ & 4 (TNK only) & STREAM (full dose TNK only): ICH
0.22%
0.39%
0.48%
0.45%
0.76%
1.21%
1.93%
2.61%
1.99%
  0.00%
  0.10%
  0.20%
  0.30%
  0.40%
  0.50%
  0.60%
  0.70%
  0.80%
  0.90%
  1.00%
  1.10%
  1.20%
  1.30%
  1.40%
  1.50%
  1.60%
  1.70%
  1.80%
  1.90%
  2.00%
  2.10%
  2.20%
  2.30%
  2.40%
  2.50%
  2.60%
  2.70%
2290
<45
2309
45-49
3099
50-54
3128
55-59
3311
60-64
3302
65-69
4344
70-74
727
75-79
1456
>=80

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19 
 
Figure 2: Major non-intracranial bleeding 
 
N=
Age (yrs)
Assent 2 TNK+Activase & 3 (full dose TNK only) & 3+ & 4 (TNK only) & STREAM (full dose TNK only): Major Bleed
1.79%
2.82%
2.61%
3.33%
4.77%
5.42%
7.05%
7.84%
9.77%
  0.00%
  1.00%
  2.00%
  3.00%
  4.00%
  5.00%
  6.00%
  7.00%
  8.00%
  9.00%
 10.00%
2289
<45
2308
45-49
3099
50-54
3127
55-59
3311
60-64
3301
65-69
4342
70-74
727
75-79
1454
>=80

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20 
 
Figure 3: ICH and major non-intracranial bleeding 
 
These data indicate that the risk of major bleeding and/or ICH begins to increase around the age 
of 60 years. Based on all of the above considerations the STREAM-2 protocol has been amended 
in order to include patients ≥ 60 years with no upper age limit. The benefit of earlier reperfusion 
would be expected to translate into a lower % cardiogenic shock, congestive heart failure and 
improved long-term survival as already suggested by the STREAM-1 study.16  
 
 The current trial will therefore evaluate the safety and efficacy of a treatment strategy designed to 
reflect optimal clinical practice that includes early fibrinolysis and appropriate contemporary 
adjunctive medical therapy followed by coronary intervention, as required (‘lyse now, stent 
later’)43, or standard PPCI with adequate medical therapy in  patients ≥ 60 years with STEMI 
presenting less than 3 hours after symptom onset.  
1.4 
BENEFIT / RISK ASSESSMENT 
Patients assigned to the PhI group will receive tenecteplase combined with antiplatelet 
N=
Age (yrs)
Assent 2 TNK+Activase & 3 (full dose TNK only) & 3+ & 4 (TNK only) & STREAM (full dose TNK only): ICH + Major Bleed
2.01%
3.16%
3.10%
3.74%
5.47%
6.54%
8.73%
10.18%
11.62%
  0.00%
  1.00%
  2.00%
  3.00%
  4.00%
  5.00%
  6.00%
  7.00%
  8.00%
  9.00%
 10.00%
 11.00%
 12.00%
2289
<45
2308
45-49
3099
50-54
3127
55-59
3311
60-64
3301
65-69
4342
70-74
727
75-79
1454
>=80

Version 5, 19 April 2021 
 
 
21 
 
(acetylsalicylic acid), antithrombin (enoxaparin) treatment and clopidogrel 300 mg. Thereafter 
they will undergo cardiac catheterisation within 6-24 hours or rescue coronary intervention as 
required and, if indicated, stent implantation.  
As previously indicated, fibrinolysis is a well-established treatment recommended by clinical 
guidelines. The main risk associated with fibrinolytic treatment is bleeding. Patients will be 
carefully screened to minimise bleeding risk. Hence in the current study, patients ≥60 years, who 
are known to have an increased bleeding risk44, will receive half-dose tenecteplase. As was the 
case in STREAM-1, the initial bolus of enoxaparin will be omitted to conform to the evidence-
based strategy of the ExTRACT trial25, 27, 29 which supports this approach as safe and effective. 
Based on the study of Larson et al20 attesting to the safety of ½ dose fibrinolytic and a 600 mg 
loading dose of clopidogrel in elderly patients, clopidogrel 300 mg will be administered in Group 
PhI. In addition, patients with low body weight (i.e. below 55 kg) will be excluded to minimise 
the small but definitive risk of ICH noted from prior trials. Insufficient reperfusion or vessel 
reocclusion after fibrinolysis will be addressed, as per current guidelines, by measuring ST-
segment resolution. Patients who do not show ECG and/or clinical evidence of adequate 
reperfusion 90 min after bolus tenecteplase will undergo prompt rescue PCI.  
Patients randomised to PPCI will be treated in accordance with international PCI guidelines in the 
prehospital setting. PPCI is a routine treatment in patients with STEMI and will therefore serve as 
a comparator to the PhI arm. It has been shown to be safe and effective in securing and maintaining 
coronary artery patency. Patients with contraindications will be excluded.  
During the course of the trial a Data Safety Monitoring Board (DSMB) will review, on a regular 
basis and whenever necessary, all safety data and evaluate the patients’ safety and possible risks. 
The DSMB will report to the Executive Committee and is entitled to recommend any measures 
required to secure the patients’ safety. 
 
2. 
TRIAL OBJECTIVES 
2.1 
GENERAL AIM  
This study will evaluate the efficacy of 2 reperfusion strategies based on ST-segment resolution in 
patients ≥ 60 years presenting with acute STEMI within 3 hours of symptom onset in a pre-hospital 
setting/community hospital. Following randomisation to a strategy of early (pre-hospital) 
tenecteplase and additional enoxaparin and a loading dose of clopidogrel, patients will undergo 
cardiac catheterisation within 6-24 hours with timely coronary intervention as appropriate (or by 
rescue coronary intervention if required) in Group PhI. Patients randomized to group PPCI will 
receive concomitant antithrombotic treatment according to local practice. The efficacy will be 
evaluated by ST-segment resolution (cfr infra), TIMI flow grades and need for rescue PCI (in PhI 
group). 

Version 5, 19 April 2021 
 
 
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Clinical events i.e. death, shock, heart failure, recurrent MI and aborted MI will be recorded and 
assessed as single or composite endpoints for evaluation as noted in the statistical analytical plan. 
All statistical tests on clinical events are of exploratory nature based on descriptive p-values with 
estimation of 95% confidence limits for formal statistical hypotheses generation. For comparison 
the same composite clinical event rates (for example the composite of death, shock, congestive 
heart failure and re-infarction = primary endpoint of STREAM-1) will be analysed (see 
APPENDICES). 
2.2 
EFFICACY ENDPOINT 
The trial is of exploratory nature with the aim to examine the potential benefits of this pharmaco-
invasive strategy. Therefore, no confirmatory statistical hypothesis is pre-specified. All statistical 
tests are of exploratory nature based on descriptive p-values with accompanying 95% confidence 
limits for formal statistical hypotheses generation. Efficacy for early reperfusion will be 
evaluated by the number of patients achieving ≥ 50 % ST-segment resolution before and after 
PCI in lead with maximal ST elevation at baseline; % rescue PCI; TIMI flow grades. 
 
An intent-to-treat analysis of all randomised patients will be carried out. After 50 % of the planned 
recruitment a formal interim analysis will be performed by the DSMB to evaluate and advise the 
Executive Committee on the feasibility and justification of enlarging the sample size with 
provision to proceed with a confirmatory trial. 
3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION 
3.1 
OVERALL TRIAL DESIGN AND PLAN - DESCRIPTION 
The current trial is designed as an open-label, prospective, randomised, parallel, comparative 
international multi-centre trial.  
In patients > 60 years with acute ST-elevation myocardial infarction randomised within 3 hours of 
onset of symptoms, the efficacy and safety of a strategy of early fibrinolytic treatment with half-
dose tenecteplase and additional antiplatelet and antithrombin therapy followed by catheterisation 
within 6-24 hours or rescue coronary intervention as required will be compared to a strategy of 
PPCI according to local standards.  
 
 

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Figure 4: Overall Trial Design 
 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL 
GROUPS 
Although several studies and registries have compared fibrinolytic treatment with PPCI in patients 
with acute myocardial infarction, limited trial data are available in older patients ≥60 years 
regarding the strategy of early fibrinolysis followed by PCI versus a strategy of PPCI, in particular 
in the pre-hospital setting.5, 10, 18, 42  Moreover, limited data exists concerning the efficacy and safety 
of a loading dose of clopidogrel combined with fibrinolytic therapy in such patients. 
The groups of interest are:  
 
Group PhI: fibrinolytic treatment with half-dose tenecteplase combined with clopidogrel 
300 mg and followed by catheterisation within 6-24 hours or rescue coronary 
intervention as required.  
 
 Group PPCI: PPCI according to local standards.  

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3.3 
SELECTION OF TRIAL POPULATION 
Patients with ST-elevation acute myocardial infarction (STEMI) within 3 hours of symptom onset 
in the pre-hospital setting will be randomised to Group PhI for a strategy of early pre-hospital/ER 
community hospital fibrinolysis or to PPCI, if the eligibility criteria mentioned below are met.  
Approximately 600 patients (400 patients to group PhI and 200 patients to group PPCI) will be 
enrolled in approximately 65 sites located in different countries (for sample size calculation see 
section 7).  A minimum of 100 patients ≥ 70 years of age will be randomized to the PhI arm 
3.3.1 
Inclusion criteria 
1. Age equal or greater than 60 years  
2. Onset of symptoms < 3 hours prior to randomisation 
3. 12-lead ECG indicative of an acute STEMI (ST-elevation will be measured from the J point; 
scale: 1 mm per 0.1 mV): 
- 
 2 mm ST-elevation across 2 contiguous precordial leads (V1-V6) or leads I and aVL for 
a minimum combined total of  4 mm ST-elevation  
or 
- 
 2 mm ST-elevation in 2 contiguous inferior leads (II, III, aVF) for a minimum combined 
total of  4 mm ST-elevation   
 
4. Informed consent received  
3.3.2 
Exclusion criteria 
1. Expected performance of PCI < 60 minutes from diagnosis (qualifying ECG) or 
inability to arrive at the catheterisation laboratory within 3 hours  
2. Previous CABG 
3. Left bundle branch block or ventricular pacing  
4. Patients with cardiogenic shock - Killip Class 4  
5. Patients with a body weight < 55 kg (known or estimated) 
6. Uncontrolled hypertension, defined as sustained blood pressure  180/110 mm Hg 
(systolic BP  180 mm Hg and/or diastolic BP  110 mm Hg) prior to randomisation  
7. Known prior stroke or TIA 
8. Recent administration of any i.v. or s.c. anticoagulation within 12 hours, including 
unfractionated heparin, enoxaparin, and/or bivalirudin or current use of oral 
anticoagulation (i.e. warfarin or a NOACs) 
9. Active bleeding or known bleeding disorder/diathesis 
10. Known history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or 
spinal surgery) or recent trauma to the head or cranium (i.e. < 3 months) 

Version 5, 19 April 2021 
 
 
25 
 
11. Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 
months (this includes any trauma associated with the current myocardial infarction) 
12. Clinical diagnosis associated with increased risk of bleeding including known active peptic 
ulceration and/or neoplasm with increased bleeding risk 
13. Known severe renal insufficiency  
14. Prolonged cardiopulmonary resuscitation (> 2 minutes) within the past 2 weeks 
15. Known acute pericarditis and/or subacute bacterial endocarditis 
16. Known acute pancreatitis or known severe hepatic dysfunction, including hepatic failure, 
cirrhosis, portal hypertension (oesophageal varices) and active hepatitis  
17. Dementia 
18. Previous enrolment in this study or treatment with an investigational drug or device 
under another study protocol in the past 7 days 
19. Known allergic reactions to tenecteplase, clopidogrel, enoxaparin and aspirin 
20. Inability to follow the protocol and comply with follow-up requirements or any other 
reason that the investigator feels would place the patient at increased risk if the 
investigational therapy is initiated. 
 
4. 
TREATMENTS 
4.1 
TREATMENTS TO BE ADMINISTERED 
4.1.1 
Identity of investigational products 
Tenecteplase (Metalyse®) manufactured by Boehringer Ingelheim (Metalyse®) or Genentech Inc. 
(TNKase®), will be taken off the shelf or made available according to local regulations. Vials 
contain either 50 mg or 40 mg of tenecteplase lyophilized powder and excipients, L-arginine, 
phosphoric acid and polysorbate 20, for reconstitution with sterile water from a 10 mL or 8 mL 
vial, respectively 
Clopidogrel will be taken of the shelf. Tablets contain 75 mg of clopidogrel for oral use. 1 tablet 
containing 300 mg clopidogrel can be given as loading dose instead of 4 tablets of 75 mg. 
4.1.2 
Methods of assigning patients to treatment groups 
Immediately after screening in the pre-hospital setting, eligible patients will be randomised 2:1 to 
the pharmaco-invasive therapy or to PPCI.  
Randomisation will be performed centrally by means of an interactive voice response system 
(IVRS), which has to be called by the investigator or an authorised member of site staff.  

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4.1.3 
Selection of doses in the trial 
Tenecteplase is given in a weight-adjusted dose regimen as described in the following section 
(4.1.4) according to the Basic Product Information.45 Based on the strategy used by Larson et al.20 
and after balancing the risks versus benefits the dose has been adapted for patients ≥ 60 years of 
age who will receive half dose tenecteplase. As described below, the strategy of measuring ST-
segment resolution at 90-minutes after fibrinolysis, or earlier if clinically indicated and performing 
rescue PCI, if appropriate, in Group PhI is considered to provide an optimal balance between 
efficacy and safety. 
Based on the results of the ASSENT-3 and ExTRACT trials (please refer to section 1.2 for details) 
reduced dose of LMWH enoxaparin will be used in the current trial.).25, 26 In the ExTRACT trial, 
the dose of enoxaparin was reduced for patients of at least 75 years of age, which resulted in 
positive overall results for this age group. To conform to these results the initial intravenous bolus 
of enoxaparin will be omitted and a reduced daily dose of enoxaparin (0.75 mg/kg instead of 1 
mg/kg) will be administered in this trial for patients of at least 60 years of age. 
As described in section 1.2, the dose of clopidogrel in group PhI chosen in this trial (300 mg p.o. 
initial loading dose followed by 75 mg p.o. qd.) is based on the results of CLARITY, COMMIT 
and STREAM-1.16, 20, 28, 29 
Acetylsalicylic acid is used as routine treatment after acute myocardial infarction and has been 
shown to be beneficial when combined with tenecteplase in several trials.24, 26 Recent guidelines 
recommend 150 – 325 mg p.o. given immediately, followed by 75 – 100 mg once daily with 
lifelong treatment unless it is contraindicated. 
As for the sequence of treatments, the required dose of tenecteplase administered as a single 
intravenous bolus over 5-10 seconds should be the first drug injected. Next, the s.c. dose of 
enoxaparin and then the oral drugs, i.e. clopidogrel and acetylsalicylic acid, should be given.  
Pharmacological  treatment will be followed by timely coronary angiography after 6 hours but 
within 24 hours of the start of fibrinolytic therapy and, if required, PCI or, in case of insufficient 
ST resolution at 90 min (or earlier if clinically indicated), rescue PCI. The time window of 6-24 
hours between the start of fibrinolysis and catheterisation avoids interventions when there is still 
the pro-thrombotic effect of the lytic agent on the one hand and, on the other hand, minimalizes 
the risk of spontaneous reocclusion after successful fibrinolysis. The decision on rescue PCI will, 
however, be taken 90 min (or earlier if clinically indicated) after injection of tenecteplase 
according to the ST resolution.35 Rescue PCI will be centrally adjudicated in the core ECG 
laboratory.  
In the PPCI arm, patients will receive antithrombotic treatments as soon as possible according to 
local standards and international guidelines.  
Please also refer to section 1.2 for details. 

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4.1.4 
Selection and timing of doses for each patient 
4.1.4.1 Group PhI 
Pre-PCI hospital (ambulance/ER community hospital) treatment: 
Acetylsalisylic acid 
Acetylsalicylic acid is expected to be administered routinely to all patients: a loading dose of 
150-325 mg p.o. if not on acetylsalisylic acid already. Alternatively, if the patient is unable to 
ingest tablets, the initial dose may be given intravenously (80 to 250 mg i.v.). If a patient has 
already taken acetylsalicylic acid within 12 hours prior to screening the patient will start with 
acetylsalicylic acid the next day (maintenance dose: 75 to 100 mg). 
 
Tenecteplase 
50 or 40 mg of drug reconstituted in sterile water (10 or 8 ml respectively) for injection will be 
given as single weight-adjusted i.v. bolus over 5 - 10 seconds according to the following scheme: 
Weight (kg) 
Dose (mg) 
Dose (ml) 
55 to <60 
15.0 mg 
  3.0 ml 
60 to <70 
17.5 mg 
  3.5 ml 
70 to <80 
20.0 mg 
  4.0 ml 
80 to <90 
22.5 mg 
  4.5 ml 
90  
25.0 mg 
  5.0 ml 
 
The total dose of tenecteplase is injected into an intravenous line of normal saline, as close to the 
insertion site as possible, using aseptic technique. The total dose is to be injected as a rapid 
intravenous bolus over 5 - 10 seconds. The intravenous line is to be flushed with normal saline 
immediately after injection of the tenecteplase bolus to ensure complete drug delivery. 
Tenecteplase must not be administered in dextrose or Ringer’s solution. 
The same i.v. line may be used for administration of other medication after flushing the line with 
a sufficient amount of normal saline prior to the subsequent intravenous injection. 
 
Enoxaparin 
< 75 years: 
- 
30 mg i.v. bolus  
- 
S.c. injections of 1.0 mg/kg every 12 hours until hospital discharge (4 days); the first 
injection should be given within 15 min of the bolus  
- 
For the first two s.c. injections, a maximum of 100 mg should not be exceeded  
 
≥ 75 years: 
- 
No bolus;  
- 
S.c. injections of 0.75 mg/kg every 12 hours until hospital discharge or for a maximum of 

Version 5, 19 April 2021 
 
 
28 
 
4 days; the first injection should be given immediately 
- 
For the first two s.c. injections, a maximum of 75 mg per injection should not be exceeded 
For patients of any age with a creatinine clearance < 30 ml/min, s.c. injections of 0.75 mg/kg will 
be given in intervals of 24 hours. 
 
Clopidogrel 
- 
300 mg p.o. initial loading dose (either 4x75 mg or a single 300 mg dose) 
- 
75 mg p.o. once daily as maintenance dose 
 
In-PCI hospital treatment: 
Patients randomised in the ER of a community hospital will be transferred immediately to the PCI 
hospital after receiving study medication. This is needed to ensure timely rescue coronary 
intervention if required.46 Only community hospitals without a catheterization lab and who have 
an established transfer protocol with a PCI hospital can participate in the study. 
The patient should be admitted to either the emergency department, coronary care unit or 
catheterisation laboratory (as per local practice). 
Assessment of reperfusion (by ECG) and evaluation of clinical symptoms will be done 90 min 
after injection of tenecteplase or earlier if clinically indicated. 
 
ENOXAPARIN 
Continuation of enoxaparin started at randomisation: 
 
<75 years: 1.0 mg/kg SC (max 100 mg) every 12 h (i.v. bolus already given at randomisation) 
≥75 years: 0.75mg/kg SC (max 75 mg) every 12 h 
 
Prior to catheterisation enoxaparin should be given according to the following scheme (please 
also refer to chapter 4.2.2 for restrictions). 
If cath before 2nd s.c. enoxaparin dose:  0.3 mg/kg iv enoxaparin 
If cath after 2 or more s.c. enoxaparin doses and ≤ 8 hr after last dose:  no additional enoxaparin 
If cath after 2 or more s.c. enoxaparin doses and  > 8 hr after last dose:  0.3 mg/kg iv enoxaparin 
 
After sheath removal: further use of s.c.enoxaparin is at the discretion of investigator (e.g. in 
patients where anti-thrombin treatment is indicated, as in atrial fibrillation etc.) 
 
 
 
 
 

Version 5, 19 April 2021 
 
 
29 
 
- Clarifications: 
- If catheterisation is performed ≤ 8 hours after the second or any later s.c. enoxaparin dose, no 
additional i.v. enoxaparin should be given (see box above). 
- If catheterisation is performed > 8 hours from the second or any later s.c. enoxaparin dose, 
additional 0.3 mg/kg of i.v. enoxaparin should be administered. 
If a closure device is used, the sheath should be removed at the end of the PCI; however, if no 
closure device is used, the sheath should be removed at least 6 h after the last intravenous or 
subcutaneous dose of enoxaparin.  
After sheath removal further use of s.c. enoxaparin is at the discretion of the investigator (e.g. in 
patients where antithrombin treatment is indicated, as in atrial fibrillation etc.). If longterm oral 
anticoagulation is needed (eg because of atrial fibrillation) aspirin may be stopped (at the discretion 
of local investigator). 
Important Note: For patients who received enoxaparin according to the protocol a change to a 
different type of heparin (e.g., unfractionated heparin) before or during catheterisation should be 
avoided (cf. 4.2.2). 
 
CLOPIDOGREL 
The maintenance dose of clopidogrel (75 mg p.o. per day) should be continued for 1 year. 
 
CATHETERISATION: for details please refer to section 6.2.2.1. 
 
4.1.4.2 Group PPCI 
Pre-PCI hospital (ambulance/ER community hospital) treatment: 
Acetylsalisylic acid 
Acetylsalicylic acid is expected to be administered routinely to all patients at a dose of 150-325 
mg p.o.  Alternatively, if the patient is unable to ingest tablets, the initial dose may be given 
intravenously (80 to 150 mg i.v.). If a patient has already taken acetylsalicylic acid within 12 
hours prior to screening the patient will start with acetylsalicylic acid the next day (maintenance 
dose: 75 to 100 mg). 
 
P2Y12 antagonist 
A P2Y12 antagonist is to be administered according to local practice and international guidelines. 
Prasugrel should not be administered to any patient ≥ 75 years of age. cfr FDA product label. 
 
Antithrombin treatment according to local standards and in accordance with international PCI 
guidelines (e.g., unfractionated heparin/ enoxaparin/ bivalirudin). 
 

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In-PCI hospital treatment: 
At the receiving PCI hospital transfer to the catheterisation laboratory should be organised as soon 
as possible as per local practice and in accordance with the protocol timelines. The patient should 
be admitted preferably directly to the catheterisation laboratory.  
 
Standard PPCI 
Standard PPCI procedure following angiography (use of additional GP IIb/IIIa antagonists is at 
the investigator’s discretion). As per current guidelines, only PCI of the infarct related vessel 
should be performed. PCI of non-infarct related vessels is NOT recommended. For details please 
refer to section 6.2.2.2. 
4.1.5 
Blinding 
This is an open-label trial. All treatment strategies will be performed in an unblinded manner.  
4.1.6 
Study medication 
No study kits will be provided and medications will be taken “off the shelf” or made available 
according to local regulations. All medications to be administered in the study are commercially 
available in the participating countries. Investigators will be asked to make sure that study 
medications are available in ambulances/ERs of community hospitals. All concomitant or rescue 
treatment(s) taken during the course of the trial must be recorded in the source documents (e.g. 
patient files). 
4.2 
ADDITIONAL THERAPIES 
4.2.1 
Rescue medication and additional treatments 
Protamine (sulphate or hydrochloride) administered as a slow i.v. injection (1 mg protamine per 1 
mg of enoxaparin) may be used to neutralise the effect of enoxaparin (maximum effect: 60 % of 
the anti-Xa-activity).  
4.2.2 
Restrictions 
Enoxaparin and heparin 
Patients who received enoxaparin should not be administered a different type of heparin prior to 
catheterisation (and vice versa) as this may result in excessive anticoagulation well above 
therapeutic levels.47, 48 If heparin was initially used for PPCI patients, subsequent treatment 
should not be switched to enoxaparin prior to catheterisation. 
 
Prior to catheterisation a dose of 0.3 mg/kg i.v. enoxaparin should be given to patients in Group 
PhI, unless the last subcutaneous dose of enoxaparin was given within the previous 8 hrs.  

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GP IIb/IIIa antagonists 
GP IIb/IIIa antagonists should not be used in Group PhI except if required for bail-out situations 
in the catheter laboratory. The use of GP IIb/IIIa antagonists in PPCI arm is at the investigator’s 
discretion in accordance with STEMI/PCI guidelines and local standards. 
4.3 
TREATMENT COMPLIANCE 
As all study treatments will be given out of hospital by the emergency physician and/or by 
experienced paramedics (as per local regulations) or in the ER of a community hospital by 
physicians and nursing staff, few compliance problems are foreseen. The only reasons for 
deviations from the treatment schedule in the protocol are considered to take place in emergency 
situations, for patients’ safety, or due to the rare events of dosing mistakes by the study team. 
Information on dosing will be collected in the eCRF. 
 
5. 
OBSERVATIONS 
All observations that represent or contribute to a trial endpoint are listed in the Trial Flow Chart. 
Observations will be taken during different trial periods: the pre-PCI hospital (including 
ambulance/ER community hospital), the in-PCI hospital period, end of trial (30 days) and the 
follow-up period (1-year), respectively, as described below. Data have to be recorded on 
appropriate written or electronic source data, e.g. ambulance file, patient file, hospital chart, 
electronic ECG recording or printout, laboratory print-out, or any trial-specific worksheet. All 
required data will be transcribed into the eCRF.  
If needed, worksheets and instruction leaflets will be made available to the ambulance or hospital 
staff to facilitate data collection and ensure sample collection required for diagnostic and baseline 
purposes.  
Please refer to section 8.2.4 for further details regarding source documents. 
5.1 
EVALUATION OF EFFICACY 
ST-segment resolution on the ECG taken 90 min (or earlier if clinically indicated) after bolus 
tenecteplase and in both arms on the ECG taken in the PCI hospital before and 30 min after first 
catheterization (PCI), % rescue PCI and TIMI flow grades. 
5.1.1 
ECGs to be taken/analysed 
Twelve-lead ECGs at screening/baseline for initial diagnosis in all patients and subsequently: 
- 
In PhI group:  

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o 90 min (or earlier if clinically indicated) after bolus tenecteplase  
o Immediately before and 30 minutes after the catheterization procedure (with or 
without PCI/stenting). 
o In case of rescue/urgent PCI, ECGs will be taken immediately before the 
procedure and 30 minutes after the end of the procedure. 
- 
In PPCI group: an ECG will be taken before PCI procedure and 30 min after the PCI 
procedure. 
In all patients, additional ECGs will be recorded before hospital discharge or on day 4, 
whichever occurs first. Serial ECGs should be taken in case of symptoms of recurrent ischaemia 
or reinfarction (see tables 4 and 5). ECGs will be centrally adjudicated.  
 
ECG changes will be used to determine:  
- 
Infarct size: It will be calculated at hospital discharge or day 4 whichever is earlier) using 
Selvester QRS scoring system49 previously used in the ASSENT-3/3 Plus and ASSENT-4 
PCI studies.23, 42 
5.1.2. Clinical events 
Death, shock, heart failure, recurrent MI, rescue PCI and aborted MI will be recorded and assessed 
as single or composite endpoints for evaluation as noted in the statistical analytical plan. All 
statistical tests on clinical events are of exploratory nature based on descriptive p-values with 
estimation of 95% confidence limits for formal statistical hypotheses generation. 
 
For definitions of clinical events: see APPENDICES 
5.2 
SAFETY RECORDING 
5.2.1 
General assessment of safety 
During screening and baseline the patient’s condition is assessed. Results of routine observations 
– demographic data, medical history and concomitant diseases, physical assessment, vital signs, 
concomitant treatments – will be a part of the check for patient eligibility.  
- Medical history/current diseases:  
Data on previous and current relevant diseases will be collected, in particular information about 
any cardiovascular disease, hypertension, diabetes mellitus or renal insufficiency. 
- Concomitant therapy: 
 
Any chronic/concomitant antihypertensive, antiplatelet or anticoagulant treatment or otherwise 
significant therapy at screening and during the course of the study will be recorded. 

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- Physical assessment: 
 
It will be done as routine procedure at screening and will be used as check for patient eligibility. 
It comprises assessment of heart, lung, abdomen, etc. and should be recorded in the source 
documents. Results will not be collected in the eCRF. 
- Vital signs:  
Assessment of systolic and diastolic blood pressure and heart rate.  
- Haematology: 
 
Haematology laboratory samples (at least haemoglobin, haematocrit, erythrocytes, leucocytes 
and platelets) will be taken at baseline pre-hospital or, if this is not possible, on hospital arrival, 
and before hospital discharge according to the local hospital procedures. Values will be 
recorded in the eCRF as categories relative to the local reference ranges (i.e., 
below/within/above normal range). In case of bleeding or relevant laboratory abnormalities 
during the in-hospital period (until discharge) the laboratory values will be cross-checked with 
baseline values and with adverse events reports. 
- Renal function: 
 
Serum creatinine level (as per Cockcroft-Gault formula) should be measured at the first 
occasion to rule out renal insufficiency. In Group PhI patients with a creatinine clearance of 
< 30 ml/min, the dose of subsequent enoxaparin injections should be adjusted as described in 
section 4.1.4.1)27 . 
- Cardiac markers:  
Troponin I/T (or CK, CK-MB) will be measured at baseline, i.e. pre-hospital or on arrival at 
ER of the community hospital, as well as 8-12 hrs and 24 hrs after randomisation. If symptoms 
suggest occurrence of recurrent myocardial ischaemia or reinfarction during in-hospital stay, 
marker levels should be determined to confirm the diagnosis. Individual values will not be 
recorded in the eCRF, for the qualifying myocardial infarction only peak values expressed as 
times exceeding upper limit of normal will be recorded (cf. also section 5.1.2). 
- 12-lead ECG:  
For ECG measurements please refer to section 5.1.2. 
- TIMI flow grade:  
TIMI flow grade of the infarct-related artery (IRA) will be assessed by standard angiographic 
measurement during routine catheterisation in PhI Group or, for the PPCI Group, before PCI 
(first contrast injection) and after PCI (last contrast injection) as measured by the local 
investigator.  
- Killip class: 
Killip class will be determined before randomisation to check for patient eligibility. In case the 
ambulance staff consists of paramedics only, the responsible PI (or sub-investigator) must make 
sure the staff is sufficiently trained to perform the Killip classification. In the exceptional case 
that the Killip classification cannot be done at randomisation, it will be done upon arrival at the 
hospital. 

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- Adverse events:  
 
Expected adverse events (AEs) related to tenecteplase are listed in the current version of the 
Tenecteplase Investigator Brochure50, filed in the Investigator Site File.  
Adverse events will be recorded according to the following procedure until day 30 (cf. Figure 
2): 
All adverse events (serious and non-serious) need to be reported in the eCRF. 
In addition an SAE form must be completed and submitted within 24 hours for any SERIOUS 
adverse event: 
 related to study treatment (Tenecteplase, Clopidogrel, catheterisation/PCI) 
 not related to study treatment AND not on the list of the STEMI related events 
 
 
 
Figure 5: Adverse Event Reporting  
 
During screening/baseline, the patient’s condition is assessed; any relevant changes from 

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baseline will be noted subsequently in the source data (cf. section 8.2.4 for details).  
Patients and investigators will be required – according to the procedure described above –to 
report spontaneously any AEs as well as the time of onset, end and seriousness of these events. 
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. All 
events, including those persisting after trial completion must be followed up until they have 
resolved or have been sufficiently characterised. 
Definitions and requirements for documentation and reporting of AEs and SAEs during a trial 
are provided in sections 8.4.1. 
Worsening of pre-existing conditions 
 Expected fluctuations or expected deterioration of the underlying disease will not be 
recorded as an AE. Worsening of the disease under study will be recorded as an AE if one 
of the following criteria is met. 
o Worsening of disease meets the criteria for an SAE. 
o Treatment is required (concomitant medication is added or changed). 
o The investigator believes a patient has shown a clear, unexpected deterioration from 
baseline symptoms. 
 The same criteria as above apply to recording of AEs resulting from worsening of other pre-
existing conditions. Pre-existing conditions are not recorded as AEs if they do not meet the 
criteria above. Specifically, the following will not be recorded as an AE: 
o Pre-existing conditions present at baseline, which remain unchanged during the trial. 
o Expected fluctuations or expected deterioration of a pre-existing condition. 
 
Vital Signs, ECG and Laboratory test results qualifying as AE 
Changes in safety tests including blood pressure, pulse rate, ECG and laboratory tests will be 
recorded as AEs, if: 
o they are not associated with an already reported AE, symptom or diagnosis  
or 
o treatment is required (concomitant medication is added or changed) 
5.2.2 
Specific safety recording within 30 days 
Specific safety events to be recorded in this trial will be: 
- Clinically suspected stroke (total (fatal, disabling, non-disabling); ischaemic; intracranial 
haemorrhage)  
Patients experiencing any new neurological deficit at any time after randomisation (up to day 
30) are to be taken for immediate (within 24 hours) computed tomography scanning (CT) or 

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magnetic resonance imaging (MRI) to determine whether a stroke or intracranial haemorrhage 
(ICH) has occurred. CT is preferred, but MRI is also acceptable. In addition, all patients 
concerned should also be seen by a neurologist who may assist with the completion of the 
necessary documentation.  
If, in case of a fatal stroke and no imaging was done, an autopsy should be performed whenever 
possible. 
 
Detailed information on the stroke (date and time of onset, type, method of detection, outcome) 
will be collected in the eCRF.  
 
If a stroke occurs after discharge (up to day 30) or after referral to another hospital, the 
investigator and/or study team ought to use their best efforts to obtain the required information 
from that hospital.  
All strokes will be centrally adjudicated by the Stroke Review Panel (cf. section 8.10). 
- Non-intracranial bleeds (total, major, minor, and blood transfusions):   
Any reported bleeding, i.e. minor or major bleeds or any bleeding requiring blood transfusion, 
will be collected in the eCRF to assess the safety of the treatment. Serious bleeds will be 
reported as serious adverse events as described in section 5.2.1. All bleeds will be recorded in 
the eCRF. For bleed categories please refer to Appendices. 
- 
Serious cardiac events: 
 
Serious clinical events such as stent thrombosis, reinfarction, CHF, cardiogenic shock will be 
recorded in the eCRF. For all serious adverse events requiring expedited reporting according 
to the procedure described in section 5.2.1 a special eSAE form  must be completed in addition 
and must be submitted for further distribution to the Coordinating Center within 24 hours of 
the investigator becoming aware of the event (see section 8.4.1). 
5.3 
OTHER RECORDINGS 
5.3.1 
Duration of hospitalization 
- Total duration of hospital stay (PCI hospital and possibly community hospital):  
 
Days from initial admission to PCI hospital until discharge home or referral to a rehabilitation 
centre or nursing home will be calculated.  Patients coming from a community hospital can be 
transferred back to the referring community hospital after PCI. 
- Duration of rehospitalisation started until and including day 30 day:  
 
The duration of any rehospitalisation subsequent to discharge from index hospitalisation that 
commenced within 30 days of randomisation (i.e., starting at the latest on day 30) will be 
counted. 
5.3.2 
Evaluations at 1 year 
- All-cause mortality: 
 
The patient’s vital status at day 365 has to be evaluated. In case of the patient’s death between 

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day 31 and day 365, the date and primary cause of death will be collected retrospectively at the 
1-year follow up. 
- Rehospitalisation:  
If a patient is readmitted to the hospital for cardiovascular reasons between day 31 up to and 
including day 365, the date(s) and primary reason(s) must be recorded in the eCRF. 
5.3.3 
Evaluations specific for group PhI 
- Need for recue PCI 
ST resolution will be calculated according to methods described by Armstrong et al.51 and will also be 
used to determine the adherence to ECG criteria for rescue.  
Rescue coronary intervention is anticipated in approximately 25 to 30 % of patients receiving 
pharmacologic reperfusion therapy, if ST-segment resolution at 90 minutes (or earlier, if 
clinically indicated), is <50 % in the lead showing the greatest ST-segment elevation noted at 
baseline (randomisation) with the ECG measured from J-point with or without clinical 
symptoms.  
All rescue or urgent coronary interventions (as defined in section 6.2.2.1) will be centrally 
adjudicated to ensure protocol adherence with feedback provided to investigators as warranted.  
5.4 
APPROPRIATENESS OF MEASUREMENTS 
All methods selected as efficacy and safety assessments in this trial are standard methods and/or 
widely used in trials on myocardial infarction.  
A strong step-wise correlation has been demonstrated across the lytic trials between the degree of 
ST-segment resolution and clinical outcome.52, 53 More recently analysis of resolution of maximal 
post-lysis ST-segment elevation from the single lead showing maximal initial ST-elevation has 
been shown to discriminate clinical outcomes following fibrinolysis for STEMI. Adoption of a 50 
% cut-off for ST-segment resolution appears to confer similar sensitivity for prediction of death or 
development of heart failure (around 90 %) to that of <70% maximal ST resolution threshold, with 
fewer false positive results (specificity around 60% at the 50 % threshold). A single criterion of 
<50% ST-segment resolution in the lead with previous maximal ST-elevation acquired 90 minutes 
after fibrinolysis equips physicians and nursing staff with a simple, convenient and reasonably 
accurate bed-side tool to diagnose lytic failure. 
5.5 
DATA QUALITY ASSURANCE 
This trial will be conducted according to the principles of the International Conference on 
Harmonisation (ICH), Declaration of Helsinki (2013), Good Clinical Practice (GCP), the 
applicable national and international laws and guidelines and all applicable standard operating 
procedures (SOPs). The following measures will be taken to ensure accurate, consistent, complete 
and reliable data: 

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- All required trial documents will be distributed to every trial site and kept in the Investigator 
Site File (ISF). Site initiation will be performed by the CRO / ARO to assure a high quality and 
standardisation across sites (and countries).   
- Trial teams at the sites will be trained on protocol requirements, trial procedures, adverse event 
reporting, and remote data capture. 
- ECGs for assessment of ST resolution, clinical and ECG data for assessment of aborted 
infarction, and clinical and imaging data for assessment strokes will be centrally adjudicated. 
- Monitoring: Data captured in the eCRF will be verified against source data by CRAs. The 
identity and informed consent as well as SAE reporting will be checked. A risk based 
monitoring approach will be implemented.   
- The trial sites are to use validated and calibrated equipment (ECG) as required. 
- Auditing (internal and, if required by any regulatory authorities, external) can be performed as 
necessary. 
- Coding (e.g., according to MedDRA for adverse events) will be performed.  
- Data quality review meetings (DQRMs) will be held at regular intervals to check for data 
accuracy across sites and discrepancies will be handled. 
 
6. 
INVESTIGATIONAL PLAN 
Prerequisites: 
During the site selection process the qualification of a trial site for participation in the trial has to 
be determined. Sites (ambulances or ER of community hospitals) must be experienced in 
fibrinolysis and have access to a hospital with a catheterisation laboratory providing 24/7 PPCI 
service. (e.g., by hub and spoke relationship) to ensure the performance of delayed or timely rescue 
PCI, as required (Group PhI), or of PPCI according to the protocol. Each site enrolling patients 
will be assigned an individual site number and IVRS code. 
 
Before an ambulance site commences enrolling patients, the composition of the ambulance staff 
involved in pre-hospital trial procedures should be clearly established. In instances where an 
ambulance vehicle is staffed entirely with paramedics, the principal investigator will confirm that 
the diagnosis of STEMI as well as the acquisition of consent and initiation of pre-hospital treatment 
is undertaken with appropriate ethical and regulatory authorisation as established in the region 
and/or country participating. In addition, the principal investigator must ensure that the staff is able 
to make any trial-related diagnoses as, e.g. congestive heart failure and cardiogenic shock and to 
perform the trial procedures according to protocol. Patient eligibility criteria will be provided in a 
translated comprehensible version for use by paramedics. Similarly in the ER of community 
hospitals the principal investigators must ensure that the staff of the emergency department is 

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39 
 
familiar with the existence and details of the protocol. 
6.1 
VISIT SCHEDULE 
The trial consists of the following periods: 
- Pre-PCI hospital: screening/baseline assessments, informed consent, randomisation, early study 
treatment 
- In-PCI hospital period: continuation of trial treatment as necessary 
- Discharge: pre-discharge assessments 
- End of trial (day 30): check for AEs and rehospitalisations 
- 1-year follow-up: check for vital status and rehospitalisations for cardiovascular reasons. 
All assessments per visit are listed in the Trial Flow Chart and are described in section 6.2 and, in 
more detail, section 5. 
6.2 
TRIAL PROCEDURES AT EACH VISIT 
6.2.1 
Pre-PCI hospital period 
As soon as the ambulance arrives at the scene or the patient arrives at the emergency department 
of a community hospital, the patient will be screened for eligibility and enrolled by the investigator 
or authorised ambulance staff. Routine and/or rescue procedures are performed according to local 
practice and established guidelines. The following assessments will be done (for details of the 
individual assessments please refer to the Flow Chart and to section 5.2):  
- Informed consent, demographic data, medical history/current diseases; physical assessment, 
vital signs (blood pressure for evaluation of exclusion criterion 6), concomitant therapy; 
haematology, renal function, troponin I/T (CK/CK-MB) (if pre-hospital blood samples are 
taken); twelve-lead ECG, Killip class; inclusion/exclusion criteria, randomisation, and 
administration of trial medication. 
 
Randomisation and treatment allocation 
 Patients will be randomised by authorised staff by means of an interactive voice response 
system (IVRS). A study number will be given by the system after recording a minimal set 
of data (gender, date of birth, informed consent, inclusion/exclusion criteria). 
 For patients randomized to PhI arm tenecteplase should be given first followed by 
enoxaparin, aspirin (if not yet on aspirin) and clopidogrel. 
For a detailed description of study treatment please refer to section 4.1.4 of this protocol.  
Following randomisation and administration of study treatments, immediate transfer to the PCI 
hospital must be arranged. 

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The following documents/samples should accompany any patient when transferred to the receiving 
PCI hospital: 
- Diagnostic/baseline ECG, either as a paper copy or transferred electronically 
- Any ambulance files or worksheets in the ambulance/ER community hospital  where the 
required source data are recorded 
- Baseline blood samples for diagnostic cardiac markers/enzymes (troponin I/T or CK/CK-MB), 
haematology, and renal function, if taken on scene/pre-hospital. In case no blood samples are 
taken on scene/pre-PCI hospital, they should be taken immediately after arrival at the receiving 
PCI hospital. 
 
6.2.2 
In-PCI hospital period (including day of discharge) 
The “in-PCI hospital period” starts with the patient’s arrival at the PCI hospital.  
A patient is considered admitted to hospital when he/she reaches the hospital alive and medical 
responsibility is taken over by the PCI hospital medical team (irrespective of whether it occurs in 
the emergency room, the coronary care unit (CCU), the intensive care unit (ICU) or any other 
ward/unit). 
- If not already taken before, baseline blood samples for diagnostic cardiac markers (Troponin 
I/T or CK/CK-MB), renal function, and haematology should be taken as soon as possible after 
hospital arrival.  
- Patients will then receive further treatment according to the treatment group they have been 
randomised to.  
 
6.2.2.1 Group PhI  
Assessment of reperfusion 
At the receiving PCI hospital patients should be admitted to either the emergency department, 
coronary care unit or catheterisation laboratory (as per local practice) to assess reperfusion.  
The patient's need for rescue coronary intervention will be assessed by both ECG and evaluation 
of clinical symptoms 90 min (or earlier if clinically indicated) after injection of tenecteplase. These 
patients may undergo coronary intervention immediately, if indicated, in accordance with the 
protocol criteria described below.  
An additional ECG should be taken before starting the procedure. If there are clinical or 
electrocardiographic signs of reperfusion that have occurred after the previous ECG, the planned 
coronary intervention may be postponed. 
Cardiac Catheterisation 
- 
If ST-segment resolution is  50 % in the qualifying lead (that had the maximum initial ST-
segment elevation in the baseline ECG), diagnostic coronary angiography (followed by 

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41 
 
elective PCI +/- stenting, if indicated) should be performed no sooner than 6 hours, but within 
24 hours after administration of tenecteplase. This will be considered as planned catheterisation 
according to protocol 
- 
If ST-segment resolution is < 50 % relative to the ST-segment elevation in the qualifying lead 
at baseline, irrespective of the presence or absence of clinical symptoms, rescue coronary 
intervention should be performed promptly.  
- 
If any of the following indications require coronary intervention (irrespective of previous ST-
segment resolution), urgent coronary intervention is indicated at any time: 
 haemodynamic instability (presence of any of the following requiring inotropic 
support: sustained hypotension, cardiogenic shock, or congestive heart failure) 
 refractory ventricular arrhythmias requiring cardioversion or pharmacological 
treatment 
 worsening ischaemia  
 progressive or sustained ST-segment elevation which, in the judgement of the 
investigator, requires immediate coronary intervention 
 
All rescue and urgent coronary interventions will be adjudicated by an independent clinical expert 
as previously described.19 Feedback to participating sites regarding adherence to protocol defined 
indications for rescue will be provided as appropriate. 
Further ECG measurements 
Further ECG measurements are listed in Table 4. 
 
Table 4: Overview of ECG measurements in Group PhI   
Timing of ECG 
Location  
Reason for ECG 
Baseline  
Pre-PCI hospital: 
on site/ambulance/ER 
community hospital  
ECG for assessment of STEMI 
entry criteria 
90 min after bolus tenecteplase or 
earlier if indicated 
In-PCI hospital: 
emergency dept. or CCU 
Assessment of reperfusion 
In case of catheterisation (with or 
without PCI/stenting) or rescue or 
urgent PCI, respectively:  
- immediately before  
- and 30 min after the end of 
 the procedure.   
In-PCI hospital: catheter 
laboratory 
 
Re-assessment of reperfusion 

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42 
 
Timing of ECG 
Location  
Reason for ECG 
Any time, if indicated 
(serial ECGs) 
In-PCI hospital 
Verification of ischaemia or 
reinfarction  
At 4 days or hospital discharge 
whichever comes first 
In-PCI hospital 
Assessment infarct size using 
QRS score 
 
Collection of data 
During the patient’s stay in hospital (i.e., until and including the day of discharge) the following 
data will be collected:  
- Concomitant therapy 
- Troponin I/T (CK/CK-MB) 8-12 hrs and 24 hrs after randomisation, respectively, and also at 
any time in case of signs and symptoms suggestive of recurrent myocardial ischaemia or 
reinfarction 
- 12-lead ECG (please refer to Table 4) 
- Data on catheterisation/coronary intervention(s) 
- TIMI flow grade (before PCI and at the end of the angiographic procedure) 
- Any occurrence of adverse events, and serious adverse events/serious clinical events 
 
The following assessments will be performed on the day of discharge from hospital (or transfer 
to a rehabilitation centre or nursing home)  
- Blood test for haematology as per hospital routine 
- 12-lead ECG (cf. Table 4) 
- Any occurrence of adverse events, and serious adverse events/serious clinical events 
6.2.2.2 Group PPCI 
Patients randomized to PPCI will receive medical treatment before, during and after PPCI 
according to established local standards. Additional GP IIb/IIIa antagonists may be given at the 
investigator’s discretion. 
During the in-hospital period several 12-lead ECGs will be taken as summarised in Table 5. 
 
Table 5: Overview of ECG measurements in PPCI Group C  
Timing of ECG 
Location  
Reason for ECG 
Baseline  
Pre-hospital: 
on site/ambulance/ER 
community hospital  
ECG for assessment of STEMI 
entry criteria 

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Timing of ECG 
Location  
Reason for ECG 
Immediately prior to PCI 
after arrival in PCI hospital 
In-PCI hospital: catheter 
laboratory 
Assessment of pre-PCI patency  
30 min after the end of the 
intervention  
In-PCI hospital 
Reassessment of reperfusion 
Any time, if indicated 
(serial ECGs) 
In-PCI hospital 
Verification of ischaemia or 
reinfarction  
At 4 days or hospital 
discharge whichever comes 
first  
In-PCI hospital 
QRS score for infarct size 
 
During the patient’s stay in hospital, data on PPCI will be collected. All further assessments during 
the initial hospitalisation and prior to the patient’s discharge from hospital (or transferral to a 
rehabilitation centre or nursing home) are identical to those assessed in Group PhI (please refer to 
the above paragraph, 6.2.2.1). 
6.2.3 
End of trial and follow-up period 
6.2.3.1 End of trial (day 30) 
The end-of-trial visit will take place at day 30. Data may however be collected until and including 
day 37. If a visit at the outpatient clinic is not possible the patients may be contacted by phone. 
 
The following data will be collected: 
- Data on any rehospitalisation occurring after hospital discharge up to (including) day 30 
- Any occurrence of adverse events, and serious adverse events/serious clinical events since 
hospital discharge or (if the patient is still hospitalised) that have not yet been recorded 
6.2.3.2 Follow-up 
Data for the 1-year follow up should be collected at day 365 (up to and including day 395).  
The required evaluations may be assessed via phone (if a physical visit is not performed) or can 
also be obtained from medical records. 
The following data will be collected at 1-year: vital status/all-cause mortality and rehospitalisation 
for cardiovascular reasons (since day 30). 
 
6.3 
REMOVAL OF PATIENTS FROM THERAPY ASSESSMENT 
As soon as the patient is randomised, the patient is considered a trial participant irrespective of 

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whether he or she received any trial-specific treatment or not. 
A patient may withdraw from the trial at any time without the need to justify the decision. 
In case of withdrawal all data collected until (and including) the day of withdrawal will be kept in 
the trial database. Furthermore vital status at 30 days and 1 year will be collected. 
7. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE 
7.1 
STATISTICAL DESIGN/MODEL 
The trial is a prospective, multi-centre, international, randomised (2:1), open-label, parallel-group 
comparison, conducted for investigating the efficacy and safety of 
A. 
Study treatment (Group PhI) 
B. 
Primary PCI according to local standards (Group PPCI) 
in patients with acute myocardial infarction randomised < 3 hours from symptom onset. 
The principal aim of the trial is to evaluate the safety and efficacy in the 2 treatment groups 
measured by ST segment resolution, TIMI flow grades, and clinical events as listed in section 2.1. 
7.2 
PLANNED ANALYSES 
Baseline characteristics will be tabulated and differences among the two treatment groups will be 
examined by means of descriptive statistics. 
The primary analysis is an intent-to-treat analysis of all randomised patients. Patients will be 
analysed according to the treatment group to which they were randomised, irrespective of which 
study drug was given or if any study drug was received. 
7.2.1 
Interim analyses 
After 50 % of the planned recruitment a formal interim analysis will be performed by the Data and 
Safety Monitoring Board (DSMB) to evaluate and advise the Executive Committee on the 
feasibility of enlarging the sample size and to turn the study into a confirmatory trial.  Continuous 
safety monitoring will be done by the DSMB with particular emphasis on the incidence of systemic 
bleeding and intracranial haemorrhage (ICH); details are documented in the DSMB charter.  
7.3 
HANDLING OF MISSING DATA 
No imputation of missing data is foreseen. Best efforts will be made to collect complete data for 
the clinical events of interest. Distribution of the missing data will be checked across groups. 

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7.4 
RANDOMISATION 
The randomisation will be stratified by centre and, within the centres, performed in blocks to 
ensure balanced distribution of the treatment groups at any time. Randomisation will be available 
daily for 24 hours via a centralised telephone Interactive Voice Response System (IVRS) or web 
randomization. Each site (ambulance/ER of community hospital) will be provided with a telephone 
number and a PIN code that will connect them to a computerised script identifying the treatment 
group. For details on the use of IVRS see the manual in the Investigator Site File. 
Patients are considered randomised as soon as the treatment group has been assigned.   
7.5 
DETERMINATION OF SAMPLE SIZE 
As mentioned before this is a hypothesis generating trial. No primary hypothesis or primary 
endpoint have been formulated. Approximately 600 patients are planned to be randomized with 
400 receiving PhI therapy and 200 PPCI. A minimum of approximately 100 patients ≥ 70 years of 
age will be randomized to the PhI arm. The aim is to combine ECG and angiographic data from 
the latter group with similar data from STREAM-116, 18 in order to have a more reliable estimate 
of the efficacy of the PhI strategy in elderly patients. The analysis of ECG data, angiographic data 
and clinical events will be described in detail in the statistical analysis plan. Although the study of 
600 patients is not powered to show a difference in clinical events, given the elderly nature of the 
population there will be ample efficacy and safety events to observe. They will be reported along 
with their 95% confidence limits. For reference, in patients ≥ 60 years from STREAM-1 the 30 
day composite of death, shock, heart failure and re-MI ranged between 18 and 20 % for PhI and 
PPCI groups. Bleeding data in this age group were 1.7 % and 0 % ICH and 8.8 % and 7 % non-
intracranial major bleeding respectively. If the study would turn into a confirmatory trial after the 
interim analysis a primary hypothesis on a combined clinical endpoint will be pre-specified. 
 
8. 
ADMINISTRATIVE MATTERS 
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, version as of 2013 in accordance with the ICH Harmonised Tripartite 
Guideline for Good Clinical Practice (GCP) and relevant SOPs. 
The applicable international and local laws and treatment guidelines will be adhered to. 
A no fault insurance cover will be provided and explained in the informed consent form. 
8.1 
ETHICS 
8.1.1 
Institutional Review Board or Independent Ethics Committee 
The trial will not be initiated before the clinical trial protocol (CTP) and informed consent and 

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patient information form have been reviewed and received approval from the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) and approval by the Competent 
Authority (CA) or applicable regulatory authority as required by local laws and regulations. Should 
a CTP amendment be made that needs IRB/IEC approval and authority notification/approval, the 
changes in the CTP will not be instituted until the amendment and revised informed consent (if 
appropriate) have been reviewed and received approval / favourable opinion from the local 
IRB/IEC and the CA or applicable regulatory authority, as required by local laws and regulations. 
A CTP amendment intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately providing that the regulatory authority and IRB / IEC are notified as 
soon as possible and an approval is requested. CTP amendments exclusively for logistical or 
administrative changes may be implemented with notification of the IRB / IEC and CA or 
competent authority only. 
The constitution of the IRB/IEC must meet the requirements of the participating countries. A list 
of the IRB/IEC members, with names and qualifications, needs to be provided by the IRB/IEC to 
the investigator or, if applicable, sponsor.  
8.1.2 
Informed Consent and Patient Information 
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) or initial verbal and subsequent written 
consent according to the regulatory and legal requirements of the participating country. Each 
signature must be 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 informed that his/her personal trial-related data will be used by the study 
sponsor in accordance with the local data protection law. The level of disclosure must also be 
explained to the patient. 
The patient must be informed that his/her medical records may be examined by authorised 
monitors (CRA) or Clinical Quality Assurance auditors appointed by the sponsor, by appropriate 
IRB / IEC members, and by inspectors from regulatory authorities.   
Should a CTP amendment become necessary, the patient consent form and patient information 
form may need to be revised to reflect the changes to the CTP. It is the responsibility of the 
investigator or, if applicable, sponsor to ensure that an amended consent form is reviewed and has 
received approval / favourable opinion from the IRB / IEC and CA or applicable regulatory 
authority, as required by local laws and regulations, and that it is signed by all patients 
subsequently entered in the trial and those currently in the trial, if affected by the amendment. 

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8.2 
RECORDS 
8.2.1 
Drug accountability 
The local investigator or pharmacist must maintain records of the delivery and use of medications 
for the study.  
8.2.2 
Case Report Forms (CRFs) 
All of the clinical data will be captured via electronic data capture (EDC) using Open Clinica, a 
web-based application. The investigator site staff will enter and edit the data via a secure network, 
with secure access features (username, password and secure identification – an electronic password 
system). A complete electronic audit trail will be maintained. The investigator will approve the 
data using an electronic signature (Ref: 21 CFR Part 11), and this approval is used to confirm the 
accuracy of the data recorded. 
Electronic CRFs (eCRFs) will be used for all patients. The investigator’s data will be accessible 
from the investigator’s site throughout the trial. Relevant medical history prior to enrolment will 
be documented at the baseline visit. The eCRFs must be kept current to reflect patient status at 
each phase during the course of the trial. The patients must not be identified on the eCRF by name. 
Appropriate coded identification (i.e. Patient Number) must be used. The investigator must make 
a separate confidential record of these details (patient identification code list) to permit 
identification of all patients enrolled in a clinical trial in case follow-up is required.  
The investigator will be responsible for retaining all records pertaining to the trial as specified in 
the appropriate contract. 
8.2.3 
Source documents 
According to ICH/GCP source documents provide evidence for the existence of the patient and 
substantiate the integrity of the data collected. Source documents are filed at the investigative site 
and will be verified to the eCRF by the CRA when indicated. 
Data entered in the eCRFs that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records. Current medical records must also be available. 
8.2.4 
Direct access to source data / documents 
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data / documents. ECRFs and 
all source documents, including progress notes and copies of laboratory and medical test results, 
must be available at all times for review by the sponsor’s clinical trial monitor and inspection by 
health authorities.  The on-site monitor may review all eCRFs, and written informed consents. The 
accuracy of the data will be verified by reviewing the source documents to the eCRF. 

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8.3 
QUALITY ASSURANCE AUDIT 
A quality assurance audit of this trial may be conducted by the sponsor or sponsor’s designees. 
The quality assurance auditor will have access to all medical records, the investigator’s trial-related 
files and correspondence, and the informed consent documentation that is relevant to this clinical 
trial. 
8.4 
PROCEDURES 
8.4.1 
Adverse events 
An adverse event (AE) is defined as any untoward medical occurrence, including an exacerbation 
of a pre-existing condition, in a patient in a clinical investigation who received a pharmaceutical 
product. The event does not necessarily have to have a causal relationship with this treatment. 
A serious adverse event (SAE) is defined as any AE which results in death, is immediately life-
threatening, results in persistent or significant disability / incapacity, requires or prolongs patient 
hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for any other 
reason representing a significant hazard, which is comparable to the aforementioned criteria. 
Adverse events occurring during the course of the clinical trial (i.e. from signing the informed 
consent onwards through the observational phase) will be collected, documented and reported by 
the investigator according to the specific definitions and instructions detailed in the ‘Adverse Event 
Reporting’ section of the Investigator Site File and in section 5.2.1 of the trial protocol. Figure 2 
in section 5.2.1 of the trial protocol shows an overview of the adverse event reporting. 
Reporting of serious adverse events (SAE)s: 
On an SAE form: 
For the following events an SAE form (in addition to entering the SAE data in the eCRF) will need 
to be completed and emailed for expedited reporting: 
o Serious and treatment-related SAEs 
o Serious, not treatment-related and not mentioned on the ‘list of STEMI-related 
events’ 
For each SAE, the investigator will provide the onset, end, treatment required, outcome, 
seriousness and action taken with the investigational drug. The investigator will also determine the 
relationship of the investigational drug to all SAEs. 
The basis for judging the causal relationship between the investigational product and the SAE is 
described below. 
Causal relationship* 
Yes There is a reasonable causal relationship between the study drug 
administered and the AE. 

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No 
There is no reasonable causal relationship between the study drug 
administered and the AE. 
*Medical judgement should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history.  
These completed SAE forms need to be emailed within 24 hours (1 workday) after the Investigator 
(or any member of the study team) has become aware of the event. Timelines are the same for 
initial reports and for follow-up reports. 
Upon receipt of these SAE forms the treatment relationship, the category classification, listedness 
and seriousness of reported SAE cases will be assessed. Expedited reporting of serious adverse 
events, e.g. suspected unexpected serious adverse reactions (SUSARs), will be done according to 
local regulatory requirements within the required timelines.  
In the eCRF: 
Any SAE, whether or not considered related to the study medication, and whether or not the study 
medication has been administered, must be reported immediately in the eCRF.   
Reporting of non-serious adverse events: 
Non-serious events need to be recorded in the eCRF  
8.5 
RULES FOR AMENDING PROTOCOL 
All CTP amendments must be documented, dated and signed by all signatories (or their successors) 
of the original protocol. This also applies to any local amendment that may become necessary. 
Amendments need to be submitted to the IRB / IEC for review/approval and to the competent 
authority (CA) or the applicable regulatory authority for approval/ notification, as described in 
section 8.1.1. 
8.6 
DISCONTINUATION OF THE TRIAL  
The sponsor who initiated the study reserve the right to discontinue the trial at any time for the 
following reasons (please also refer to section 8.10): 
1.) Failure to meet expected enrolment goals, 
2.) Emergence of any efficacy/safety information that could significantly affect continuation of 
the trial or any other administrative reasons, 
3.) Violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing the 
appropriate conduct of the trial. 

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8.7 
STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of this trial is considered confidential 
and disclosure to third parties is prohibited with the exceptions noted below.  Patient 
confidentiality will be ensured by using patient identification code numbers. 
Treatment data may be given to the patient’s personal physician or to other appropriate medical 
personnel responsible for the patient’s welfare. Data generated as a result of the trial need to be 
available for inspection on request by the participating physicians, the sponsor’s representatives, 
by the IRB / IEC and the regulatory authorities. 
8.8 
PUBLICATION POLICY 
This study represents an investigator initiated effort supported by a pharmaceutical company and 
research foundations, and as such, the parties agree that the recommendation of the pharmaceutical 
company concerning manuscripts or text shall be taken into consideration in the preparation of 
final scientific documents for publication or presentation whenever these recommendations are 
related to their drugs. 
 
The Executive Committee in conjunction with the Steering Committee will prepare a 
manuscript(s) plan to ensure timely and high quality presentation and publication of the study 
results and provide this also to the pharmaceutical company for due consideration.  
 
Investigators are encouraged to propose additional analyses from the final available data. All 
proposed publications and presentations by investigators or their personnel and associates resulting 
from or relating to this study must be submitted to the Executive Committee in conjunction with 
the Steering Committee for review and approval prior to submission for publication or 
presentation. Manuscripts submitted for publication must be in compliance with applicable laws 
and regulations regarding patient privacy.  
8.9 
COMPLETION OF TRIAL 
The IEC/competent authority in each participating EU member state and any other countries where 
notification is required needs to be notified about the end of the trial (last patient out) or early 
termination of the trial.  
8.10 
STUDY COMMITTEES 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will monitor the accruing safety and 
outcome data. 
The DSMB will be composed of independent cardiologists including at least one interventional 

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cardiologist and one independent biostatistician.  
The DSMB will review safety data. The DSMB will also conduct analyses of the data at the request 
of the Steering Committee and/or Executive Committee. The DSMB analyses and operations will 
be formally separated from the sponsor, pharmaceutical companies, the investigators and the 
Steering/Executive Committee. The DSMB will advise the executive committee- by giving 
recommendations on the trial continuation or aspects of the study conduct. After recruiting 50 % 
of the planned population a formal interim analysis will be performed by the DSMB to evaluate 
and advise the Executive Committee on the feasibility of increasing the sample size in order to 
turn the study into a confirmatory trial.  The tasks of the DSMB will be described in detail in the 
DSMB charter. 
Stroke Review Panel 
An independent Stroke Review Panel will perform a final evaluation and classification of 
documented clinically suspected strokes.  
The Stroke Review Panel members will include an independent neurologist and a neuroradiologist. 
All the clinically suspected stroke events will be reviewed by the Stroke Review Panel blinded to 
the allocated treatment. On the basis of the stroke event documentation the Stroke Review Panel 
will assess and classify each stroke event as primary haemorrhagic or ischaemic or unclassifiable.
 
  
The classification of the strokes will be made available for the periodical DSMB reviews. 
Executive Committee 
The Executive Committee is composed of F. Van de Werf (co-chair), P.W. Armstrong (co-chair), 
Peter Sinnaeve (co-PI), Robert Welsh (co-PI), P. Goldstein. It provides scientific direction of the 
study and assesses the study progress. The Executive Committee is assisted by the Steering 
Committee. The Executive Committee Chairmen are responsible for communicating with the 
DSMB when appropriate. 
The Executive Committee meets periodically by telephone or webcast. 
Steering Committee 
The Steering Committee is composed of the Executive Committee and members from all 
participating countries, usually the national coordinator(s) of every country. The Steering 
Committee meets periodically at the major international cardiology congresses to assess the 
progress, provide scientific input and address policy issues and operational aspects of the protocol. 
At the end of the trial the Steering Committee will meet in a closed session to discuss the trial 
results. 

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Operations Committee 
The Operations Committee is responsible for all operational management issues in running the 
study on a daily basis. It is composed of members with operative responsibility for different areas 
like overall management, regulatory issues, monitoring, safety reporting, data management etc. It 
interacts closely with the Study Chairmen and the Executive Committee, the local clinical monitors 
and data management for the day-to-day conduct of the study. 
 
 

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APPENDIX A: CLINICAL EVENTS TO BE RECORDED IN ECRF 
Cardiac events within 30 days 
 All-cause mortality 
 Cardiac mortality 
 Cardiogenic shock 
 Congestive heart failure 
 Recurrent myocardial infarction 
 Stent thrombosis 
 Rehospitalisation for cardiac reasons 
 Rehospitalisation for non-cardiac reasons 
Safety events with 30 days 
Total stroke, intracranial haemorrhage, ischaemic stroke, haemorrhagic conversion within 30 
days 
 Procedure related major bleeds (within 48 hours) 
 Non-intracranial bleeds (major, minor) and need for blood transfusions up to 30 days 
Evaluations at 1 year  
 All-cause mortality 
 
 

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APPENDIX B: DEFINITIONS OF CLINICAL EVENTS  
B1. 
BLEEDS 
Major bleeds 
Severe bleed: a bleed that leads to haemodynamic compromise requiring intervention (e.g. blood 
or fluid replacement, inotropic support, surgical repair) or life-threatening or fatal bleeds. 
Moderate bleed: bleeding requiring transfusion of blood but which does not lead to haemodynamic 
compromise requiring intervention. 
Minor bleeds 
Bleeding neither requiring blood transfusion nor leading to haemodynamic compromise. 
PS Intracranial bleeds will be reported separately 
B2. 
MAJOR CARDIAC EVENTS 
Congestive heart failure 
A positive diagnosis consists of at least one of the following conditions requiring treatment with 
diuretics: 
- Pulmonary oedema/congestion on chest x-ray without suspicion of a non-cardiac cause; 
- Rales >1/3 up from the lung base (Killip class 2 or higher); 
- Pulmonary capillary wedge pressure (PCWP) >25 mmHg; 
- Dyspnea with pO2 < 80 mmHg or O2 sat < 90 % (no supplemental O2) in the absence of 
known lung disease 
 
Killip class 
I: 
The absence of rales over the lung fields and the absence of an S3. 
II: 
The presence of rales that do not clear with coughing, over one half or less of the lung 
fields or the presence of an S3. 
III: 
The presence of rales that do not clear with coughing, over more than half of the lung fields. 
IV: 
Cardiogenic shock. 
Cardiogenic shock 
Defined as one of the following: 
1. Systolic blood pressure < 90 mmHg for at least 30 min (or the need for supportive measures to 
maintain a systolic blood pressure of > 90 mmHg) in the presence of a heart rate of >60 beats/min 

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in association with signs of end organ hypoperfusion (cold extremities, low urinary output < 30 
ml/h and/or mental confusion); 
2. A cardiac index < 2.2 l/min/m2 in the presence of a pulmonary capillary wedge pressure (PCWP) 
of >15 mmHg. 
Reinfarction 
Reinfarction in the absence of a coronary intervention and within 18 hours after randomization: 
Recurrent signs and symptoms of ischaemia at rest, accompanied by new or recurrent ST-
segment elevations of  0.1 mV in at least two contiguous leads lasting  30 min. 
 
Reinfarction related to PCI  
≤48 h after the index procedure: 
Coronary intervention related myocardial infarction is arbitrarily defined by 
elevation of cardiac troponin values >5 multiplying 99th percentile URL in patients 
with normal baseline values (≤99th percentile URL) or a rise of cardiac troponin 
values >20% if the baseline values are elevated and are stable or falling. In addition, 
either symptoms suggestive of myocardial ischemia or new ischemic ECG changes 
or angiographic findings consistent with a procedural complication or imaging 
demonstration of new loss of viable myocardium or new regional wall motion 
abnormality are required.  
 
  
>48 h after the index procedure: 
Detection of a rise and/or fall of cardiac troponin values with at least one value 
above the 99th percentile URL and with at least one of the following:  
 Symptoms of ischemia; 
 New or presumed new significant ST-T changes or new left bundle branch 
block;  
 Development of pathological Q waves in the ECG;  
 Imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality;  
 Identification of an intracoronary thrombus eg stent thrombosis by angiography 
or autopsy  
 
Reinfarction related to cardiac surgery  
≤48 h after the index procedure: 
Cardiac and non-cardiac surgeries related myocardial infarction are arbitrarily 
defined by elevation of cardiac troponin values >10 multiplying 99th percentile 
URL in patients with normal baseline values (≤99th percentile URL) or a rise of 
cardiac troponin values >20% if the baseline values are elevated and are stable or 
falling plus either new pathological Q waves or new left bundle block or 
angiographic documented new graft or new native coronary artery occlusion or 
imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality.  

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>48 h after the index procedure: 
Detection of a rise and/or fall of cardiac troponin values with at least one value 
above the 99th percentile URL and with at least one of the following:  
 Symptoms of ischemia; 
 New or presumed new significant ST-T changes or new left bundle branch;  
 Development of pathological Q waves in the ECG;  
 Imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality;  
 Identification of an intracoronary thrombus by angiography or autopsy  
Aborted myocardial infarction 
Aborted myocardial infarction54 will be assessed by means of ECG as ST-segment resolution 
relative to baseline value and cardiac marker enzymes as done previously in STREAM-155. Peak 
levels of troponin I/T (CK/CK-MB) will be collected at baseline, and 8-12 hrs and 24 hrs after 
randomisation. Quantification of aborted myocardial infarction will be defined as troponin values  
 5 times the upper limit of normal (ULN) within 24 hours of randomisation (or CK/CK-MB levels 
 2 times ULN). Only peak values of markers of necrosis (expressed as times exceeding the upper 
limit of normal) will be recorded in the eCRF; the complete set of measured values will however 
be kept in the source documents.  
 
Rescue PCI post PhI therapy 
If ST-segment resolution is <50% relative to the ST-segment elevation in the qualifying lead at 
baseline, irrespective of the presence or absence or clinical symptoms 
Refractory ischaemia 
Symptoms of ischaemia with ST-deviation or definite T-wave inversion persisting for at least 10 
min despite medical management while in-hospital and not fulfilling the diagnosis of infarction. 
Major arrhythmias 
Sustained ventricular tachycardia (ventricular tachycardia lasting  30 seconds or requiring 
cardioversion or causing symptoms/hypotension), ventricular fibrillation, asystole, atrial 
fibrillation, 2nd and 3rd degree atrio-ventricular block.  
Invasive procedures 
Include CABG, PTCA, stent placement, intra-aortic balloon. 

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Other major cardiac events 
Other major cardiac events include sustained hypotension, acute mitral regurgitation, acute 
ventricular septum defect, pericarditis, pulmonary embolism and tamponade. 
Sustained hypotension 
SBP < 90 mmHg for > 30 minutes 
Rehospitalisation for cardiac reasons 
If, after discharge, a patient is readmitted to the hospital until day 30 due to cardiac reasons, this 
information must be recorded in the eCRF. Any event requiring unscheduled readmission will be 
considered a serious adverse event (SAE) and recorded as described in section 5.2.1. Only if 
readmission was scheduled, e.g. because of a routine or planned procedure, will the event leading 
to rehospitalisation not be considered as a serious adverse event. 
Rehospitalisation for non-cardiac reasons 
Data about any rehospitalisation for non-cardiac reasons occurring after discharge from initial 
hospitalisation until day 30 will be collected in the eCRF and have to be recorded on SAE reports 
in accordance with section 5.2.1. Only if rehospitalisation was scheduled, e.g. because of a routine 
or planned procedure, will it not be considered as a serious adverse event. 
Statistical analysis of clinical events 
The analysis will be described in detail in the statistical analysis plan. Clinical events of interest 
will be assessed as single or composite endpoints for evaluation. All statistical tests on clinical 
events are of exploratory nature based on descriptive statistics for formal statistical hypotheses 
generation. For comparison the same composite clinical event rates as in STREAM-1 will be 
analysed (see APPENDICES). The primary comparisons will be based on the differences 
between Group PhI and PPCI. Differences between groups and their 95% CI will be calculated. 
Should a statically significant difference appear in at least one clinical endpoint, i.e. the 
corresponding CI excludes 0 (no difference), and if there is also consistency for the other 
endpoints, then this will be considered evidence for a clinically meaningful difference between 
treatments which should be confirmed in a later study. Should no statistically significant 
difference be apparent, the CI will be examined to determine to what level a worse outcome can 
be excluded as has been done with the primary endpoint in STREAM-1. 
A formal interim analysis will be performed after 50 % of the planned recruitment. The aim of 
this analysis is to evaluate the usefulness and feasibility of enlarging the study based on the 
results. 
 

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APPENDIX C 
The following adverse events are expected as disease-related events (i.e. related to acute 
myocardial infarction): 
Arrhythmias 
All arrhythmias occurring later than 3 hours after fibrinolysis 
All arrhythmias in patients who did not receive fibrinolysis 
Ischaemia and symptoms of coronary artery disease 
Angina pectoris (stable) 
Angina pectoris (unstable) 
Back pain (of cardiac origin) 
Cardiac enzymes (abnormal) 
Cardiac markers (abnormal) 
Chest pain 
Electrocardiogram abnormalities 
Myocardial ischaemia 
Myocardial reinfarction 
Recurrent myocardial ischaemia 
ST-elevation 
Substernal chest pain 
Substernal pain 
Artery disorders 
Aortic dissection 
Coronary artery dissection 
Coronary artery disorder 
Coronary artery thrombosis 
Coronary occlusion 
Vascular anomaly 
Cardiac failure 
Acute pulmonary oedema 
Cardiogenic shock 
Congestive heart failure 
Cor pulmonale 
Heart failure 
Left heart failure 

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Pulmonary oedema 
Haemodynamic and circulatory shock 
Pericardium disorders 
Pericardial effusion 
Pericarditis 
Other cardiac disorders 
Acute mitral regurgitation 
Acute ventricular septum defect 
Cardiac rupture  
Cardiomyopathy 
Electro-mechanical dissociation 
Other events 
Deep thrombophlebitis 
Hypertension 
Livedo reticularis 
Peripheral oedema 
Peripheral vascular disorder 
Syncope 
Thrombocytosis 
Vascular disorder 
Venous thrombosis 
 
 

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INVESTIGATOR PROTOCOL AGREEMENT 
STUDY TITLE: STREAM-2 (STrategic Reperfusion in elderly patients Early After Myocardial 
Infarction) 
By signing below I confirm that I have read and understand the protocol and agree to comply 
with the conduct and terms of the study specified herein and any reference documents in the trial 
protocol. I agree to assume responsibility for the conduct of the study at this site including 
complying with the International Conference on Harmonization (ICH) and Good Clinical 
Practice (GCP) guidelines, the Declaration of Helsinki and all applicable local and federal 
regulations relating to the conduct of clinical studies and protection of human patients. 
 
 
Investigator Signature: 
 
 
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Institution 
 
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