Conditions: COVID-19 Respiratory Failure ARDS
Keywords: COVID-19 ARDS thrombolysis tenecteplase
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 13
Healthy volunteers: no

Brief summary:
This is a placebo-controlled, double blind, randomized, Phase II dose escalation study intended to evaluate the potential safety and efficacy of tenecteplase for the treatment of COVID-19 associated respiratory failure. The hypothesis is that administration of the drug, in conjunction with heparin anticoagulation, will improve patients' clinical outcomes.

Detailed description:
Patients with COVID-19 who suffer from acute hypoxemic respiratory failure have a poor prognosis. COVID-19 has been associated with a hyperinflammatory and hypercoagulable state, leading to a range of thromboembolic complications from pulmonary embolism to ischemic stroke. Furthermore, emerging data suggest that the associated acute respiratory failure is, at least in part, due to pulmonary vascular disease caused by micro- and/or macro-emboli, creating pulmonary vascular shunting and dead-space ventilation. In this placebo-controlled, double blind, randomized, Phase II dose escalation study, we plan to evaluate the clinical efficacy and safety of low-dose IV bolus tenecteplase together with anticoagulation compared with control patients on therapeutic anticoagulation alone in hospitalized adults diagnosed with COVID-19 respiratory failure with elevated D-dimer. We believe these patients can be successfully treated without significantly increasing the risk of major bleeding while improving recovery rates, shorten hospitalization time, and perhaps ultimately prove to improve survival.

Arms:
arm 1: First 20 patients randomized to treatment will receive tenecteplase 0.25 mg/kg (maximum 25 mg). Last 20 patients randomized to treatment will receive tenecteplase 0.50 mg/kg (maximum 40 mg). arm 2: Placebo control

Interventions: intervention 1: Tenecteplase intervention 2: Placebo
Intervention descriptions: intervention 1: First 20 patients randomized to treatment arm will receive 0.25 mg/kg of tenecteplase. Next 20 patients randomized to treatment arm will receive 0.50 mg/kg of tenecteplase. Both will receive concomitant heparin to maintain activated partial thromboplastin time between 2.0 and 2.5 upper limit of normal. intervention 2: Patients will receive placebo with concomitant heparin to maintain activated partial thromboplastin time between 2.0 and 2.5 upper limit of normal.

Protocol document:
Prot_SAP_000.pdf: 
Protocol: Tenecteplase With Concomitant Anticoagulation for Severe Acute 
Respiratory Failure in Patients With COVID-19 
PI: Hooman Poor, MD
NCT04505592
Document Date: June 15, 2021


CONFIDENTIAL
This is a Icahn School of Medicine at Mount Sinai document that contains confidential 
information.  It is intended solely for the recipient clinical investigator(s) and must not 
be disclosed to any other party.  This material may be used only for evaluating or 
conducting clinical investigations; any other proposed use requires written consent 
from Icahn School of Medicine at Mount Sinai.
Tenecteplase⎯ Icahn School of Medicine at Mount Sinai
Protocol ML42492
PROTOCOL
TITLE:
Tenecteplase with Concomitant Anticoagulation for 
Respiratory Failure in Patients with COVID-19: a 
Randomized Controlled Trial
STUDY NUMBER:
ML42492
VERSION NUMBER:
3
TEST PRODUCTS:
Tenecteplase (RO5490263)
INDICATION:
INVESTIGATOR:
Hooman Poor, MD
One Gustave L Levy Place, Box 1232
Telephone:  212-241-5656
Fax:  212-241-8866
E-mail:  hooman.poor@mountsinai.org
SUB-INVESTIGATORS:
J Mocco, MD
STUDY PROJECT 
MANAGER:
STUDY DATA 
MONITOR:
Nicole Smeck
Timolin Jeffers
SUPPORT PROVIDED 
BY:
Genentech, Inc.
PROTOCOL DATE:
February 10, 2021
Effective Date: 6/15/2021
End Date: 12/7/2021


Tenecteplase⎯{Icahn School of Medicine at Mount Sinai)
Protocol {1}, Version {3}
2
TABLE OF CONTENTS
1.
Background
7
1.1
Background
7
1.2
CURRENT THERAPIES AND UNMET MEDICAL NEED
7
1.3
Background on Tenecteplase
7
1.3.1
Approved Indication in US and Europe
8
1.4
Overview of Clinical Development
8
1.4.1
Acute Myocardial Infarction Clinical Development
8
1.4.2
Acute Ischemic Stroke Clinical Development
8
1.5
Study Rationale and Benefit-Risk Assessment
9
2.
Objectives and Endpoints
9
2.1
Primary Objective(s)
9
2.2
Primary efficacy outcome
10
2.3
Study Outcomes
10
3.
Study Design
10
3.1
Description of the Study
10
3.2
End of Study and Length of Study
10
3.3
Rationale for Study Design
11
3.3.1
Rationale for Tenecteplase Dose and Schedule
11
3.3.2
Rationale for Patient Population
13
4.
MATERIALS AND METHODS
13
4.1
Patients
13
4.1.1
Inclusion Criteria
13
4.1.2
Exclusion Criteria
13
4.2
Method of Treatment Assignment
14
4.3
Study Treatment
15
4.3.1
Study Treatment Formulation, Packaging, and Handling
15
4.3.1.1
Tenecteplase
15
4.3.2
Study Treatment Dosage, Administration, and Compliance
16
4.3.2.1
Tenecteplase
16
4.4
Concomitant Therapy
16
4.4.1
Cautionary Therapy
16
4.4.2
Prohibited Therapy
17
Effective Date: 6/15/2021
End Date: 12/7/2021


TABLE OF CONTENTS (CONT.)
Tenecteplase⎯Icahn School of Medicine at Mount Sinai
Protocol ML42492
3
4.5
Study Assessments and Procedures
17
4.5.1
Informed Consent
17
4.5.2
Screening
17
4.5.3
Pre-Randomization
19
4.5.4
Post-Randomization
19
4.5.5
Follow Up Period (Day 4 -27)
20
4.5.6
End of Study (Day 28)
20
4.6
Treatment, Patient, and Study Discontinuation
21
4.6.1
Patient Discontinuation from Study
21
4.6.2
Study Discontinuation
22
5.
ASSESSMENT OF SAFETY
22
5.1
Safety Plan
22
5.1.1
Stopping Rules
22
5.1.2
Risks Associated with Tenecteplase
23
5.1.2.1
Bleeding
23
5.1.2.2
Arrhythmias
23
5.1.2.3
Thromboembolism
24
5.1.2.4
Cholesterol Embolization
24
5.1.2.5
Use with Percutaneous Coronary Intervention
24
5.1.3
Precautions
24
5.1.3.1
Re-administration
24
5.1.3.2
Hypersensitivity
24
5.1.3.3
Drug Interactions
25
5.1.3.4
Drug/Laboratory Test Interactions
25
5.1.4
Management of Patients Who Experience Adverse Events
25
5.1.4.1
Management Guidelines
25
5.2
Safety Parameters and Definitions
26
5.2.1
Adverse Events
26
5.2.2
Serious Adverse Events
26
5.2.3
Adverse Events of Special Interest
26
5.3
Methods and Timing for Assessing and Recording Safety Variables
27
5.3.1
Adverse Event Reporting Period
27
5.3.2
Assessment of Adverse Events
27
5.4
Procedures for Eliciting, Recording, and Reporting Adverse Events
28
Effective Date: 6/15/2021
End Date: 12/7/2021


TABLE OF CONTENTS (CONT.)
Tenecteplase⎯Icahn School of Medicine at Mount Sinai
Protocol ML42492
4
5.4.1
Data Safety Monitoring/CEC
28
5.4.2
Eliciting Adverse Event Information
28
5.4.3
Specific Instructions for Recording Adverse Events
28
5.4.3.1
Diagnosis versus Signs and Symptoms
28
5.4.3.2
Deaths
29
5.4.3.3
Preexisting Medical Conditions
29
5.4.3.4
Hospitalizations for Medical or Surgical Procedures
29
5.4.3.5
Assessment of Severity of Adverse Events
29
5.4.4
Assessment of Causality of Adverse Events
30
5.4.4.1
Pregnancies
31
5.4.4.2
Post-Study Adverse Events
31
Case Transmission Verification of Single Case Reports
31
5.4.5
MedWatch 3500A Reporting Guidelines
34
5.4.5.1
Follow-up Information
35
5.4.6
Reporting to Regulatory Authorities, Ethics Committees and Investigators
35
5.5
Aggregate Reports
36
5.6
Study Close-Out
36
6.
Statistical Considerations
37
6.1
Determination of Sample Size
37
6.2
Primary Efficacy Variable
38
6.3
Primary Safety Variable
38
6.4
Ongoing Safety Analysis
38
6.5
Method of Analysis
38
7.
Investigator Requirements
38
7.1
Retention of Records
38
7.2
Study Medical Monitoring Requirements
39
7.3
Study Medication Accountability
39
7.4
Data Collection
39
7.5
Data monitoring
40
8.
Ethical Considerations
40
8.1
Compliance with Laws and Regulations
40
8.2
Informed Consent
40
8.3
Institutional Review Board or Ethics Committee
40
Effective Date: 6/15/2021
End Date: 12/7/2021


TABLE OF CONTENTS (CONT.)
Tenecteplase⎯Icahn School of Medicine at Mount Sinai
Protocol ML42492
5
8.4
Confidentiality
41
9.
References
42
LIST OF TABLES
Table 1
Guidelines for Management of Patients Who Experience Bleeding
33
Table 2
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
38
Table 3
Causal Attribution Guidance
39
LIST OF APPENDICES
Appendix 1
Study Flowchart
57
Appendix 2
Safety Reporting Fax Cover Sheet
63
Appendix 3
FDA MedWatch 3500 Form
64
Effective Date: 6/15/2021
End Date: 12/7/2021


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
GLOSSARY OF ABBREVIATIONS
ADR
adverse drug reaction
AE
adverse event
AHA
American Health Association
AIS
acute ischemic stroke
AV
arteriovenous
AMI
acute myocardial infarction
BFR
blood-flow rate
CCDS
company core data sheet
CT
CEC
computed tomography
Clinical Events Committee
CVCs
DSMC
central venous catheters
Data & Safety Monitoring Committee
EVT
endovascular treatment
ED50
effective dose at which 50% of a clot is lysed
GD
gestational day
HD
HFNC
hemodialysis
High Flow Nasal Cannula
ICH
International Conference on Harmonisation
IH
intracranial hemorrhage
IQR
interquartile range
IV
intravenous
MAD
Mutual Acceptance of Data
MCA
NIPPV
middle cerebral artery
noninvasive positive-pressure ventilation
NRB
non-rebreather mask
NOAEL
No-observed-adverse-effect-level
PAI-1
plasminogen activator inhibitor 1
PCI
percutaneous coronary intervention
p-PCI
primary percutaneous coronary intervention
SADR
serious adverse drug reaction
SAE
serious adverse event
sICH
symptomatic intracranial hemorrhage
t-PA
tissue plasminogen activator
USPI
United States Package Insert
Effective Date: 6/15/2021
End Date: 12/7/2021


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1.
BACKGROUND
1.1
BACKGROUND 
In less than five months since the emergence of a novel coronavirus (SARS-CoV-2) in 
December 2019, millions of patients worldwide have suffered acute respiratory conditions, many 
of whom ultimately require mechanical ventilation due to hypoxemic respiratory failure. This 
disease (COVID-19) has been associated with a hyperinflammatory and hypercoagulable state1 
leading to a range of thromboembolic complications from pulmonary embolism to ischemic 
stroke.2,3 Furthermore, emerging data suggest that the associated acute respiratory failure is, at 
least in part, due to pulmonary vascular disease caused by micro- and/or macro-emboli creating 
pulmonary vascular shunting and dead-space ventilation.4,5 The relatively preserved lung 
compliance, particularly in certain individuals and early in the disease course, has brought into 
question whether the respiratory failure is in fact caused by the traditional acute respiratory 
distress syndrome (ARDS).6,7 
Given these observations, in the early phase of the COVID-19 pandemic hitting New York City, 
critically ill patients with severe hypoxemic respiratory failure due to COVID-19 were treated with 
intravenous thrombolysis with alteplase, tissue plasminogen activator (tPA). In a case series of 
four patients, rapid physiologic improvements in alveolar ventilation, oxygenation, and/or 
hemodynamics was noted.18 Wang et al8 also noted similar results with tPA in this patient 
population. In both of these case series, the physiologic effects of tPA were only temporary. It 
was only with the concomitant use of anticoagulation with heparin were these physiologic 
benefits sustained, likely because anticoagulation prevented immediate rethrombosis in this 
exceptionally prothrombotic condition.18 Given that tPA is contraindicated for concomitant use 
with heparin infusion, this protocol is created to assess tenecteplase as a thrombolytic agent in 
patients with COVID-19, as there is a very long-standing literature documenting the safety of 
tenecteplase with concomitant heparin infusion.  There is an additional logistic benefit to 
tenecteplase, in that it is given as a single bolus.  The logistic challenges of providing a 
prolonged alteplase infusion to a COVID-19 patient, wherein the IV pumps are outside the room 
and the IV tubing is in excess of 7 feet long, is quite formidable. 
1.2
CURRENT THERAPIES AND UNMET MEDICAL NEED 
Currently, there is no proven therapy for COVID-19 associated respiratory failure.  A recent 
publication has suggested that systemic anticoagulation may help these patients19, but the data 
is far from definitive.  Additionally, a case series and ongoing clinical trial (at other centers) is 
assessing the potential value of tPA thrombolysis in this patient population.  We believe that 
TNK is uniquely situated to be of benefit for this population.
1.3
BACKGROUND ON TENECTEPLASE
Tenecteplase (TNKase) is a modified form of human tissue plasminogen activator (tPA) that 
binds to fibrin and converts plasminogen to plasmin.  In vitro studies demonstrated that in the 
presence of fibrin, tenecteplase conversion of plasminogen to plasmin is increased relative to its 
conversion in the absence of fibrin.  This fibrin specificity decreases systemic activation of 
plasminogen and the resulting degradation of circulating fibrinogen compared with a molecule 
lacking this property, which could potentially decrease the incidence of bleeding.
Effective Date: 6/15/2021
End Date: 12/7/2021


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Refer to the Tenecteplase Investigator's Brochure for details on nonclinical and clinical studies.
1.3.1
Approved Indication in US and Europe
In the US, TNKase® (tenecteplase) is indicated for use in the reduction of mortality associated 
with AMI.  
1.4
OVERVIEW OF CLINICAL DEVELOPMENT
Tenecteplase has been previously developed in other indications and has been approved for 
the treatment of AMI.  Tenecteplase is being developed by Genentech as a treatment for AIS 
4.5 to 24 hours after stroke onset, in patients who show a salvageable brain pattern by 
advanced imaging technology.  
Tenecteplase has been studied extensively in patients with acute myocardial infarction (AMI). 
The ASSENT-2 trial,9 for example, analyzed 16,949 patients with AMI randomized to either IV 
bolus of tenecteplase or infusion of alteplase, followed by maintenance therapy with heparin for 
48-72 hours (goal aPTT 50-75). All-cause mortality was nearly identical between the two 
groups; however, the authors noted a pragmatic advantage inherent with a single bolus of 
tenecteplase compared to an infusion of alteplase. Tenecteplase is also associated with a lower 
rate of systemic bleeding compared to alteplase.  The ASSENT-3 and ASSENT-3 PLUS trials 
provide further confirmation of the safety of anticoagulation administration following 
tenecteplase,10,11 
Tenecteplase has been studied for patients with pulmonary embolism.15 In the PEITHO trial, the 
use of tenecteplase at a dose of 0.5 mg/kg with concomitant anticoagulation reduced the rate of 
hemodynamic decompensation in patients with intermediate-risk pulmonary embolism. This 
benefit, along with lower bleed rates, was particularly notable in participants younger than 75 
years old. Eight of 13 (62%) participants who suffered stroke in PEITHO were > 75 years old; 
two of the eleven (18%) participants who suffered hemorrhagic stroke were < 75 years old.
Completed and ongoing clinical studies of tenecteplase are summarized in the Tenecteplase 
Investigator’s Brochure. 
1.4.1
Acute Myocardial Infarction Clinical Development
Tenecteplase is indicated for use in the reduction of mortality associated with AMI and has been 
approved since 2000.  Completed and ongoing clinical studies of tenecteplase are summarized 
in the Tenecteplase Investigator's Brochure.  
1.4.2
Acute Ischemic Stroke Clinical Development
Tenecteplase is being evaluated for safety and efficacy in a Phase III in AIS stroke patients, 
4.5−24 hours after symptom onset, who show a salvageable brain pattern by advanced imaging 
technology (Study ML40787).  Study ML40787 TIMELESS (Thrombolysis in Imaging Eligible 
Late Window Patients to assess the efficacy and safety of Tenecteplase) is currently enrolling 
and plans to enroll 456 acute ischemic stroke patients in the US and Canada.  Patients with 
large vessel occlusions, with a diffusion/perfusion mismatch, in the 4.5−24 hour window may be 
eligible to receive tenecteplase 0.25 mg/kg or placebo in conjunction with mechanical 
thrombectomy.
Effective Date: 6/15/2021
End Date: 12/7/2021


Tenecteplase⎯Icahn School of Medicine at Mount Sinai
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Completed and ongoing clinical studies of tenecteplase are summarized in the Tenecteplase 
Investigator’s Brochure.
Studies have also demonstrated the benefit of tenecteplase in acute ischemic stroke. In the 
EXTEND-IA TNK trial,13 tenecteplase combined with endovascular thrombectomy was 
associated with higher probability of radiographic reperfusion as well as long term functional 
outcomes in patients with large vessel intracranial occlusions as compared to alteplase.  This 
benefit was seen at a lower dose (0.25 mg/kg) than the MI studies (0.5 mg/kg).  A subsequent 
study, EXTEND-IA TNK II, found no increased risk but no clinical benefit in stroke to increasing 
the TNK dose to 0.4 mg/kg.13 Further studies are in progress to assess a longer window to 
treatment time, including a Phase III clinical trial for patients with a salvageable penumbra on 
brain perfusion imaging.14
1.5
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Based on a recent JAMA publication, intubated COVID-19 patients in NYC can expect a 
mortality rate as high as 88%.16 This dismal mortality rate has driven us to make clinical 
decisions regarding the use of off-label application of otherwise FDA approved medications in a 
hope to improve outcomes.  Therefore, we undertook the off-label utilization of tenecteplase (at 
the lower EXTEND-IA TNK dosing) with concomitant heparin administration for the treatment of 
5 refractory COVID-19 patients. We were highly encouraged by this experience in that all 
patients had improvement in oxygenation, alveolar ventilation, and hemodynamics within 24-48 
hours. Four of the five patients had shock resolution, while the fifth patient had dramatic 
reductions in vasopressor requirements. No clinically significant bleeding was noted in any of 
these patients. As a result, we believe that a high-quality prospective Phase II, dose escalation 
trial is indicated. 
To assess the efficacy of tenecteplase on critically ill patients with COVID-19 and hypoxic 
respiratory failure, we propose a multi-center, randomized, controlled, double-blind, dose-
escalation trial comparing tenecteplase versus placebo. We intend to enroll 60 subjects: 40 
randomized for intervention (20 each at doses of TNK, 0.25 mg/kg and 0.50 mg/kg) and 20 for 
placebo. Planned inclusion criteria are confirmed respiratory failure requiring mechanical 
ventilation for not greater than 48 hours, or non-rebreather (NRB), high-flow nasal cannula 
(HFNC), or non-invasive positive pressure ventilation (NIPPV) for less than 96 hours, with 
confirmed infection with SARS-CoV-2 virus (PCR positive within 14 days), elevated D-dimer (2 
times upper limit of normal,17 and lack of stringent exclusion criteria. Primary efficacy outcome 
will be clinical status assessment at 28 days (proportion of patients alive and free of respiratory 
failure). Primary safety outcome will be rate of ICH or major acute hemorrhage (defined as 
bleeding episode leading to hemodynamic compromise requiring emergency intervention [such 
as replacement of fluid and/or blood products, inotropic support, or surgical treatment], or life-
threatening or fatal bleeding).  Secondary outcomes include survival, ventilator-free days, 
respiratory failure-free days, vasopressor-free days, improvement in PaO2/FiO2, and ICU and 
hospital length of stay. 
Effective Date: 6/15/2021
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2.
OBJECTIVES AND ENDPOINTS
2.1
PRIMARY OBJECTIVE(S)
The study objective is to evaluate the potential effect of tenecteplase on patients presenting with 
COVID-19. The hypothesis is that administration of the drug, in conjunction with heparin 
anticoagulation, will improve patients’ clinical outcomes.
2.2
PRIMARY EFFICACY OUTCOME
The primary efficacy outcome will be the proportion of patients alive and free of respiratory 
failure (defined as not requiring non-rebreather, high-flow nasal cannula, non-invasive positive 
pressure ventilation, or mechanical ventilation) at 28 days. 
2.3
STUDY OUTCOMES
The following outcomes will be tracked for the trial:
Primary outcome is: the proportion of patients alive and free of respiratory failure (not requiring 
non-rebreather, high-flow nasal cannula, non-invasive positive pressure ventilation, or 
mechanical ventilation) at 28 days
A. Primary safety outcome: Occurrence of intracranial bleeding or major bleeding 
(Definition: A bleeding episode leading to hemodynamic compromise requiring 
emergency intervention (such as replacement of fluid and/or blood products, inotropic 
support, or surgical treatment), or life-threatening or fatal bleeding) within 72 hours of 
randomization. All outcomes will be assessed in a blinded fashion by the DSMC/CEC.
B. Secondary outcomes include: 14-day in-hospital mortality, 28-day mortality, ventilator-
free days, respiratory failure-free days (not requiring NRB, HFNC, NIPPV, or mechanical 
ventilation), vasopressor-free days, vasopressor requirements at 24 and 72 hours, P/F 
ratio at 24 hours and 72 hours, ICU-free days, hospital length of stay, new renal failure, 
need for renal replacement therapy
C. Mortality: given a high mortality rate amongst this patient population, patients who die 
will be included in statistical analysis. Variables of interest will be calculated until the 
point these patients expire.
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This will be a placebo controlled, double-blind, randomized, Phase II dose escalation trial 
completed at up to 6 study centers. Subjects will be randomized in a 2:1 ratio to treatment or 
control in blocks of 15, performed twice per dose - low (0.25 mg/kg with maximum dose 25 mg) 
and high (0.50 mg/kg with maximum dose 40 mg), with randomization stratified by site. 
3.2
END OF STUDY AND LENGTH OF STUDY
The anticipated first patient, first visit will occur on June 15, 2020. Enrollment is anticipated to 
take approximately 5 months, with our last patient, first visit to occur on November 15, 2020. 
Follow up will be completed by December 15, 2020. It will take the study team approximately 2 
Effective Date: 6/15/2021
End Date: 12/7/2021


Tenecteplase⎯Icahn School of Medicine at Mount Sinai
Protocol ML42492
11
months to clean and analyze the data, with a final study report expected by mid-February, 
2021.  
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 8 months.
3.3
RATIONALE FOR STUDY DESIGN
This is a phase II dose escalation study intended to evaluate the potential safety and efficacy of 
tenecteplase for the treatment of COVID-19 associated respiratory failure. This study is not 
powered for significance, but is instead designed to provide an estimate of the potential benefit-
signal and better inform a subsequent phase III RCT. 
3.3.1
Rationale for Tenecteplase Dose and Schedule
Tenecteplase is a triple combination mutant of alteplase, with a longer half-life, improved 
specificity for fibrin, and higher resistance to degradation by plasminogen-activator inhibitor.22 
One practical clinical advantage over other thrombolytic drugs is the ability to bolus a single 
dose of tenecteplase, compared to longer infusions required for efficacy (i.e. alteplase). 
Tenecteplase was first studied in acute myocardial infarction (AMI) in the 1990s. In the TIMI 10A 
trial, tenecteplase was found to be effective for coronary reperfusion in patients with AMI and 
had a safety profile comparable to wild-type tPA.23 The follow up TIMI 10B trial randomized 886 
patients with early (≤12 hr) AMI to either bolus tenecteplase or bolus + infusion of tPA, plus 
coronary angiography and postprocedural heparin infusion.24 The study authors found that 
overall rates of TIMI grade 3 reperfusion were similar between the two groups, but this finding 
was found in patients who received higher doses of tenecteplase (50 mg versus 30 mg), albeit 
with higher risk of symptomatic bleeding and intracranial hemorrhage. The risks of hemorrhage 
were reduced in both groups by lowering heparin infusion rates. A further safety assessment of 
tenecteplase, relative to alteplase, was published in 1999 through the ASSENT-1 trial, in which 
a total of 325 patients were given a single bolus of tenecteplase in escalating doses (30, 40, or 
50 mg).25 Overall rates of intracranial hemorrhage were low (0.77% overall), did not depend on 
dose, and were comparable to historical data on tPA. Overall, the authors recommend a weight-
based dosing strategy for patients with AMI.
Based on these positive safety trials, subsequent trials were published directly comparing 
tenecteplase and alteplase. ASSENT-2 was a double-blind, controlled trial randomizing 16,949 
patients to either weight based tenecteplase bolus (0.5 mg/kg) or infusion with tPA, plus aspirin 
and heparin infusion.26 The primary outcome of all-cause mortality at 30 days was similar for the 
two groups (6.18% and 6.15% for tenecteplase and tPA, respectively). Rates of intracranial 
hemorrhage were also similar between the two groups, although the risk of other hemorrhage 
was higher for tPA.
Given the positive results in the cardiac literature, tenecteplase has also been trialed for acute 
ischemic stroke; however, there has been limited adoption compared to alteplase following the 
NINDS trial in 1995.27 Smaller phase II trials were performed throughout the 2010s, again 
suggesting equivalent efficacy regarding reperfusion with a similar safety profile between 
tenecteplase and alteplase. The first dose-escalation study was published in 2005 and 
assessed tenecteplase doses between 0.1 and 0.5 mg/kg.28 Despite and increasing incidence of 
asymptomatic intracranial hemorrhage (ICH) between 0.1 and 0.4 mg/kg doses, no symptomatic 
ICH were seen. However, the 0.5 mg/kg tier was terminated prematurely given a high incidence 
Effective Date: 6/15/2021
End Date: 12/7/2021


Tenecteplase⎯Icahn School of Medicine at Mount Sinai
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of symptomatic ICH (2 of 13 patients). Overall long-term functional outcomes were similar 
between the lower dose tenecteplase and historical controls treated with tPA.
The ATTEST trial randomized 104 patients with acute ischemic stroke to receive either TNK or 
tPA.29 The primary endpoint of salvaged penumbra was identical between the two groups 
(68%), and rates of symptomatic intracranial hemorrhage were not statistically different (2% and 
4% for TNK and tPA, respectively, p=0.55). Another randomized controlled trial published in 
2012 assessed either alteplase infusion or dose-escalated tenecteplase (0.1 or 0.25 mg/kg) in 
patients with acute ischemic stroke less than 6 hours after symptom onset.30 Patients treated 
with tenecteplase had better rates of radiographic reperfusion as well as short- and long-term 
clinical improvement, with higher doses (0.25 mg/kg) performing better than lower. Rates of 
intracranial and non-intracranial hemorrhages were consistent in all three groups.
Most recently the EXTEND-IA TNK trial assessed 202 patients randomized to either 
tenecteplase bolus (0.25 mg/kg) or alteplase prior to endovascular thrombectomy for large 
vessel occlusion.31 The primary outcome of angiographic reperfusion prior to thrombectomy (or 
absence of retrievable thrombus) was significantly greater in the TNK group, compared with 
tPA, present in 22% and 10%, respectively. Tenecteplase was also associated with 
improvement in 90-day functional outcomes, and similar rates of symptomatic intracranial 
hemorrhage.
Tenecteplase has also been assessed for use in treating pulmonary embolism (PE). In general, 
thrombolysis for PE has been shown to have minimal evidence for clinical benefit compared 
with heparin, except in those with the highest risks of recurrence or death.32 In clinical trials, 
thrombolysis with alteplase has been associated with improvements in hemodynamic 
parameters (including pulmonary resistance and cardiac index) but have indeterminate effects 
on overall clinical outcomes given a paucity of data.33 In one randomized, placebo-controlled 
trial of tenecteplase (at a dose of 0.5 mg/kg) plus heparin versus heparin alone, intermediate-
risk patients with PE treated with TNK had lower risk of hemodynamic decompensation or 
death.34 Symptomatic intracranial hemorrhage was more frequent in the TNK group, though 
occurred predominantly in patients older than 75 years old. Patients with submassive PE have 
also been found to have increased odds of good outcome after treatment with tenecteplase, 
compared with placebo, according to a randomized trial published in 2014.35
Based on this evidence, dosing guidelines for this trial will be as follows:
Patients will be monitored in the ICU immediately post-treatment and until 24 hours have 
passed and they are considered stable to downgrade to lower level of care.
A. For patients already on therapeutic heparin, continue heparin infusion
B. For patients not already on heparin or other anticoagulant, begin heparin with 
tenecteplase infusion starting with bolus dose of 60 Units/kg IV once (maximum dose of 
5000 Units), followed by 12 Units/kg/hr (patients will only receive one dose of 
tenecteplase in total)
C. For patients who were receiving enoxaparin at time of inclusion, tenecteplase infusion 
can be given immediately. Delay heparin to 12 hours after the most recent enoxaparin 
dose, beginning at an infusion rate of 12 Units/kg/hr. Do not administer a bolus dose of 
heparin.
-Check PTT every 6 hours; adjust heparin to achieve target PTT between 2 and 
2.5 times ULN
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Patients will continue with the unfractionated heparin infusion for 24 hours from the beginning of 
the study. After 24 hours, they may be transitioned to low molecular weight heparin according to 
institutional standard of care. 
3.3.2
Rationale for Patient Population
This patient population has been chosen because they have objective indications of respiratory 
failure (intubation, NRB, HFNC, or NIPPV) but that failure is recent in onset. There has been 
increasing literature demonstrating the progressive thrombosis that occurs in multiple organ 
systems during COVID-19, including the lungs. By administering tenecteplase to this early stage 
respiratory failure population, who also have demonstrable thrombosis occurring (as indicated 
by their D-dimer) we hope to reverse the progressive pulmonary thrombosis that is occurring 
and thereby improve their outcome. 
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 60 total patients with COVID-19 will be enrolled in this study. 40 intervention (20 
low dose subjects at 0.25 mg/kg with maximum dose 25 mg, 20 high dose subjects at 0.50 
mg/kg with maximum dose 40 mg), 20 control subjects. 
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:
●
Patient/legally authorized representative has completed the Informed Consent Form
●
Age ≥18 years
●
Ability to comply with the study protocol, in the investigator’s judgment
●
Respiratory failure secondary to COVID-19 requiring mechanical ventilation for no greater 
than 48 hours, or high-flow nasal cannula (HFNC), non-rebreather (NRB) mask or non-
invasive positive pressure ventilation (NIPPV) for less than 96 hours 
●
Confirmed infection with SARS-CoV-2 virus (PCR positive within 14 days) 
●
Elevated D-dimer (>2 times upper limit of normal within past 72 hours) 
●
For patient who are intubated >12 hours prior to randomization or with any evidence of 
neurologic deficit a head CT within 12 hours demonstrating no evidence of acute or 
subacute infarct or hemorrhage
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
General 
●
Current participation in another investigational drug study within the prior 7 days
●
Known hypersensitivity or allergy to any ingredients of tenecteplase
●
Active internal bleeding
●
Known bleeding diathesis
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●
Use of one of the new oral anticoagulants within the last 24 hours (dabigatran, rivaroxaban, 
apixaban, edoxaban)
●
Treatment with a thrombolytic within the last 3 months prior to randomization (exception for 
the use of Cathflo alteplase for occlusions of central venous catheters)
●
Baseline platelet count 80,000/L (results must be available prior to treatment)
●
Baseline blood glucose 400 mg/dL (22.20 mmol/L)
●
Baseline blood glucose 50 mg/dL needs to be normalized prior to randomization
●
Intracranial or intraspinal surgery or trauma within 2 months
●
Other, non-COVID-19 related, serious, advanced, or terminal illness (investigator judgment) 
or life expectancy is less than 6 months
●
History of acute ischemic stroke in the last 90 days
●
History of intracranial bleeding, including hemorrhagic stroke
●
Presumed septic embolus; suspicion of bacterial endocarditis
●
Mechanical ventilation > 48 hours, HFNC, NIPPV, NRB, or any combination, for greater 
than 96 hours 
●
Mechanical ventilation, HFNC, NRB, or NIPVV (for reasons other than obstructive sleep 
apnea) within the prior 30 days (excluding 96 hours prior to randomization) 
●
Moribund status suggesting imminent vascular collapse and inability to survive > 72 hours 
(investigator determination) 
●
Uncontrolled hypertension defined as systolic BP > 180 mm Hg and/or diastolic BP > 110 
mm Hg 
●
Age > 75 years
●
History of traumatic brain injury within 2 months
●
Recent head trauma with fracture or brain injury
●
History of Heparin Induced Thrombocytopenia (HIT) and/or other hereditary or acquired 
hemorrhagic diathesis or coagulation factor deficiency
●
INR > 2 or recent oral anticoagulant therapy with INR >1.7 
●
Pregnancy or lactation within the prior 30 days; women of childbearing age (<55 years old) 
should have documentation of a negative pregnancy test 
●
Chronic liver disease defined as > Childs-Pugh Class B
●
Patients with history of atrial fibrillation, mitral stenosis, or known left heart thrombosis
●
Atrial fibrillation, mitral stenosis, or known left heart thrombosis
●
Any other condition that, in the opinion of the investigator, precludes administration of 
tenecteplase or poses a significant hazard to the patient receives tenecteplase
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4.2
METHOD OF TREATMENT ASSIGNMENT 
This trial will be a randomized, blinded, placebo-controlled trial with an escalating-dose 
randomized design. Randomization will be completed as follows:
●
Block randomization of 2:1 (treatment:control) in blocks of 15, performed twice 
per dose
●
The first block of 15 patients (10 treatment at 0.25 mg/kg dose and 5 placebo 
control) will be assessed for safety trigger by the DSMC/CEC within 5 working 
days of the 15th patient completing 72 hours post treatment; if no safety trigger is 
met (as determined by DSMC/CEC), a second cohort of 15 patients will be 
enrolled (10 at the 0.25 mg/kg dose and 5 placebo control).
●
If no safety trigger occurs after 30 patients enrolled (20 at the 0.25 mg/kg dose 
and 10 placebo control) then the first cohort 15 patients will be enrolled at the 
0.50 mg/kg dose with randomization of 2:1 (treatment:placebo control). If no 
safety trigger occurs, the last cohort of 15 patients will be enrolled (10 at the 0.50 
mg/kg dose and 5 placebo control).
●
All SAE’s will be reviewed by the DSMC/CEC every 15 patients enrolled and 
each death will be reviewed within 72 hrs of reporting. Safety trigger is defined as 
a greater than two patient differential in the occurrence of symptomatic 
intracranial hemorrhage or major acute bleeding event (defined below) within 72 
hours between control and treatment arms.
●
Randomization will be stratified according to site. 
Tenecteplase and placebo will be provided by Genentech. They will be labeled accordingly, 
indicating which vials contain active drug and which contain placebo. The DCC research 
pharmacy will de-identify the drugs for distribution to each study center (with tracking of all 
product) and therefore will remain unblinded to treatment randomization and will be in charge of 
assigning the correct vials for dosing. Study staff, investigators, and subjects will remain blinded 
to treatment assignments.  
4.3
STUDY TREATMENT
The investigational medicinal product (IMP) for this study is tenecteplase. This will be given to 
patients in combination with heparin, as outlined in section 3.3.1.
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4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Tenecteplase
Tenecteplase will be supplied by Genentech as a sterile, lyophilized powder in a 50-mg vial 
under partial vacuum.  Sites will be expected to provide the diluent, 10mL Sterile Water for 
Injection. 
Placebo will be supplied by Genentech as a sterile lyophilized powder in a 50 mg vial under 
partial volume that will be labeled as Tenecteplase Placebo 50mg.
For information on the formulation and handling of tenecteplase, see the local prescribing 
information for Tenecteplase or the Tenecteplase Investigator’s Brochure.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.3.1.
Any overdose or incorrect administration of tenecteplase or placebo should be noted in the 
patient’s medical records and reported according to Section 5.5 (Special Situations Reports).  
Adverse events associated with an overdose or incorrect administration of any of the study 
treatments should be recorded in the patient’s medical records.
4.3.2.1
Tenecteplase
Store lyophilized Tenecteplase at controlled room temperature not to exceed 30C (86F) or 
under refrigeration 2C−8C (36F−46F).  Do not use beyond the expiration date stamped on 
the vial.
For information on the formulation and handling of tenecteplase, see the local prescribing 
information for Tenecteplase or the Tenecteplase Investigator’s Brochure.
Please see section 3.3.1 for dosing schedule. 
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient in 
addition to protocol-mandated treatment from 7 days prior to initiation of study treatment to the 
treatment discontinuation visit.  All such medications should be reported to the investigator and 
recorded in the patient’s medical records. Medications indicated as “prn” or “as needed” will not 
be reported in the EDC. 
4.4.1
Cautionary Therapy
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
herbal/homeopathic remedies, preventative vaccines, vitamins, nutritional supplements) used by 
a patient from 1 week prior to randomization to the patient’s last visit.  All concomitant 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.
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Patients who use oral contraceptives or maintenance therapy for comorbidities should continue 
their use.
Formal interaction studies of tenecteplase with other drugs have not been performed.  Patients 
studied in clinical trials of tenecteplase were routinely treated with heparin and aspirin.  
Anticoagulants (such as heparin and vitamin K antagonists) and drugs that alter platelet function 
(such as acetylsalicylic acid, dipyridamole, and glycoprotein [GP] IIb/IIIa inhibitors) may increase 
the risk of bleeding if administered prior to, during, or after tenecteplase therapy.  
The investigator should consult the prescribing information when determining whether a 
concomitant medication can be safely administered with study treatment.  In addition, the 
investigator should contact the Medical Monitor if questions arise regarding medications not 
mentioned above.
4.4.2
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:
●
Investigational therapy (other than protocol-mandated study treatment) is prohibited within 
30 days prior to initiation of study treatment, during study treatment, and until the patient’s 
last study assessment.
4.5
STUDY ASSESSMENTS AND PROCEDURES
The schedule of activities to be performed during the study is provided in Appendix 1.  All 
activities must be performed and documented for each patient.  Patients will be closely 
monitored for safety and tolerability throughout the study.  Patients should be assessed for 
toxicity prior to each dose; dosing will occur only if the clinical assessment and local laboratory 
test values are acceptable.
4.5.1
Informed Consent
Written informed consent for participation in the study must be obtained before performing 
any study-related procedures (including screening evaluations).  Informed Consent Forms for 
enrolled patients and for patients who are not subsequently enrolled will be maintained at the 
study site. Given the circumstances that may exist at sites due to COVID-19, sites will work with 
their IRBs to determine the best method of obtaining consent. This may be in person or 
electronically depending on requirements. 
4.5.2
Screening 
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before enrollment.  The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening failure, 
as applicable.
The following data points will be collected during the Screening timepoint. 

Medical History, Concomitant Medication, and Demographic Data
Medical history includes clinically significant diseases and procedures.  All medication taken in 
the last 7 days prior to randomization (including prescription, over-the-counter, and 
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herbal/homeopathic remedies and therapies) are to be recorded. Inpatient concomitant 
medications that are indicated as “prn” or “as needed” will not be recorded in the EDC. A 
detailed history of medication used for UC is required for the past 5 years.
Demographic data, including age, sex, and self-reported race/ethnicity will be collected.

Neurological Examinations
A neurological examination will be performed according to the Schedule of Assessments.  New 
or worsened abnormalities from screening will be recorded as adverse events if appropriate.  In 
addition, a symptom-driven examination should be conducted as indicated in the Schedule of 
Assessments. 
The neurological exam will be documented by a GCS score and NIHSS.

Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, systolic and diastolic blood 
pressure (via arterial line or BP cuff if arterial line is not in place), and temperature.
In addition, vital signs should be measured at other specified timepoints as outlined in the 
schedule of activities (see Appendix 1).

Laboratory Samples
Results from the following are required prior to randomization and should be processed locally:
●
CBC: Platelet, WBC, Hb, Hct
●
BMP: Na, K, Cl, HCO3, BUN, Cr
●
Glucose (finger stick or lab)
●
LFT: ALT, AST, Bili, Alk Phos, LDH, Total Protein, Albumin, D-dimer, fibrinogen, CRP, 
ferritin, troponin-I, BNP
●
Coagulation:  INR, aPTT, PT, anti-Xa
●
Arterial Blood Gas: pH, pCO2, pO2, SaO2, Lactate
-
Will be conducted every 12 hours
●
Thromboelastograms (when available according to standard practice)
●
Urine/serum pregnancy test
–
All women of childbearing potential will have a pregnancy test at screening.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test.

SARS-CoV-2 PCR Test
A SARS-CoV-2 PCR Test will be conducted during screening to determine if the patient is 
COVID positive.

Respiratory Status / Ventilator Settings
Respiratory or Ventilator settings will be collected at Screening.
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●
Ventilator settings (if appropriate): RR, TV, PI (if PCV or PSV) FiO2, PEEP, Plateau 
Pressure
●
NIPPV settings (if appropriate): RR, IPAP, EPAP, FiO2
●
HFNC settings (if appropriate): FiO2, flow
●
NRB settings (if appropriate): flow

Ordinal Scale Assessment
The Ordinal Scale Assessment will be conducted daily to determine the patient’s current status.

Imaging
If the patient has a standard of care CT Scan or X-Ray performed, the imaging result will be 
captured in the Screening CRF.
4.5.3
Pre-Randomization
All study assessments during Pre-Randomization must be collected or confirmed within 2 hours 
of study drug administration.
●
Neurological Exam
●
Vitals
●
Laboratory Samples
CBC: Platelet, WBC, Hb, Hct
BMP: Na, K, Cl, HCO3, BUN, Cr
Glucose (finger stick or lab)
LFT: ALT, AST, Bili, Alk Phos, LDH, Total Protein, Albumin, D-dimer, fibrinogen, CRP, ferritin, 
troponin-I, BNP
Coagulation:  INR, aPTT, PT, anti-Xa
Thromboelastograms (when available according to standard practice)
●
Respiratory Status / Ventilator Settings
●
Ordinal Scale Assessment
●
Concomitant medication review (excluding “prn” or “as needed” medications)
4.5.4
Post-Randomization
Post Randomization assessments will be collected every 6 hours up to 72 hours after study 
drug administration.
●
Randomization and Study Drug Administration
●
Neurological Exam
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The subject will be evaluated every 15 minutes for the first hour following study drug 
administration. Evaluation will then occur every 30 minutes for 4 hours, then every hour for 12 
hours. The neurological exam will be documented by a GCS score and NIHSS. 
●
Vitals
Vital signs should be measured every 15 minutes after study drug administration for one hour, 
then every hour for 4 hours, then every 6 hours.  
●
Laboratory Samples (q6 hours for 24 hrs and then daily for subsequent 48 hours)
Coagulation: INR, aPTT, PT, anti-Xa
Arterial Blood Gas: pH, pCO2, pO2, SaO2, Lactate
●
Respiratory Status / Ventilator Settings
●
Doses of all vasopressors every 6 hours for first 72 hours then daily 
●
Heparin Dosing
If subject was not previously on heparin, please begin infusion as specified in protocol. Begin 
heparin with tenecteplase infusion starting with bolus dose of 60 Units/kg IV once, followed by 
12 Units/kg/hr. Heparin should be adjusted to achieve target PTT of 70-90 seconds.

Concomitant medication review (excluding “prn” or “as needed” medications)
4.5.5
Follow Up Period (Day 4 -27)
The subject will have a daily follow up collecting all of the below assessments. If the 
patient reaches an aPTT value of 70-90 seconds, subsequently daily aPTT values will 
be record until discharge or Day 28.
●
Neurological Exam
●
Vitals
●
Laboratory Samples (Standard of care)
●
Respiratory Status / Ventilator Settings
●
Ordinal Scale Assessment
●
Imaging (Standard of Care)
●
Concomitant medication review (excluding “prn” or “as needed” medications)
4.5.6
End of Study (Day 28)
The following assessments will be collected at the final End of Study timepoint if the patient is 
still admitted:
●
Neurological Exam
●
Vitals
●
Laboratory Samples (Standard of care)
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Thromboelastograms (when available according to standard practice)
●
Respiratory Status / Ventilator Settings
●
Imaging (Standard of Care)
●
Concomitant medication review (excluding “prn” or “as needed” medications)
The ordinal scale assessment will be completed at day 28 regardless of whether the 
patient is admitted or discharged. 
4.6
TREATMENT, PATIENT, AND STUDY DISCONTINUATION
Patients must permanently discontinue study treatment (tenecteplase or placebo) if they 
experience any of the following:
●
Intolerable toxicity related to study treatment, including development of an immune-
mediated adverse event determined by the investigator to be unacceptable given the 
individual patient’s potential response to therapy and severity of the event
●
Any medical condition that may jeopardize the patient’s safety if he or she continues study 
treatment
●
Investigator determines it is in the best interest of the patient
●
Pregnancy
●
Anaphylaxis or other severe hypersensitivity reaction
●
Loss of clinical benefit as determined by the investigator after an integrated assessment of 
clinical status (e.g., symptomatic deterioration such as pain secondary to disease) (see 
Section 3.1.1 for details)
The primary reason for study treatment discontinuation should be documented in the patient’s 
medical records.  Patients who discontinue study treatment prematurely will not be replaced.
4.6.1
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  In 
addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:
●
Withdrawal of consent
●
Study termination or site closure
●
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the Investigator
Every effort should be made to obtain information on patients who withdraw from the study.  The 
primary reason for withdrawal from the study should be documented in the patient’s medical 
records.  If a patient requests to be withdrawn from the study, this request must be documented 
in the source documents and signed by the investigator.  Patients who withdraw from the study 
will not be replaced.
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If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status.
4.6.2
Study Discontinuation
The Investigator has the right to terminate this study at any time.  Reasons for terminating the 
study may include, but are not limited to, the following:
●
The incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to patients
●
Patient enrollment is unsatisfactory
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on clinical experience with tenecteplase in 
completed and ongoing studies.  The anticipated important safety risks for tenecteplase are 
outlined below.  Please refer to the Tenecteplase Investigator's Brochure for a complete 
summary of safety information. 
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  Patients 
will undergo safety monitoring during the study, including assessment of the nature, frequency, 
and severity of adverse events.  In addition, guidelines for managing adverse events are 
provided below.
Measures will be taken to ensure the safety of patients participating in this study, including the 
use of stringent inclusion and exclusion criteria and close monitoring of patients during the 
study.  Administration of tenecteplase, and the placebo, will be performed in a monitored setting 
in which there is immediate access to trained personnel and adequate equipment and medicine 
to manage potentially serious reactions.  Refer to Sections 5.2−5.6 for details on safety 
reporting (e.g., adverse events, pregnancies) during the study.
5.1.1
Stopping Rules
In the case of any Mortality during the 28 day follow up period, enrollment will be halted and 
DSMC/CEC review will be performed within 72 hrs of notification.  The DSMC will then issue a 
report back to the study PI regarding their recommendation as to re-opening the study or 
permanently closing the study. 
Should there occur, at any time during the study, a difference between the control and treatment 
cohorts of >2 intracerebral hemorrhages then the study will be halted.  Per protocol, the 
DSMC/CEC will review all ICH’s (SAE’s). Following each of these individual case reviews (after 
analysis/interpretation locked), the DSMC/CEC statistician (who is unblinded, not the study 
statistician, who will remain blinded) will provide summary data on the ICH’s according to 
cohort. If there is a greater than 2 ICH differential then the study will be halted.  Additionally, the 
DSMC/CEC will be reviewing all enrollments, with summary statistics for each cohort (provided 
by the DSMC/CEC statistician) after each 15 patients are enrolled. They are empowered to halt 
study enrollment at each of these review points should there be safety concerns. After each of 
these planned DSMC/CEC reviews the DSMC/CEC will generate a formal report to provide to 
the study PI.  
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5.1.2
Risks Associated with Tenecteplase
Standard management of myocardial infarction should be implemented concomitantly with 
tenecteplase treatment.  
Arterial and venous punctures should be minimized. Non-compressible arterial puncture must 
be avoided, and internal jugular and subclavian venous punctures should be avoided to 
minimize bleeding from the non-compressible sites.  In the event of serious bleeding, heparin 
and antiplatelet agents should be discontinued immediately and treated appropriately.  Heparin 
effects can be reversed by protamine.
5.1.2.1
Bleeding
The most common complication encountered during tenecteplase therapy is bleeding. This may 
be either superficial from punctures or damaged blood vessels or internal bleeding at any site or 
body cavity.  Bleeding may result in life-threatening situations, permanent disability, or death. 
●
The incidence of ICH, especially sICH, in patients with AIS is higher in alteplase-treated 
patients than placebo-treated patients in published studies (for detailed information, see the 
alteplase USPI).
The type of bleeding associated with thrombolytic therapy can be divided into two broad 
categories:
●
Internal bleeding, involving intracranial and retroperitoneal sites, or the gastrointestinal, 
genitourinary, or respiratory tracts
●
Superficial or surface bleeding, observed mainly at vascular puncture and access sites (e.g., 
venous cutdowns, arterial punctures) or sites of recent surgical intervention
Management of Bleeding 
Patients will be excluded for the presence of conditions related to risks of bleeding (as outlined 
in Section 4.1.2 Exclusion Criteria). 
Should an arterial puncture be necessary during the first few hours following tenecteplase 
therapy, the use of an upper extremity vessel that is accessible to manual compression is 
preferable.  Pressure should be applied for at least 30 minutes, a pressure dressing applied, 
and the puncture site checked frequently for evidence of bleeding.
Each patient being considered for therapy with tenecteplase should be carefully evaluated and 
anticipated benefits weighed against potential risks associated with therapy.
Guidelines for management of patients who develop bleeding are provided in Table 1. 
In addition, any ICH events (symptomatic and/or asymptomatic), if not already reported as an 
SAE by the investigator, are considered non-serious adverse events of special interest for this 
study (Section 5.2.3) and should be reported and submitted to the Sponsor (Section 5.4 ).
5.1.2.2
Arrhythmias
Coronary thrombolysis may result in arrhythmias associated with reperfusion.  These 
arrhythmias (such as sinus bradycardia, accelerated idioventricular rhythm, ventricular 
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premature depolarizations, ventricular tachycardia, etc.) are not different from those often seen 
in the ordinary course of AMI and may be managed with standard anti-arrhythmic measures.  It 
is recommended that anti-arrhythmic therapy for bradycardia and ventricular irritability be 
available when tenecteplase is administered.
5.1.2.3
Thromboembolism 
The use of thrombolytics can increase the risk of thromboembolic events in patients with high 
likelihood of left heart thrombus, such as patients with mitral stenosis or atrial fibrillation.
5.1.2.4
Cholesterol Embolization
Cholesterol embolism has been reported rarely in patients treated with all types of thrombolytic 
agents; the true incidence is unknown.  This serious condition, which can be lethal, is also 
associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, 
vascular surgery) and/or anticoagulant therapy. Clinical features of cholesterol embolism may 
include livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, 
hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, 
retinal artery occlusion, bowel infarction, and rhabdomyolysis.
5.1.2.5
Use with Percutaneous Coronary Intervention
In patients with ST segment elevation myocardial infarction, physicians should choose either 
thrombolysis or PCI as the primary treatment strategy for reperfusion. Rescue PCI if medically 
appropriate or subsequent elective PCI may be performed after administration of thrombolytic 
therapies; however, the optimal use of adjunctive antithrombotic and antiplatelet therapies in 
this setting is unknown.
5.1.3
Precautions
Standard management of acute ischemic stroke should be implemented concomitantly with 
tenecteplase treatment.  Arterial and venous punctures should be minimized. Noncompressible 
arterial puncture must be avoided and internal jugular and subclavian venous punctures should 
be avoided to minimize bleeding from the noncompressible sites. In the event of serious 
bleeding, heparin and antiplatelet agents should be discontinued immediately. Heparin effects 
can be reversed by protamine.
5.1.3.1
Re-administration
Re-administration of plasminogen activators, including tenecteplase, to patients who have 
received prior plasminogen activator therapy has not been systematically studied.  Three of 487 
patients tested for antibody formation to tenecteplase had a positive antibody titer at 30 days.  
The data reflect the percentage of patients whose test results were considered positive for 
antibodies to tenecteplase in a radioimmunoprecipitation assay and are highly dependent on the 
sensitivity and specificity of the assay.  Additionally, the observed incidence of antibody 
positivity in an assay may be influenced by several factors including sample handling, 
concomitant medications, and underlying disease. For these reasons, comparison of the 
incidence of antibodies to tenecteplase with the incidence of antibodies to other products may 
be misleading.  Although sustained antibody formation in patients receiving one dose of 
tenecteplase has not been documented, re-administration should be undertaken with caution.
5.1.3.2
Hypersensitivity 
Hypersensitivity, including urticarial/anaphylactic reactions, have rarely ( 1%) been reported 
after administration of tenecteplase (e.g., anaphylaxis, angioedema, laryngeal edema, rash, and 
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urticaria).  Monitor patients treated with tenecteplase during and for several hours after infusion. 
If symptoms of hypersensitivity occur, appropriate therapy should be initiated.
5.1.3.3
Drug Interactions
Formal interaction studies of tenecteplase with other drugs have not been performed. Patients 
studied in clinical trials of tenecteplase were routinely treated with heparin and aspirin.  
Anticoagulants (such as direct oral anticoagulants, heparin and vitamin K antagonists) and 
drugs that alter platelet function (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa 
inhibitors) may increase the risk of bleeding if administered prior to, during, or after tenecteplase 
therapy.
5.1.3.4
Drug/Laboratory Test Interactions
During tenecteplase therapy, results of coagulation tests and/or measures of fibrinolytic activity 
may be unreliable unless specific precautions are taken to prevent in vitro artifacts.  
Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, 
remains active under in vitro conditions.  This can lead to degradation of fibrinogen in blood 
samples removed for analysis.
5.1.4
Management of Patients Who Experience Adverse Events
5.1.4.1
Management Guidelines
Guidelines for management of specific adverse events are outlined in Table 1.
Table 1
Guidelines for Management of Patients Who Experience Bleeding
Event
Action to Be Taken
Bleeding
●
In the event of serious bleeding, heparin and antiplatelet 
agents should be discontinued immediately and treated 
appropriately.  Heparin effects can be reversed by 
protamine. 
●
Intramuscular injections and nonessential handling of the 
patient should be avoided for the first few hours following 
treatment with tenecteplase. 
●
Venipunctures should be performed and monitored 
carefully.
●
Should an arterial puncture be necessary during the first 
few hours following tenecteplase therapy, it is preferable 
to use an upper extremity vessel that is accessible to 
manual compression. Pressure should be applied for at 
least 30 minutes, a pressure dressing applied, and the 
puncture site checked frequently for evidence of bleeding.
Refer to Sections 5.2−5.6 for details on safety reporting (e.g., adverse events, pregnancies) for 
this study.
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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and reporting adverse events and serious 
adverse events per protocol.  This includes all events of death and any study-specific issue of 
concern.
5.2.1
Adverse Events
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, 
regardless of attribution.
This includes the following:
●
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with AMI that were not present 
prior to the AE reporting period.
●
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations).
●
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention.
●
Pre-Existing medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
5.2.2
Serious Adverse Events
An AE should be classified as an SAE if the following criteria are met:
●
It results in death (i.e., the AE actually causes or leads to death).
●
It is life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death.  It does not include an AE that, had it occurred in a more severe 
form, might have caused death.).
●
It requires or prolongs inpatient hospitalization.
●
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the patient’s ability to conduct normal life functions).
●
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to the IMP.
●
It is considered a significant medical event by the investigator based on medical judgment 
(e.g., may jeopardize the patient or may require medical/surgical intervention to prevent one 
of the outcomes listed above).
5.2.3
Adverse Events of Special Interest
Non-serious adverse events of special interest are required to be reported by the investigator to 
the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  Non-serious 
adverse events of special interest for this study are as follows:
●
Any ICH events (symptomatic and/or asymptomatic), if not already reported as an SAE 
●
The non-drug specific AESIs:
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●
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law.
●
Suspected transmission of an infectious agent by the study drug, as defined below
–
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an 
infectious agent.  A transmission of an infectious agent may be suspected from clinical 
symptoms or laboratory findings that indicate an infection in a patient exposed to a 
medicinal product.  This term applies only when a contamination of the study drug is 
suspected.
5.3
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, are collected and reported to the FDA, appropriate IRB(s), and Genentech, 
Inc. in accordance with CFR 312.32 (IND Safety Reports). 
5.3.1
Adverse Event Reporting Period
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of any study procedures and ends 28 days following the last 
administration of study treatment or study discontinuation/termination, whichever is earlier.  
After this period, investigators should only report SAEs that are attributed to prior study 
treatment.
5.3.2
Assessment of Adverse Events
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to tenecteplase 
(see following guidance), and actions taken.
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline:
Yes
There is a plausible temporal relationship between the onset of the AE and administration of 
tenecteplase, and the AE cannot be readily explained by the patient’s clinical state, intercurrent 
illness, or concomitant therapies; and/or the AE follows a known pattern of response to 
tenecteplase; and/or the AE abates or resolves upon discontinuation of tenecteplase or dose 
reduction.
No
Evidence exists that the AE has an etiology other than tenecteplase (e.g., preexisting medical 
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE 
has no plausible temporal relationship to tenecteplase administration (e.g., cancer diagnosed 2 
days after first dose of tenecteplase).
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert (P.I) or current Investigator Brochure (I.B). 
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Unexpected adverse events are those not listed in the P.I. or current I.B or not identified.  This 
includes adverse events for which the specificity or severity is not consistent with the description 
in the P.I. or I.B.  For example, under this definition, hepatic necrosis would be unexpected if the 
P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis.
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy.
5.4
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE EVENTS
5.4.1
Data Safety Monitoring/CEC
A Data Safety Monitoring Committee/Clinical Events Committee (DSMC/CEC), compiled of 1 
neurosurgeon, 1 pulmonologist, and 1 cardiologist, will review safety events throughout the trial.  
Review of clinical events will be done in a completely blinded fashion.  Each event will be 
reviewed by all DSMC/CEC members and if discrepancy exists in their determinations, then 
consensus adjudication will be required.  The committee will meet to review all Serious Adverse 
Events (SAEs) and unexpected and related Adverse Events (AEs) every 15 patients. For each 
15 patient interval assessment, summary statistics for each cohort will be provided to the 
DSMC/CEC (after completion of all blinded clinical events review).  Following each of these 
individual case reviews (after analysis/interpretation locked), the DSMC/CEC statistician (who is 
unblinded, not the study statistician, who will remain blinded) will provide summary data on the 
ICH’s according to cohort. If there is a greater than 2 ICH differential then the study will be 
halted.  Additionally, the DSMC/CEC will be reviewing all enrollments, with summary statistics 
for each cohort (provided by the DSMC/CEC statistician) after each 15 patients are enrolled. 
The DSMC/CEC will review SAEs, both related and unrelated, as well as unexpected and 
related AEs. If a mortality or related serious adverse event occurs, the committee will meet 
within 72hrs of reporting to review. The committee will have the power to recommend a halt in 
study enrollment, should there be a safety concern.
5.4.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting adverse 
event information at all patient evaluation timepoints.  Examples of non-directive questions 
include the following: 
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.4.3
Specific Instructions for Recording Adverse Events
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  
Avoid colloquialisms and abbreviations.
5.4.3.1
Diagnosis versus Signs and Symptoms
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to 
report the information that is currently available.  If a diagnosis is subsequently established, it 
should be reported as follow-up information.
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5.4.3.2
Deaths
All deaths that occur during the protocol-specified AE reporting period (see Section 5.2.2), 
regardless of attribution, will be reported to the appropriate parties.  When recording a death, 
the event or condition that caused or contributed to the fatal outcome should be reported as the 
single medical concept.  If the cause of death is unknown and cannot be ascertained at the time 
of reporting, report “Unexplained Death”.
5.4.3.3
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the start of the study.  Such conditions 
should be reported as medical and surgical history.  A preexisting medical condition should be 
re-assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study.  When reporting such events, it is important 
to convey the concept that the preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”).
5.4.3.4
Hospitalizations for Medical or Surgical Procedures
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE.  If a patient is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE.  For example, if a patient is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE.
●
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:
●
Planned hospitalization required by the protocol (e.g., for study drug administration or 
insertion of access device for study drug administration) 
●
Hospitalization for a preexisting condition, provided that all of the following criteria are met:
–
The hospitalization was planned prior to the study or was scheduled during the study 
when elective surgery became necessary because of the expected normal progression 
of the disease
–
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not considered to be 
a serious adverse event, but should be reported as an adverse event instead:
●
Hospitalization that was not necessary because of the patient requirement for outpatient 
5.4.3.5
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for assessing 
adverse event severity.  Table 2 will be used for assessing severity for adverse events that are 
not specifically listed in the NCI CTCAE.
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Table 2
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.4.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding the 
event, and an evaluation of any potential alternative causes to determine whether an adverse 
event is considered to be related to the study drug, indicating "yes" or "no" accordingly.  The 
following guidance should be taken into consideration (see also Table 3):
●
Temporal relationship of event onset to the initiation of study drug
●
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)
●
Known association of the event with the study drug or with similar treatments
●
Known association of the event with the disease under study
●
Presence of risk factors in the patient or use of concomitant medications known to increase 
the occurrence of the event
●
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
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Table 3
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YE
S
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy.
5.4.4.1
Pregnancies
If a female patient becomes pregnant while receiving tenecteplase or within 9014 days after 
the last dose of tenecteplase, a report should be completed and expeditiously submitted to 
Genentech, Inc.  Follow-up to obtain the outcome of the pregnancy should also occur.  
Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as 
serious, and expeditiously reported to Genentech as an SAE.  Similarly, any congenital 
anomaly/birth defect in a child born to a female patient exposed to the tenecteplase should be 
reported to Genentech, Inc.  as an SAE.
5.4.4.2
Post-Study Adverse Events
The investigator should expeditiously report any SAE occurring after a patient has completed or 
discontinued study participation if attributed to prior tenecteplase exposure.  If the investigator 
should become aware of the development of cancer or a congenital anomaly in a subsequently 
conceived offspring of a female patient who participated in the study, this should be reported as 
an SAE.
Case Transmission Verification will be performed by both parties during this period to ensure 
successful transmission of Single case reports.
CASE TRANSMISSION VERIFICATION OF SINGLE CASE REPORTS
The Sponsor agrees to conduct the Case Transmission verification to ensure that all single 
case reports have been adequately received by Genentech via Dr Hooman Poor emailing 
Genentech a Quarterly line-listing documenting single case reports sent by Dr Hooman Poor  
to Genentech in the preceding time period.
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The periodic line-listing will be exchanged within seven (7) calendar days of the end of the 
agreed time period. Confirmation of receipt should be received within the time period mutually 
agreed upon.
               
If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a case-by-
case basis until satisfactory resolution.  The sponsor shall receive reconciliation guidance 
documents within the ‘Activation Package’.
 
Following Case Transmission Verification, single case reports which have not been received by 
Genentech shall be forwarded by Dr Hooman Poor to Genentech within five (5) calendar days 
from request by Genentech.
 
At the end of the study, a final cumulative Case Transmission Verification report will 
be sent to Genentech.
AEs of Special Interest (AESIs)
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the 
product, for which ongoing monitoring and rapid communication by the Investigator to the 
Sponsor is required. Such an event might require further investigation in order to characterize 
and understand it. Depending on the nature of the event, rapid communication by the trial 
Sponsor to other parties (e.g., Regulatory Authorities) may also be warranted.
Adverse events of special interest for this study include the following:
●
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law:
●
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin  2  ULN
●
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice
●
Data related to a suspected transmission of an infectious agent by the study drug 
(STIAMP), as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent.  
A transmission of an infectious agent may be suspected from clinical symptoms or laboratory 
findings that indicate an infection in a patient exposed to a medicinal product.  This term applies 
only when a contamination of the study drug is suspected
Exchange of Single Case Reports
 
Dr Hooman Poor will be responsible for collecting all protocol-defined Adverse Events 
(AEs)/Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), Special Situation 
Reports (including pregnancy reports) and Product Complaints (with or without an AE) 
originating from the Study for the Product.
 
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Investigators must report all the above-mentioned single case reports adequately to Genentech 
within the timelines described below. The completed MedWatch forms should be faxed/emailed 
immediately upon completion to Genentech at the following contacts:
 
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy reports) 
and Product Complaints with an AE should be sent to:
Fax: 650-238-6067
Email: usds_aereporting-d@gene.com
All Product Complaints without an AE should be sent to:
Phone: 800-334-0290 
It is understood and agreed that the Sponsor will be responsible for the evaluation of AEs/SAEs, 
AESIs, Special Situation Reports (including pregnancy reports) and Product Complaints (with or 
without an AE) originating from the study. [MR{SF2] 
These single case reports will be exchanged between the parties as outlined below so that 
regulatory obligations are met.
●
SADRs
Serious AE reports that are related to the Product shall be transmitted to Genentech 
within fifteen (15) calendar days of the awareness date.
●
 Other SAEs
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech 
within thirty (30) calendar days of the awareness date.
●
AESIs
AESIs requiring expedited reporting shall be forwarded to Genentech within fifteen (15) calendar 
days of the awareness date.  
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it 
becomes available.
●
Special Situation Reports
o   Pregnancy reports
While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per 
se, as defined herein, any reports of pregnancy (including pregnancy occurring in 
the partner of a male study subject), where the fetus may have been exposed to 
the Product, shall be transmitted to Genentech within thirty (30) calendar days of 
the awareness date. Pregnancies will be followed up until the outcome of the 
pregnancy is known, whenever possible, based upon due diligence taken to 
obtain the follow-up information.
o   Pregnancies in Female Partners of Male Patients
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Male patients will be instructed through the Informed Consent Form to 
immediately inform the investigator if their partner becomes pregnant during the 
study or within 30 days after the last dose of study drug.  A Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to Genentech 
within thirty (30) calendar days of the awareness date.
In addition to all AEs, pregnancy reports and AESIs, the following Special Situations Reports 
should be collected and transmitted to Genentech/Roche even in the absence of an Adverse 
Event within thirty (30) calendar days:
●
Data related to product usage during breastfeeding
●
Data related to overdose, abuse, off-label use, misuse, inadvertent/erroneous 
administration, medication error (including potentially exposed in case of medication errors 
or intercepted medication errors) or occupational exposure, with or without association with 
an AE/SAE unless otherwise specified in the protocol
●
Lack of therapeutic efficacy
●
Drug interaction
●
Use of a Medicinal Product in a Pediatric and Elderly population 
●
In addition, reasonable attempts should be made to obtain and submit the age or age group 
of the patient, in order to be able to identify potential safety signals specific to a particular 
population
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom an adverse event was reported
●
Product Complaints
All Product Complaints (with or without an AE) shall be forwarded to Genentech within fifteen 
(15) calendar days of the awareness date.
A Product Complaint is defined as any written or oral information received from a complainant 
that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, durability, 
effectiveness, or performance of a product after it has been released and distributed to the 
commercial market or clinical trial.
5.4.5
MedWatch 3500A Reporting Guidelines
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (Section 5) of the 
MedWatch 3500A form:
●
Protocol description (and number, if assigned)
●
Description of event, severity, treatment, and outcome if known
●
Supportive laboratory results and diagnostics
●
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication
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5.4.5.1
Follow-up Information
Additional information may be added to a previously submitted report by any of the following 
methods:
●
Adding to the original MedWatch 3500A report and submitting it as follow-up
●
Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500A form 
●
Summarizing new information and faxing it with a cover letter including patient identifiers 
(i.e., D.O.B. initial, patient number), protocol description and number, if assigned, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted (The patient identifiers are important so that the new information is added to the 
correct initial report)
MedWatch 3500A (Mandatory Reporting) form is available at
https://www.fda.gov/media/69876/download
5.4.6
Reporting to Regulatory Authorities, Ethics Committees and 
Investigators
Hooman Poor, MD, as the Sponsor of the Study, will be responsible for the expedited reporting 
of safety reports originating from the Study to the Regulatory Authorities (FDA) where it has filed 
a clinical trial approval, in compliance with local regulations. 
Genentech will be responsible for the expedited reporting of safety reports originating from the 
Study to the EMA through Eudravigilance Clinical Trial Module (EVCTM), where applicable.
Hooman Poor, MD will be responsible for the distribution of safety information to its own 
investigators, where relevant.
Additional Reporting Requirements for IND Holders 
For Investigator-Initiated IND Studies, some additional reporting requirements for the FDA apply 
in accordance with the guidance set forth in 21 CFR § 600.80.
Events meeting the following criteria need to be submitted to the Food and Drug Administration 
(FDA) as expedited IND Safety Reports according to the following guidance and timelines:
7 Calendar Day Telephone or Fax Report
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that 
is unexpected and assessed by the Investigator to be possibly related to the use of 
tenecteplase.  An unexpected adverse event is one that is not already described in the 
tenecteplase Investigator Brochure.  Such reports are to be telephoned or faxed to the FDA and 
Genentech within 7 calendar days of first learning of the event.
15 Calendar Day Written Report
The Investigator is also required to notify the FDA and all participating investigators, in a written 
IND Safety Report, of any serious, unexpected AE that is considered reasonably or possibly 
related to the use of tenecteplase.  An unexpected adverse event is one that is not already 
described in the tenecteplase Investigator Brochure.
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Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32.  All safety reports previously filed by the investigator with the IND 
concerning similar events should be analyzed and the significance of the new report in light of 
the previous, similar reports commented on.
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech, and all participating investigators within 15 calendar days of first learning of the 
event.  The FDA prefers these reports on a MedWatch 3500 form, but alternative formats are 
acceptable (e.g., summary letter).
FDA fax number for IND Safety Reports:
Fax:  1 (800) FDA 0178
All written IND Safety Reports submitted to the FDA by the investigator must also be 
faxed to Genentech Drug Safety:
Fax:  (650) 225-4682 or (650) 225-4630
And to the coordinating center:
Denise.Balili@mountsinai.org or fax: 646-537-9656
For questions related to safety reporting, please contact Genentech Drug Safety:
Tel:  (888) 835-2555
Fax:  (650) 225-4682 or (650) 225-4630
5.5
AGGREGATE REPORTS
IND ANNUAL REPORTS
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech
Copies of such reports should be emailed to Genentech at:  Genentech Drug Safety CTV mail 
box: ctvist_drugsafety@gene.com 
hyperlink to email:ctvist_drugsafety@gene.com 
Other Reports  
Hooman Poor will forward a copy of the Publication to Genentech upon completion of the Study.
Note: Investigators should also report events to their IRB as required.
Randomization Codes for Blinded Clinical Trials 
The blind will be broken for ADR reports that are Serious and Unexpected, unless otherwise 
agreed with applicable regulatory authorities.
5.6
STUDY CLOSE-OUT
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech.  This includes all IND annual reports and the Clinical Study Report (final study 
Effective Date: 6/15/2021
End Date: 12/7/2021


Tenecteplase⎯Icahn School of Medicine at Mount Sinai
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report).  Additionally, any literature articles that are a result of the study should be sent to 
Genentech.  Copies of such reports should be mailed to the assigned 
Clinical Operations contact for the study:  lytics-gsur@gene.com
hyperlink to email:     lytics-gsur@gene.com 
lytics-gsur@gene.com
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com
hyperlink to email: ctvist_drugsafety@gene.com 
QUERIES
Queries related to the Study will be answered by Hooman Poor, MD. However, responses to all 
safety queries from regulatory authorities or for publications will be discussed and coordinated 
between the Parties.  The Parties agree that Genentech shall have the final say and control 
over safety queries relating to the Product.  Hooman Poor, MD agrees that it shall not answer 
such queries from regulatory authorities and other sources relating to the Product independently 
but shall redirect such queries to Genentech.
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent 
requests for information or review of data are met.  The Parties will clearly indicate on the 
request the reason for urgency and the date by which a response is required.
6.
STATISTICAL CONSIDERATIONS
6.1
DETERMINATION OF SAMPLE SIZE
Assuming a total of 60 subjects enrolled with a 2:1 ratio in the tenecteplase:control arms and a 
good outcome rate of 15% in the control arm, this study has approximately 70% power to detect 
an absolute difference of 35% in the good outcome rate between the combined tenecteplase 
arms (40 patients) and the control arm (20 patients) and approximately 55% power to detect an 
absolute difference of 35% between each of the tenecteplase arms (20 patients) and the control 
arm (20 patients), at the 2-sided 0.05 significance level based on the Fisher’s exact test. Good 
outcome rate is defined as the proportion of patients who are alive and free of respiratory failure 
at 28 days. If the true rate of symptomatic ICH or major bleeding requiring transfusion is 3%, the 
chance of observing at least one of these events in 20 patients is at least 45%. The chance of 
observing at least one event in 20 patients increases to at least 70% if the true event rate is 6%.
6.2
PRIMARY EFFICACY VARIABLE
Data will be analyzed according to clinical status at day 28.  Outcome will be the proportion of 
patients who are alive and free of respiratory failure (no use of HFNC, NIPPV, Intubation). All 
other patients, those on HFNC, NIPPPV, or mechanical ventilation, or dead, will be assessed as 
Effective Date: 6/15/2021
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failures for the purposes of the primary analysis. In the case of missing data, a last carry forward 
methodology will be used. 
6.3
PRIMARY SAFETY VARIABLE
Data will be analyzed according to the occurrence, at any time between tenecteplase 
administration and day 28, of intracranial hemorrhage or major bleeding event (defined above).  
Outcome will be the proportion of patients who have suffered no intracranial hemorrhage or 
major bleeding event. Those patients who have suffered an intracranial hemorrhage or major 
bleeding event will be assessed as failures for the purposes of the safety analysis. 
6.4
ONGOING SAFETY ANALYSIS
Should there occur, at any time during the study, a difference between the control and treatment 
cohorts of >2 intracerebral hemorrhages then the study will be halted.  Per protocol, the 
DSMC/CEC will review all ICH’s (SAE’s). Following each of these individual case reviews (after 
analysis/interpretation locked), the DSMC/CEC statistician (who is unblinded, not the study 
statistician, who will remain blinded) will provide summary data on the ICH’s according to 
cohort. If there is a greater than 2 ICH differential then the study will be halted.  Additionally, the 
DSMC/CEC will be reviewing all enrollments, with summary statistics for each cohort (provided 
by the DSMC/CEC statistician) after each 15 patients are enrolled. They are empowered to halt 
study enrollment at each of these review points should there be safety concerns. After each of 
these planned DSMC/CEC reviews the DSMC/CEC will generate a formal report to provide to 
the study PI.  
6.5
METHOD OF ANALYSIS
Continuous and categorical variables will be presented and summarized by using means with 
standard deviations and frequencies with percentages respectively. Tukey’s method for pairwise 
comparison and large sample based multiple comparison of logits will be performed for 
continuous variables. Logistic regression modeling will be used for covariates adjustments and 
subgroup analyses. Survival functions will be estimated by applying Kaplan-Meier method. 
Statistical testing will be performed at two-sided 5% level of significance.
7.
INVESTIGATOR REQUIREMENTS
7.1
RETENTION OF RECORDS
FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see Section 4.9 of the 
guideline) require that records and documents pertaining to the conduct of clinical trials and the 
distribution of investigational drug, patient records, consent forms, laboratory test results, and 
medication inventory records, must be retained for 2 years after the last marketing application 
approval in an ICH region or after at least 2 years have elapsed since formal discontinuation of 
clinical development of the investigational product.  All state and local laws for retention of 
records also apply. 
For studies conducted outside the U.S. under a U.S. IND, the Principal Investigator must comply 
with the record retention requirements set forth in the FDA IND regulations and the relevant 
national and local health authorities, whichever is longer.
Effective Date: 6/15/2021
End Date: 12/7/2021


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7.2
STUDY MEDICAL MONITORING REQUIREMENTS
This clinical research study will be monitored both internally by the PI and externally by the 
Icahn School of Medicine IRB.  In terms of internal review, the PI will continuously monitor and 
tabulate AEs.  Appropriate reporting to the Icahn School of Medicine IRB will be made.  The PI 
of this study will also continuously monitor the conduct, data, and safety of this study to ensure 
that:
●
Stopping rules for toxicity and/or response are met,
●
Risk/benefit ratio is not altered to the detriment of the patients,
●
Appropriate internal monitoring of AEs and outcomes is done,
●
Over-accrual does not occur,
●
Under-accrual is addressed with appropriate amendments or actions, and
●
 Data are being appropriately collected in a reasonably timely manner.
Routine monitoring will be carried out via a periodic team conference among investigators 
during which toxicity data, including all SAEs, will be reviewed and other issues relevant to the 
study such as interim assessment of accrual, outcome, and compliance with study guidelines, 
will be discussed.  Monitoring will be carried out on an ongoing basis.  The severity, 
relatedness, and whether or not the event is expected will be reviewed.
7.3
STUDY MEDICATION ACCOUNTABILITY 
The Sponsor Investigator of the study will ensure maintenance of complete and accurate 
records of the receipt, dispensation, and disposal or return of all study drug in accordance with 
21 Code of Federal Regulations (CFR), Part 312.57 and 312.62 and Genentech requirements.
All unused remaining product at the end of the study should be disposed of at the study site 
according to institutional standard operating procedure. If there is no SOP at the site for drug 
destruction, return study drug with the Inventory of Returned Clinical Material form as directed 
by Genentech.
7.4
DATA COLLECTION
The study coordinator and investigators are responsible for ensuring that the eligibility checklist 
is completed in a legible and timely manner for every patient enrolled in the study, and that data 
are recorded on the appropriate forms and in a timely manner.  Any errors on source 
data should be lined through, but not obliterated, with the correction inserted, initialed, and 
dated by the study coordinator or PI.  All source documents will be available for inspection by 
the FDA and the Icahn School of Medicine IRB.
7.5
DATA MONITORING
The entire study will be conducted using an electronic data acquisition method where all clinical 
data on enrolled subjects will be data entered (single-keyed) by the site personnel into a web-
based data management system, REDCap. In order to provide user-friendly and easy-to-
navigate interfaces, the REDCap data capture screens are designed based upon individual 
CRFs. Prior to study start, the system is validated to ensure the data entry screens mirror the 
CRFs and that the pre- programmed data rules appropriately detect incorrect data. The data will 
be managed after data entry via data queries from the study monitor. Monitoring will be 
conducted in real time, allowing for early identification of adverse events and protocol 
Effective Date: 6/15/2021
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deviations. This user-friendly web-based database system, developed and validated by the 
study team, will be used for subject data entry, data validation, project progress monitoring, 
subject tracking, coordination of safety review, randomization, user customizable report 
generation and secure data transfer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
Patients who comply with the requirements of the protocol, are tolerating study treatment, and 
may be receiving benefit will be offered dosing beyond Cycle 1 at the investigator’s discretion 
after a careful assessment and thorough discussion of the potential risks and benefits of 
continued treatment with the patient.  Such patients may have the option to receive 
MPDL3280A treatment as long as they continue to experience clinical benefit in the opinion of 
the investigator until the earlier of unacceptable toxicity, symptomatic deterioration attributed to 
disease progression, or any of the other reasons for treatment discontinuation listed in 
Section 4.6.
8.2
INFORMED CONSENT
The informed consent document must be signed by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history for each 
patient shall document that informed consent was obtained prior to participation in the study.  A 
copy of the informed consent document must be provided to the patient or the patient's legally 
authorized representative.  If applicable, it will be provided in a certified translation of the local 
language.
Signed consent forms must remain in each patient’s study file and must be available for 
verification by study monitors at any time.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the informed consent document, and relevant supporting information must be 
submitted to the IRB for review and must be approved before the study is initiated.  The study 
will be conducted in accordance with FDA, applicable national and local health authorities, and 
IRB requirements.
The Principal Investigator is responsible for keeping the IRB apprised of the progress of the 
study and of any changes made to the protocol as deemed appropriate, but in any case, the IRB 
must be updated at least once a year.  The Principal Investigator must also keep the IRB 
informed of any significant AEs.
Investigators are required to promptly notify their respective IRB of all adverse drug reactions 
that are both serious and unexpected.  This generally refers to SAEs that are not already 
identified in the Investigator’s Brochure and that are considered possibly or probably related to 
the tenecteplase or study drug by the investigator.  Some IRBs may have other specific AE 
requirements to which investigators are expected to adhere.  Investigators must immediately 
forward to their IRB any written safety report or update provided by Genentech (e.g., IND safety 
report, Investigator’s Brochure, safety amendments and updates, etc.).
Effective Date: 6/15/2021
End Date: 12/7/2021


Tenecteplase⎯Icahn School of Medicine at Mount Sinai
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8.4
CONFIDENTIALITY
Patient medical information obtained by this study is confidential and may be disclosed to third 
parties only as permitted by the ICF (or separate authorization to use and disclose personal 
health information) signed by the patient or unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes.
Data generated by this study must be available for inspection upon request by representatives 
of the FDA and other regulatory agencies, national and local health authorities, Genentech 
representatives and collaborators, and the IRB/Ethics Committee (EC) for each study site, if 
appropriate.
Effective Date: 6/15/2021
End Date: 12/7/2021


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9.
REFERENCES
1.
Spiezia L, Boscolo A, Poletto F, et al. COVID-19-Related Severe Hypercoagulability in 
Patients Admitted to Intensive Care Unit for Acute Respiratory Failure [published online 
ahead of print, 2020 Apr 21]. Thromb Haemost. 2020;10.1055/s-0040-1710018.  
2.
Grillet F, Behr J, Calame P, Aubry S, Delabrousse E. Acute Pulmonary Embolism 
Associated with COVID-19 Pneumonia Detected by Pulmonary CT Angiography [published 
online ahead of print, 2020 Apr 23]. Radiology. 2020;201544.  
3.
Oxley TJ, Mocco J, Majidi S, et al. Large-Vessel Stroke as a Presenting Feature of Covid-19 
in the Young [published online ahead of print, 2020 Apr 28]. N Engl J Med. 
2020;10.1056/NEJMc2009787.  
4.
Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with 
decreased mortality in severe coronavirus disease 2019 patients with 
coagulopathy. J Thromb Haemost. 2020;18(5):1094‐1099.
5.
Poissy J, Goutay J, Caplan M, et al. Pulmonary Embolism in COVID-19 Patients: Awareness 
of an Increased Prevalence [published online ahead of print, 2020 Apr 24]. Circulation. 
2020;10.1161/CIRCULATIONAHA.120.047430.  
6.
Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. Covid-19 Does Not 
Lead to a "Typical" Acute Respiratory Distress Syndrome [published online ahead of print, 
2020 Mar 30]. Am J Respir Crit Care Med. 2020;10.1164/rccm.202003-0817LE.  
7.
Gattinoni L, Chiumello D, Caironi P, et al. COVID-19 pneumonia: different respiratory 
treatments for different phenotypes? [published online ahead of print, 2020 Apr 
14]. Intensive Care Med. 2020;1‐4.  
8.
Wang J, Hajizadeh N, Moore EE, et al. Tissue Plasminogen Activator (tPA) Treatment for 
COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS): A Case Series 
[published online ahead of print, 2020 Apr 8]. J Thromb Haemost. 2020;10.1111/jth.14828.  
9.
Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators, 
Van De Werf F, Adgey J, et al. Single-bolus tenecteplase compared with front-loaded 
alteplase in acute myocardial infarction: the ASSENT-2 double-
blind randomised trial. Lancet. 1999;354(9180):716‐722.   
10. Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 
Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, 
abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial 
infarction. Lancet. 2001;358(9282):605‐613. 
Effective Date: 6/15/2021
End Date: 12/7/2021


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11. Wallentin L, Goldstein P, Armstrong PW, et al. Efficacy and safety of tenecteplase in 
combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in 
the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic 
Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation. 
2003;108(2):135‐142.  
12. Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus Alteplase before 
Thrombectomy for Ischemic Stroke. N Engl J Med. 2018;378(17):1573‐1582.  
13. Campbell BCV, Mitchell PJ, Churilov L, et al. Effect of Intravenous Tenecteplase Dose on 
Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion 
Ischemic Stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial [published online 
ahead of print, 2020 Feb 20]. JAMA. 2020;323(13):1257‐1265.  
14. Genentech, Inc. Tenecteplase in stroke patients between 4.5 and 24 hours (TIMELESS). 
Available from: http://www.clinicaltrials.gov/ct2/show/NCT03785678. NLM identifier: 
NCT03785678. Accessed May 7, 2020.  
15. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary 
embolism. N Engl J Med. 2014;370(15):1402‐1411.  
16. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, 
and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City 
Area [published online ahead of print, 2020 Apr 22]. JAMA. 2020;e206775.  
17. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with 
decreased mortality in severe coronavirus disease 2019 patients with 
coagulopathy. J Thromb Haemost. 2020;18(5):1094‐1099.  
18. Poor H, Ventetuolo C, Tolbert T, et al. COVID-19 critical illness pathophysiology driven by 
diffuse pulmonary thrombi and pulmonary endothelial dysfunction responsive to 
thrombolysis. Clin Transl Med. May 2020
19. Paranjpe I, Fuster V, Lala A, et al. Association of Treatment Dose Anticoagulation with In-
Hospital Survival Among Hospitalized Patients with COVID-19 [published online ahead of 
print, 2020 May 5]. J Am Coll Cardiol. 2020;S0735-1097(20)35218-9. 
doi:10.1016/j.jacc.2020.05.001
20. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators, 
Van De Werf F, Adgey J, et al. Single-bolus tenecteplase compared with front-loaded 
alteplase in acute myocardial infarction: the ASSENT-2 double-
blind randomised trial. Lancet. 1999;354(9180):716‐722. 
Effective Date: 6/15/2021
End Date: 12/7/2021


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21. Pranjpe I, Fuster V, Lala A, Russak A, et al. Association of treatment dose anticoagulation 
with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol. 
2020. https://doi.org/10.1016/j.jacc.2020.05.001 
22. Keyt BA, Paoni NF, Refino CJ, et al. A faster-acting and more potent form of tissue 
plasminogen activator. Proc Natl Acad Sci U S A. 1994;91(9):3670‐3674. 
doi:10.1073/pnas.91.9.3670 
23. Cannon CP, McCabe CH, Gibson CM, et al. TNK-tissue plasminogen activator in acute 
myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A dose-
ranging trial. Circulation. 1997;95(2):351‐356.  
24. Cannon CP, Gibson CM, McCabe CH, et al. TNK-tissue plasminogen activator compared 
with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B trial. 
Thrombolysis in Myocardial Infarction (TIMI) 10B Investigators. Circulation. 
1998;98(25):2805‐2814.  
25. Van de Werf F, Cannon CP, Luyten A, et al. Safety assessment of single-bolus 
administration of TNK tissue-plasminogen activator in acute myocardial infarction: the 
ASSENT-1 trial. The ASSENT-1 Investigators. Am Heart J. 1999;137(5):786‐791.  
26. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators, 
Van De Werf F, Adgey J, et al. Single-bolus tenecteplase compared with front-loaded 
alteplase in acute myocardial infarction: the ASSENT-2 double-
blind randomised trial. Lancet. 1999;354(9180):716‐722.  
27. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue 
plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581‐1587. 
28. Haley EC Jr, Lyden PD, Johnston KC, Hemmen TM; TNK in Stroke Investigators. A pilot 
dose-escalation safety study of tenecteplase in acute ischemic stroke. Stroke. 
2005;36(3):607‐612.  
29. Huang X, Cheripelli BK, Lloyd SM, et al. Alteplase versus tenecteplase for thrombolysis 
after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint 
study. Lancet Neurol. 2015;14(4):368‐376. 
30. Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for 
acute ischemic stroke. N Engl J Med. 2012;366(12):1099‐1107.  
31. Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus Alteplase before 
Thrombectomy for Ischemic Stroke. N Engl J Med. 2018;378(17):1573‐1582.  
Effective Date: 6/15/2021
End Date: 12/7/2021


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32. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the 
initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled 
trials. Circulation. 2004;110(6):744‐749.  
33. Meyer G, Sors H, Charbonnier B, et al. Effects of intravenous urokinase versus alteplase on 
total pulmonary resistance in acute massive pulmonary embolism: a European multicenter 
double-blind trial. The European Cooperative Study Group for Pulmonary Embolism. J Am 
Coll Cardiol. 1992;19(2):239‐245.  
34.  Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk 
pulmonary embolism. N Engl J Med. 2014;370(15):1402‐1411.  
35. Kline JA, Nordenholz KE, Courtney DM, et al. Treatment of submassive pulmonary 
embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter 
double-blind, placebo-controlled randomized trial. J Thromb Haemost. 2014;12(4):459‐468. 
Effective Date: 6/15/2021
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Appendix 1
Study Flowchart
               Enrollment/Randomizationᵃ             
 
Screening
Pre-Randomization 
(must be collected 
within 2 h of study drug 
administration)
Post Randomization 
q6 hr. to 72 hr.
Follow Up Period
 (Day 4 to 27 post randomization)
End of Study
(Day 28 OR Discharge)
Informed Consent
x
 
 
 
 
Demographics
x
 
 
 
 
Medical History
x
 
 
 
 
Inclusion/Exclusion Criteria
x
x
 
 
 
Weight for Dosing
x
 
 
 
 
Vital Signsb
x
x
x
x
x
PCR COVID Test
x
 
 
 
 
Lab Testingc
x
x
xd
SOC
SOC
Arterial Blood Gase
x
x
x*
SOC
 
Respiratory Status/Ventilator Settingsf
x
x
x
x**
x
Ordinal Scale
x
x
x
x
x
Neurological Examg
x
x
x
x
x
Vasopressor Dosing
x
x
x
x
 
TNK-tPA Dosing
 
 
x
 
 
Heparin Dosingh
x***
x***
x
x
 
Imagingi
SOC
 
SOC
SOC
SOC
Pregnancy Testj
x
 
 
 
 
Adverse Events/ SAE Reviewk
x
x
x
x
x
Concomitant Medications
x
x
x
x
x
Effective Date: 6/15/2021
End Date: 12/7/2021


Appendix 1: Study Flowchart
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Effective Date: 6/15/2021
End Date: 12/7/2021


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Appendix 2
Safety Reporting Fax Cover Sheet
SAFETY REPORTING FAX COVER SHEET
GENENTECH SUPPORTED RESEARCH
AE / SAE FAX No: (650) 238-6067
Genentech Study Number
Principal Investigator
Site Name
Reporter name
Reporter Telephone #
Reporter Fax #
Initial Report Date
[DD] / [MON] / [YY]
Follow-up Report Date
[DD] / [MON] / [YY]
Patient Initials
(Enter a dash if patient has no 
middle name)
[ ] - [ ] - [ ]
SAE or Safety Reporting questions, contact Genentech Drug Safety: (888) 835-2555
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET
Effective Date: 6/15/2021
End Date: 12/7/2021


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Appendix 3
FDA MedWatch 3500 Form
This form is included in the study start-up zip file to be sent to sites via email.
Effective Date: 6/15/2021
End Date: 12/7/2021