Clinical trial NCT04558125
Conditions: Pulmonary Embolism COVID
Sponsor: Cedars-Sinai Medical Center
Start date: 2020-09-08; Completion date: 2021-08-08
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
* There is a knowledge gap associated with the management of patients with COVID-19 lung injury and a laboratory picture compatible with disseminated intravascular coagulation (DIC). Clinical data to date support that COVID-19 is associated with a prothrombotic state that is not simply explained by an influx of more critically ill individuals.
* These patients suffer from severe respiratory failure; hypoxemia and ventilator dependence are the primary concerns; ARDS with respiratory failure is frequently the cause of death. Macroscopic and probable microvascular thromboembolic events are a major concern in this population.
* When DIC is associated with COVID-19, it predicts a very poor prognosis.
* This study will evaluate the clinical efficacy and safety of low-dose IV bolus tenecteplase (TNK) together with anticoagulation compared with control patients on therapeutic anticoagulation alone in hospitalized adults diagnosed with COVID-19 and acute intermediate-risk PE.
* Prospective, multicenter, randomized two-arm trial enrolling consecutive patients who meet enrollment criteria.
* The study will generate evidence that low-dose TNK together with anticoagulation is beneficial in these patients

Detailed description:
This is a prospective, double-blind, placebo-controlled study randomizing patients with acute intermediate-risk PE who meet enrollment criteria in a 2:1 manner into intervention (TNK) versus placebo arms, respectively. There will be up to 6 sites. After 18 patients are enrolled, a safety assessment will be performed by an independent Data and Safety Monitoring Board, and if a safety issue arises, it will be considered and discussed among the investigators. The planned sample size is 45 patients (30 treatment and 15 control). Subjects will be assessed daily while hospitalized. Subjects discharged from the hospital will be asked to attend study visits at Days 14 and 30 (telephone / telemedicine, clinic or inpatient ward).

The overall objective of the study is to evaluate the clinical efficacy and safety of IV bolus tenecteplase (TNK) and therapeutic anticoagulation compared with placebo and therapeutic anticoagulation in hospitalized adults diagnosed with COVID-19 infection and acute intermediate-risk PE.

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.

After informed consent is obtained, screening assessment will be completed to confirm a patient's eligibility for participation in the study. The screening visit will include medical history, physical exam and vital signs. Standard of care (SOC). labs will be reviewed. These may include INR, aPTT, PT (if patient is currently taking an anticoagulant), CBC with diff, comprehensive chemistry panel, D-dimer and Ferritin. The results of the SARS-CoV-2 will be documented. If subject is in child-bearing age and a pregnancy test was not done for SOC, a urine pregnancy test will be performed. Electrocadiogram and CTA will be reviewed.

If the patient is determined to be eligible, the study site will obtain the patient's medical record number/unique patient identification number, and treatment assignment to either interventional (TNK) or placebo will be randomly determined. Patients will be allocated to the interventional versus placebo arms in a 2:1 manner as per a computer-generated randomization schedule using permuted blocks of random sizes. The block sizes will not be disclosed to ensure concealment. A total of 30 TNK subjects versus 15 placebo controls will be enrolled.

Before the study drug/placebo is administered, the following labs will be drawn CBC with diff, comprehensive metabolic panel, CRP, Ferritin, IL-6, Fibrinogen, D-dimer, PT/PTT, LDH, lactate, troponin, creatinine kinase, and Thromboelastography (TEG). Vital signs and echocardiogram will be obtained. Shock Index will be calculated, then the infusion will begin.

Within 10 minutes (+ 5min) of infusion, a second TEG will be collected. At 6 hours after the infusion, a second Shock Index will be calculated. At 24+/- 6 hours after the bolus, a physical exam will be performed, vital signs will be collected, an echocardiogram will be performed and D-dimer, CRP, IL-6, and Ferritin will be done. TEG will be an optional addition to the 24-hour labs. Daily safety labs will include CBC and chemistry panel. SOC lab results will be collected from the chart.

Patients will have follow-up visits on Day 14 +/- 2 days and Day 30 +/- 4 days. These visits may take place via televisit or in person. Data will be collected on adverse events, vital signs and new concomitant medications. Safety labs will be obtained if visit occurs in person.

Arms: arm 1: 1. TNKase (0.25 mg/kg) bolus Other names: Tenecteplase, TNK
2. Standard of care anticoagulation (heparin or enoxaparin) arm 2: 1. Placebo bolus (intravenous syringe identical to that of TNK )
2. Standard of care anticoagulation (heparin or enoxaparin)
Interventions: intervention 1: TNKase intervention 2: Placebo intervention 3: Enoxaparin
Intervention descriptions: intervention 1: Tenecteplase (0.25 mg/kg) supplied by Genentech, Inc. as a sterile, lyophilized powder, diluted with 10mL sterile water. intervention 2: Placebo to match supplied by Genentech, Inc. as a sterile, lyophilized powder, diluted with 10mL sterile water. intervention 3: All participants must also receive standard of care anticoagulation therapy.

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
This is a Cedars-Sinai Medical Center 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 Cedars-Sinai Medical Center. 
Tenecteplase⎯Cedars-Sinai Medical Center, Los Angeles, CA 
Protocol ML 42522 Version 5.0 
PROTOCOL 
TITLE: 
LOW-DOSE TENECTEPLASE IN COVID-
19 PATIENTS WITH ACUTE PULMONARY 
EMBOLISM: A RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED TRIAL 
STUDY NUMBER: 
ML42522 
VERSION NUMBER: 
5.0 
TEST PRODUCTS: 
Tenecteplase (RO5490263) 
INDICATION: 
COVID-19 Pneumonia & Pulmonary Embolism 
 
INVESTIGATOR: 
Victor F Tapson, MD 
Professor of Medicine 
Associate Director, Division of Pulmonary and 
Critical Care 
Director, Clinical Research Women’s Guild Lung 
Institute 
Director, Venous Thromboembolism Research 
Pulmonary Hypertension Clinic 
Cedars-Sinai Medical Center 
127 S San Vicente Blvd #A3600 
Los Angeles, CA  90048 
Telephone:  Cell: 919-971-6441 
E-mail: Victor.tapson@cshs.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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SUB-INVESTIGATORS: 
Oren Friedman, MD 
Associate Professor of Medicine 
Division of Pulmonary and Critical Care 
Cedars-Sinai Medical Center 
 
Peter Chen, MD 
Professor of Medicine 
Director, Division of Pulmonary and Critical Care 
Cedars-Sinai Medical Center 
 
Sam Torbati, MD 
Associate Professor of Emergency Medicine 
Co-Chairman and Medical Director 
Ruth and Harry Roman Emergency Department 
Cedars-Sinai Medical Center 
 
Michael Lewis, MD 
Professor of Medicine 
Director, Respiratory Care Services 
Cedars-Sinai Medical Center 
 
STUDY COORDINATORS: Susan Jackman, RN, MS   
susan.jackman@cshs.org 
Phone: 310-924-5444 
Niree Hindoyan, BS    
niree.hindoyan@cshs.org 
Phone: 818-331-3112 
Antonina Caudill, MPH 
antonina.caudill@cshs.org 
Phone: 619-708-4945 
SUPPORT PROVIDED BY: Genentech, Inc. 
PROTOCOL DATE: 
February 25, 2021 


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TABLE OF CONTENTS 
1. 
BACKGROUND ................................................................................................ 8 
1.1 
Background on COVID-19 Infection, Inflammation and 
Thrombosis ................................................................................. 8 
1.2 
Current Therapies and Unmet Medical Need Related to 
COVID-19 Pneumonia/ARDS and DIC in Patients with Acute 
Thromboembolic Events .......................................................... 11 
1.3 
Background on Tenecteplase .................................................. 11 
1.3.1 
Approved Indication in US and Europe ................................... 11 
1.3.1.1 Acute Myocardial Infarction .................................................... 12 
1.4 
Overview of Clinical Development ........................................... 12 
1.4.1 
Acute Myocardial Infarction Clinical Development .................. 12 
1.4.2 
Acute Ischemic Stroke Clinical Development.......................... 12 
1.4.3 
Previous Clinical Development ................................................ 13 
1.5 
Study Rationale and Benefit-Risk Assessment ....................... 13 
2. 
OBJECTIVES AND ENDPOINTS .................................................................. 15 
2.1 
Primary Endpoints .................................................................... 15 
2.2 
Secondary Endpoints ............................................................... 15 
2.2.1 
Exploratory Efficacy Objectives ............................................... 16 
2.3 
Safety Endpoints ...................................................................... 16 
3. 
STUDY DESIGN ............................................................................................ 16 
3.1 
Description of the Study ........................................................... 16 
3.2 
End of Study and Length of Study ........................................... 17 
3.3 
Rationale for Study Design ...................................................... 17 
3.3.1 
Rationale for Tenecteplase Dose and Schedule ..................... 17 
3.3.2 
Rationale for Patient Population .............................................. 17 
3.3.3 
Rationale for Double-blind, Placebo-controlled Study ............ 17 
3.3.4 
Rationale for Biomarker Assessments .................................... 18 
4. 
MATERIALS AND METHOODS .................................................................... 18 
4.1 
Patients ..................................................................................... 18 
4.1.1 
Study Population / Duration ..................................................... 18 
4.1.2 
Inclusion Criteria....................................................................... 18 


TABLE OF CONTENTS (CONT.) 
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4.1.3 
Exclusion Criteria ..................................................................... 19 
4.2 
Method of Treatment Assignment ........................................... 20 
4.3 
Study Treatment ....................................................................... 21 
4.3.1 
Study Treatment Formulation, Packaging, and Handling ....... 21 
4.3.1.1 Tenecteplase .......................................................................... 21 
4.3.1.2 Placebo or Other Assigned Treatment ................................... 21 
4.3.2 
Study Treatment Dosage, Administration, and Compliance ... 21 
4.3.3 
Blinding and Unblinding Procedures ....................................... 22 
4.3.4 
Cautionary Therapy.................................................................. 22 
4.3.5 
Additional Medication ............................................................... 23 
4.3.6 
Prohibited Therapy ................................................................... 23 
4.4 
Study Assessments.................................................................. 23 
4.4.1 
Informed Consent Forms and Screening Log ......................... 23 
4.4.2 
Medical History, Concomitant Medication, and Demographic 
Data 
23 
4.4.3 
Physical Examinations ............................................................. 24 
4.4.4 
Vital Signs................................................................................. 24 
4.4.5 
Laboratory, Biomarkers, and Other Biological Samples ......... 24 
4.4.6 
Echocardiograms ..................................................................... 26 
4.5 
Treatment, Patient, and Study Discontinuation ....................... 26 
4.5.1 
Patient Discontinuation from Study ......................................... 26 
4.5.2 
Study Discontinuation .............................................................. 26 
5. 
ASSESSMENT OF SAFETY ......................................................................... 26 
5.1 
Safety Plan ............................................................................... 26 
5.1.1 
Risks Associated with Tenecteplase ....................................... 27 
5.1.1.1 Bleeding .................................................................................. 27 
5.1.1.2 Risk of Hypersensitivity .......................................................... 28 
5.1.1.3 Thromboembolism .................................................................. 28 
5.1.1.4 Cholesterol Embolization ........................................................ 28 
5.1.1.5 Arrhythmias ............................................................................. 29 
5.1.1.6 Use with Percutaneous Coronary Intervention ...................... 29 
5.1.1.7 Other Adverse Reactions ....................................................... 29 


TABLE OF CONTENTS (CONT.) 
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5.1.2 
Management of Patients Who Experience Adverse Events ... 29 
5.1.2.1 Management Guidelines ......................................................... 29 
Table 1: Guidelines for Management of Patients Who Experience 
Bleeding ................................................................................................. 30 
5.2 
Safety Parameters and Definitions .......................................... 30 
5.2.1 
Adverse Events ........................................................................ 30 
5.2.2 
Serious Adverse Events ........................................................... 31 
5.2.3 
Adverse Events of Special Interest.......................................... 31 
5.3 
Methods and Timing for Assessing and Recording Safety 
Variables ................................................................................... 32 
5.3.1 
Adverse Event Reporting Period ............................................. 32 
5.4 
Procedures for Eliciting, Recording, and Reporting Adverse 
Events ....................................................................................... 33 
5.4.1 
Eliciting Adverse Event Information ......................................... 33 
5.4.2 
Specific Instructions for Recording Adverse Events ............... 33 
5.4.2.1 Diagnosis versus Signs and Symptoms ................................. 33 
5.4.2.2 Deaths ..................................................................................... 33 
5.4.2.3 Preexisting Medical Conditions .............................................. 34 
5.4.2.4 Hospitalizations for Medical or Surgical Procedures ............. 34 
5.4.2.5 Assessment of Severity of Adverse Events ........................... 34 
Table 2: Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ......................................................... 34 
5.4.3 
Assessment of Causality of Adverse Events ........................... 35 
Table 3: Causal Attribution Guidance ................................................... 36 
5.4.3.1 Pregnancies ............................................................................ 36 
5.4.3.2 Post-Study Adverse Events .................................................... 37 
5.4.3.3 Case Transmission Verification of Single Case Reports ....... 37 
5.5 
Exchange of Single Case Reports ........................................... 37 
5.5.1 
MedWatch 3500A Reporting Guidelines ................................. 40 
5.5.1.1 Follow-up Information ............................................................. 40 
5.5.2 
Reporting to Regulatory Authorities, Ethics Committees and 
Investigators ................................................................................................ 40 
5.5.2.1 Additional Reporting Requirements for IND Holders ............. 41 
5.6 
Aggregate Reports ................................................................... 42 


TABLE OF CONTENTS (CONT.) 
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5.7 
Study Close-Out ....................................................................... 42 
6. 
STATISTICAL CONSIDERATIONS............................................................... 43 
6.1 
Determination of Sample Size ................................................. 43 
6.2 
Planned Efficacy Evaluations .................................................. 43 
6.3 
Primary Efficacy Variables ....................................................... 44 
6.4 
Secondary Efficacy Variables .................................................. 44 
6.5 
Safety Analyses........................................................................ 44 
6.6 
Exploratory Endpoints .............................................................. 44 
6.7 
Interim Analysis ........................................................................ 45 
6.8 
Method of Analysis ................................................................... 45 
6.9 
Retention of Records ............................................................... 45 
6.10 
Study Medical Monitoring Requirements................................. 45 
6.11 
Study Medication Accountability .............................................. 46 
6.12 
Data Collection ......................................................................... 46 
7. 
ETHICAL CONSIDERATIONS ...................................................................... 46 
7.1 
Informed Consent ..................................................................... 46 
7.2 
Institutional Review Board or Ethics Committee ..................... 47 
7.3 
Confidentiality ........................................................................... 47 
8. 
REFERENCES ............................................................................................... 48 
Appendix 1: Schedule of Assessments ......................................................... 53 
Appendix 2: Safety Reporting Fax Cover Sheet ........................................... 54 
Appendix 3: FDA MedWatch 3500 Form ....................................................... 55 
 
LIST OF TABLES 
Table 1 Guidelines for Management of Patients Who Experience Bleeding…….31 
Table 2 Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI 
CTCAE…………………………………………………………………………………..35 
Table 3 Causal Attribution Guidance ………………………………………………...36 
 


 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
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GLOSSARY OF ABBREVIATIONS 
ADR 
adverse drug reaction 
AE 
adverse event 
AHA 
American Health Association 
AIS 
ALI 
ARDS 
acute ischemic stroke 
acute lung injury 
acute respiratory distress syndrome 
AV 
arteriovenous 
AMI 
acute myocardial infarction 
BFR 
blood-flow rate 
CCDS 
company core data sheet 
CT 
computed tomography 
CVCs 
DIC 
central venous catheters 
disseminated intravascular coagulation 
EVT 
endovascular treatment 
ED50 
effective dose at which 50% of a clot is lysed 
GD 
gestational day 
HD 
hemodialysis 
ICH 
International Conference on Harmonisation 
IH 
intracranial hemorrhage 
IQR 
interquartile range 
IV 
intravenous 
MAD 
Mutual Acceptance of Data 
MCA 
middle cerebral artery 
NOAEL 
No-observed-adverse-effect-level 
PAI-1 
plasminogen activator inhibitor 1 
PCI 
PE 
percutaneous coronary intervention 
pulmonary embolism 
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 
VTE 
United States Package Insert 
venous thromboembolism 


 
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1. 
BACKGROUND 
• There is a knowledge gap associated with the management of patients with 
COVID-19 lung injury and a laboratory picture compatible with disseminated 
intravascular coagulation (DIC). Clinical data to date support that COVID-19 is 
associated with a prothrombotic state that is not simply explained by an influx of 
more critically ill individuals.  
• These patients suffer from severe respiratory failure; hypoxemia and ventilator 
dependence are the primary concerns; ARDS with respiratory failure is frequently 
the cause of death. Macroscopic and probable microvascular thromboembolic 
events are a major concern in this population.  
• When DIC is associated with COVID-19, it predicts a very poor prognosis. 
• We plan to evaluate the clinical efficacy and safety of low-dose IV bolus 
tenecteplase (TNK) together with anticoagulation compared with control patients 
on therapeutic anticoagulation alone in hospitalized adults diagnosed with COVID-
19 and acute intermediate-risk PE. We believe that acute PE in the setting of active 
COVID-19 infections likely portend a poor prognosis.  
• Prospective, multicenter, randomized two-arm trial enrolling consecutive patients 
who meet enrollment criteria.   
• We hope to generate evidence that low-dose TNK together with anticoagulation is 
beneficial in these patients. 
• The primary outcome will be based upon improvement in shock index with 
secondary endpoints focusing on other parameters.  
• The planned sample size is 45 patients (5 sites). Subjects will be assessed daily 
while hospitalized. Subjects discharged from the hospital will be asked to attend 
study visits at Days 15 and 30 (telephone / telemedicine, clinic or inpatient ward).  
 
1.1 
BACKGROUND ON COVID-19 INFECTION, INFLAMMATION AND 
THROMBOSIS 
COVID-19: Current statistics.  At the present time (January 13, 2021) there are over 
92.7 million cases of COVID-19 infection world-wide with nearly 2 million reported deaths. 
In the U.S., there have been 23.6 million cases and nearly 400,000 deaths reported (1). 
It is unclear if this pandemic will continue, be seasonal, or will worsen in the future based 
upon continued mutations. An interesting genetic fact is that it took the genome of the 
human species 8 million years to evolve by 1%. Many animal RNA viruses can evolve 
by > 1% in a few days. It is not surprising that we have seen the emergence of zoonotic 
viruses (2). The current COVID-19 pandemic has had catastrophic health, economic, and 
psychological impact on the entire world.  
COVID-19: Clinical presentation and laboratory coagulation parameters. Before 
focusing on acute PE, we will briefly focus on aspects of COVID-19 infection and its 
relationship to inflammatory and coagulation parameters. A key feature of severe COVID-
19 infection has been abnormal coagulation parameters, and a recent study has 
demonstrated that 71.4% of patients who die of COVID-19 meet International Society of 


 
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Thrombosis and Haemostasis (ISTH) criteria for disseminated intravascular coagulation 
(DIC) with a distinct minority (0.6%) of patients who survive meeting these criteria (3).  
These patients clinically appear to have a predominantly prothrombotic state rather than 
a bleeding diathesis (4). They often have very high D-dimer levels, high fibrinogen and 
low antithrombin levels (5,6). In one large retrospective single-center review from China, 
while D-dimer levels were often normal at admission, they tended to be higher in critically 
ill patients (6). This suggests that fibrin deposition in the pulmonary microvasculature may 
contribute to the acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) 
and would be particularly likely to be seen in patients with ARDS and concomitant DIC as 
is observed in more than 70% of patients who succumb to COVID-19 (3).  
Acute venous thromboembolism (VTE) is common in COVID-19 patients as is central line 
thrombosis and vascular occlusion including ischemic limbs, and cerebrovascular 
accidents (5-7). We have seen clotted off CRRT lines and other vascular circuits. In one 
autopsy case, hemorrhagic necrosis was found on gross examination and was primarily 
present in “outer edge of the right lobe of the right lung (8).” However, clinical hemorrhage 
from the lung or other bleeding diathesis appear to be very rare in COVID-19 patients 
with acute lung injury and DIC. Unfortunately, almost no detailed autopsy data in COVID-
19 lung injury are available.   
Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) in the pre-
COVID era.  While it is well-known that high-risk (massive) PE is common in critically ill 
patients and may benefit from systemic thrombolysis, acute respiratory distress syndrome 
(ARDS) and acute lung injury (ALI) are characterized by excessive intra-alveolar fibrin 
deposition, driven, at least in part, by inflammation (9). The imbalance between activation 
of coagulation and inhibition of fibrinolysis in patients with ALI and ARDS was 
demonstrated prior to the “COVID era,” and favors fibrin formation and appears to develop 
not just systemically, but also in the lung and airspace (TF ref). With the advent of COVID-
19, it appears that we are seeing ARDS with micro and macrothrombotic potential.  
A key aspect of the pathophysiology of ALI and ARDS in the “pre-COVID-19 era” is the 
presence of fibrin-rich exudative hyaline membranes which develop in lung alveoli due to 
activation of coagulation and inhibition of fibrinolysis; i.e., a balance that is shifted in a 
procoagulant / antifibrinolytic direction favoring fibrin formation (9). Despite extensive 
research in this area, the direct effects of activation of coagulation on inflammatory 
pathways and perpetuation of lung injury are not still well understood (10). While clinical 
studies targeting the coagulation cascade in patients with, or at risk of lung injury have 
been interesting and promising, there have been no major breakthroughs impacting on 
mortality (11). One reason for this lack of impact may have been the population of 
ALI/ARDS patients studied. 
It has been demonstrated that BAL fluid from ARDS patients has decreased fibrinolytic 
activity compared with normal control subjects (12).  Furthermore, plasminogen activator 
inhibitor-1 (PAI-1) levels in plasma and edema fluid have been shown to be higher 
compared with controls with hydrostatic pulmonary edema (13). PAI-1 levels have also 
been shown to be higher in the plasma of ARDS patients than in controls (14,15). 
Genetics may play a role in susceptibility as well (10,16). More work needs to be done to 
fully characterize the fibrinolytic pathway and its modulation in patients with ALI/ARDS as 


 
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potential therapies could also be directed at this pathway. The prothrombotic phenotype 
that we are seeing in COVID-19 patients appears particularly appropriate to study. 
Thrombolytic therapy for ALI/ARDS in the pre-COVID era. Few well-controlled 
experimental and clinical studies on the role of fibrinolytic agents in modulating lung 
inflammation and injury have been completed and results of these studies have been 
mixed. In a pig model of lung injury induced by trauma, intravenous (IV) administration of 
urokinase or tissue-type plasminogen activator (tPA) was protective (17). Other models 
of lung injury have shown attenuation of bleomycin-induced fibrosis after administration 
of urokinase, either by inhalation, instillation or injection (18). An early-phase (non-COVID) 
clinical trial demonstrated the ability of both urokinase and tPA to improve lung function 
as evidenced by improvement in hypoxemia in a small group of ARDS patients (19). 
Finally, tPA has been shown to inhibit interleukin-1 induced acute lung leak in an animal 
model of lung injury, suggesting that tPA may suppress neutrophil activation in vivo and 
have anti-inflammatory effects (20). While data have been less impressive with urokinase, 
it may be that these plasminogen activators modulate lung inflammation and injury 
differentially depending on the underlying cause of lung injury or the route of 
administration of the drug. 
There may be a number of reasons for unsuccessful human trials, prior to the COVID-19 
era. These would appear to include heterogeneous patient populations, insufficient 
understanding of drug activity, interactions and metabolism in humans, and need for 
optimization of timing of therapeutic interventions, doses and duration of therapy. In 
addition, adverse effects in humans, which were not observed in experimental models, 
have also contributed to limited success with these strategies. In addition, many of the 
published clinical studies have been conducted in patients with sepsis, and have not been 
targeted specifically at ALI and ARDS. Finally, COVID-19 patients with lung injury appear 
to have a more severely prothrombotic tendency than patients with ALI/ARDS of other 
etiologies. We have witnessed this in our population of COVID patients and this concept 
is strongly supported in the rapidly evolving COVID literature, thus far. 
Thus, more trials in targeted patient populations are necessary to investigate efficacy and 
safety.  No data with tenecteplase exist but clinical data supporting its fibrinolytic activity 
in stroke (21), myocardial infarction (22), venous thromboembolism (23-25), and 
peripheral arteries and veins (26), and thus clear antifibrinolytic activity in numerous 
settings, together with administration by IV bolus make it ideal to study in COVID-19 
related lung injury with DIC. A clear reason why bolus thrombolytic dosing is favored in 
the COVID era is based on reducing nursing exposure. 
 
Finally, it should be noted that two separate documents have been published in March 
2020, offering guidance about coagulation testing and management of coagulopathy and 
bleeding in COVID-19 patients (27,28). Both are based on clinical practice from the pre-
COVID-19 era together with recent observations on COVID-19 patients. The two sets of 
recommendations are quite similar. The International Society of Thrombosis and 
Haemostasis (ISTH) suggests that patients with markedly elevated D-dimer level 
(arbitrarily defined as a 3-4-fold increase) should be considered for hospital admission 
even in the absence of other disease severity symptoms (27). In addition, it is 
recommended that all patients who require hospital admission for COVID-19 infection 


 
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should receive prophylactic dose low molecular weight heparin (LMWH), unless there are 
contraindications (e.g., active bleeding and platelet count < 25 x 109/L). While some 
institutions are setting threshold values upon which to start therapeutic dose 
anticoagulation based on certain D-dimer or fibrinogen thresholds (personal 
communication) there are not yet clinical trial data to support this. However, trials are 
ongoing (29-31). 
Acute Pulmonary Embolism in the Setting of COVID-19 Infection.  
See Section 1.5 below. 
 
1.2 
CURRENT THERAPIES AND UNMET MEDICAL NEED RELATED TO 
COVID-19 PNEUMONIA/ARDS AND DIC IN PATIENTS WITH ACUTE 
THROMBOEMBOLIC EVENTS 
At this time, only remdesivir and convalescent plasma have Emergency Use Authorization 
by the United States Food and Drug Administration for the treatment of patients with 
COVID-19. Given the results of studies outlined above, intravenous tenecteplase, along 
with therapeutic anticoagulation (standard of care treatment), could provide efficacy and 
offer the potential to treat COVID-19 patients with thromboembolic disease more 
effectively than anticoagulation alone. Safety data have previously been generated on the 
use of tenecteplase higher than proposed dosages in other indications, including 
myocardial infarction and stroke.  A study to assess safety and efficacy of intravenous 
tenecteplase plus standard of care in hospitalized patients with severe COVID-19 
pneumonia and acute pulmonary embolism is justified to address the high unmet public 
health need and burden of disease in this severely ill 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. 
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.  Outside US and Canada (except Japan), METALYSE 
(tenecteplase) is indicated for the thrombolytic treatment of AMI.   


 
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1.3.1.1 
Acute Myocardial Infarction 
Following administration of 30, 40, or 50 mg of tenecteplase for use in mortality reduction 
associated with acute myocardial infarction (AMI), decreases in circulating fibrinogen 
(4%−15%) and plasminogen (11%−24%) were observed (Refer to the Tenecteplase 
United States Package Insert [USPI]).  The clinical significance of fibrin specificity on 
safety (e.g., bleeding) or efficacy has not been established.  Biological potency is 
determined by an in vitro clot lysis assay and is expressed in tenecteplase-specific units.  
The specific activity of tenecteplase has been defined as 200 units/mg. 
In patients with AMI, tenecteplase administered as a single bolus exhibits a biphasic 
disposition from the plasma.  Tenecteplase was cleared from the plasma with an initial 
half-life of 20 to 24 minutes.  The terminal phase half-life of tenecteplase was 90 to 130 
minutes.  In 99 of 104 patients treated with tenecteplase, mean plasma clearance ranged 
from 99 to 119 mL/min (see the tenecteplase USPI).  Refer to the Tenecteplase 
Investigator's Brochure for additional details on nonclinical and clinical studies. 
 
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.   
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 to 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. 


 
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Completed and ongoing clinical studies of tenecteplase are summarized in the 
Tenecteplase Investigator’s Brochure. 
 
1.4.3 
Previous Clinical Development 
Study N0747g (ASSENT-2; BI Study: 1123.4) 
This Phase III, randomized, double-blind, double-dummy (i.e., patients received either 
tenecteplase and alteplase placebo or alteplase and tenecteplase placebo) mortality trial 
enrolled patients with AMI for study.  The primary objective of the study was to compare 
the mortality of patients 30 days after treatment on the basis of a nonparametric method 
adjusted for age, baseline systolic blood pressure, baseline heart rate, baseline Killip 
class, and infarct location.  The study has completed. 
Study N3698g (TROPICS 1) 
Study N3698g was a Phase III, randomized, double-blind, placebo-controlled study of 
patients with dysfunctional central venous catheters.  The primary efficacy endpoint of the 
study was the cumulative rate of catheter function restoration after 1 dose of study drug 
(placebo or tenecteplase) with up to a 120-minute dwell time.  The study has completed. 
Study N3699g (TROPICS 2) 
This Phase III, open-label, single-arm study assessed CVC function and restoration after 
instillation of up to a maximum of 2 doses of the study drug (placebo or tenecteplase) with 
up to a 120-minute dwell time.  The study has completed. 
Study N3700g (TROPICS 3) 
This Phase III, randomized (1:1), double-blind, placebo-controlled study evaluated the 
incidence of hemorrhagic, thrombotic, or infectious complications in 149 patients with 
dysfunctional tunneled hemodialysis catheters.  The study has completed. 
Study N3701g (TROPICS 4) 
Study N3701g was a Phase III, open-label study of patients who required hemodialysis 
(HD), and who had a dysfunctional HD catheter.  The primary outcome of the study was 
blood-flow rate (BFR)  300 mL/min and absolute change in BFR of  25 mL/min at an 
associated arterial pressure of −240 to −280 mmHg noted at both 30 min ( 10 min) and 
at the end of HD.  The study has completed. 
 
1.5 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
ALI and ARDS are characterized by profound imbalances between coagulation and 
fibrinolysis. Fibrin deposition in the alveolar spaces is a hallmark of this clinical syndrome 
that most likely results from inflammation-induced activation of the coagulation cascade 
and impairment of fibrinolysis. In COVID-19 patients with lung injury, the more frequent 
development of a DIC picture increases this prothrombotic state and increases mortality.  
There is a knowledge gap associated with the management of patients with COVID-19 


 
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lung injury and a laboratory picture compatible with DIC. These patients suffer from 
severe respiratory failure; hypoxemia and ventilator dependence are the primary 
concerns; ARDS with respiratory failure is frequently the cause of death. Patients with 
COVID-19 may well be prothrombotic independent of their reduced mobility and critically 
ill status.  
 
1.5.1  
 
Acute Pulmonary Embolism in the Setting of COVID-19 Infection 
Early data suggest that therapeutic anticoagulation may reduce mortality in COVID-19 
patients without proven PE (32). Notably, compelling data from a very large (2,700 patient) 
cohort in May 2020 suggest that therapeutic anticoagulation may be associated with a 
lower mortality in COVID patients requiring mechanical ventilation (33). Randomized trial 
data are needed. 
COVID VTE data also suggest an increase in acute DVT and PE; i.e., “macroscopic VTE” 
in COVID patients. This may well be explained by a prothrombotic tendency with this virus, 
rather than simply more critically ill patients (34,35). This is strongly supported by more 
anecdotal data in the New York area (personal communication). Thus, more aggressive 
therapy in these patients should be considered, on an individual careful basis as 
randomized data are collected. 
A recent autopsy study of 12 COVID patients from Hamburg, Germany demonstrated that 
the cause of death was massive PE in four of the 12 cases. In the seven patients with 
DVT, all were bilateral (36). 
Finally, it has been suggested that elevated maximum clot strength by TEG testing is 
predictive of COVID-19 status despite a high level of suspicion in negative patients with 
normal TEG results (37). While these results require a larger cohort for confirmation, TEG 
testing could improve confidence in negative COVID-19 testing results in suspected 
patients and perhaps suggest the need for more aggressive therapy in acute PE.  
The overall objective of the study is to evaluate the clinical efficacy and safety of IV bolus 
tenecteplase (TNK) in hospitalized adults diagnosed with COVID-19 lung infection and  
proven acute PE. 
We propose a therapeutic strategy aimed at enhancing fibrinolysis in these patients. We 
believe that low-dose IV tenecteplase (0.25 mg/kg) followed by therapeutic 
anticoagulation could prove to hasten patient recovery and shorten hospitalization in 
those with COVID-19 induced lung infection and intermediate-risk acute PE with or 
without features of DIC. We will, however, measure inflammatory parameters and 
coagulation parameters in hopes of learning more about their role in COVID patients with 
acute PE.  
We believe these PE patients can be successfully treated without significantly increasing 
the risk of major bleeding. We believe this could prove to improve recovery rates, shorten 
hospitalization time, and perhaps ultimately prove to improve survival as well as reducing 
post-ICU morbidity in these patients.  
 


 
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2. 
OBJECTIVES AND ENDPOINTS 
2.1 
PRIMARY ENDPOINTS 
The primary endpoint is percent improvement in shock index (HR/SBP) 6 hours after the 
TNK/placebo bolus. For example, a patient may start with a heart rate of 100/min and 
systolic BP of 100 mm Hg (shock index = 1) and after therapy, HR might be 90, with 
systolic BP of 110 mm Hg (shock index of 0.81), an improvement of 19%.   
 
2.2 
SECONDARY ENDPOINTS  
1. Clinical status at 24 hours after administration of TNK/placebo based upon 7-point 
scale. Assessment of patient status using an ordinal scale will be recorded at 
baseline and once daily in the morning while hospitalized. The ordinal scale 
categories are as follows: 
• Level 1: Discharged (or “ready for discharge” on ambient air or < 2L 
supplemental O2) 
• Level 2: Non-ICU hospital ward (or “ready for hospital ward”) not requiring 
supplemental O2 
• Level 3: Non-ICU hospital ward (or “ready for hospital ward”) requiring 
supplemental O2 
• Level 4. ICU or non-ICU, requiring non-invasive ventilation or high-flow O2 
• Level 5. ICU, requiring intubation and mechanical ventilation 
• Level 6: ICU, requiring ECMO or mechanical ventilation and additional organ 
support (e.g. vasopressors, renal replacement therapy) 
• Level 7: Death 
2. Clinical status at Day 7 after administration of TNK/placebo based upon the same 
7-point ordinal scale. 
3. Clinical status at Day 28 after administration of TNK/placebo based upon the same 
7-point ordinal scale. 
4. O2 sat / FIO2 ratio 6 hours and 24 hours after administration of TNK/placebo, as 
a practical, noninvasive, and reliable surrogate for pO2 / FIO2 (see refs).  
5. Percentage change in shock index 24 hours after TNK/placebo 
6. Percent change in RV/LV ratio by echocardiogram 24 hour after TNK/placebo 
7. Number of post-enrollment days with O2 requirement < 4L/min at Day 7 
8. Number of post-enrollment days with no O2 requirement at Day 7 
9. Change in D-dimer level 24 hours after enrollment  
10. Change in D-dimer level at Day 7 (if obtained) 
11. Change in ferritin, C-reactive protein (CRP), IL-6 levels 24 hours after  
TNK/placebo dose  
12. Post-enrollment documented new clinical thrombotic events at Day 7 
13. All-cause mortality at day 7 and day 30  
 


 
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2.2.1 
Exploratory Efficacy Objectives 
1. We will examine characteristics of patients prior to bolus by measuring static 
measurements of hemostasis including D-dimer, PT/PTT, INR, and fibrinogen. In 
addition, thromboelastography (TEG) will be performed (TEG 6s or TEG 5000) if 
sites have the ability to perform this test.  
2. If TEG is available at a site, it will be performed immediately prior to study drug 
administration, 10 minutes (+ 5 min) after the bolus and 24 (+/- 6) hours after study 
drug administration. The 24 hour TEG is optional. If the initial, pre-bolus TEG is not 
performed for any reason, the following post-bolus TEG(s) need not be performed. 
 
2.3 
SAFETY ENDPOINTS 
Safety outcomes will be defined as: 
1. Hemorrhagic stroke (including hemorrhagic conversion of ischemic stroke) within 
7 days after randomization, extracranial major (moderate or severe) bleeding 
within 7 days, and serious adverse events within 30 days. 
2. Major bleeding (excluding intracranial hemorrhage) within 7 days of TNK 
administration is defined as moderate or severe bleeding: 
• Moderate bleeding: A bleeding episode requiring blood transfusion(s), but 
not deemed life-threatening and not leading to hemodynamic compromise 
requiring emergency fluid replacement, inotropic support, or interventional 
treatment.  
• Severe bleeding: 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 (such as diffuse alveolar hemorrhage). In addition, any bleeding in a 
critical site (e.g., intracranial, pericardial, retroperitoneal). Bleeding in critical 
sites will be noted separately. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a prospective, double-blind, placebo-controlled study randomizing patients with 
acute intermediate-risk PE who meet enrollment criteria in a 2:1 manner into intervention 
(TNK) versus placebo arms, respectively. We will have up to 5 sites. After 18 patients are 
enrolled, a safety assessment will be performed by an independent Data and Safety 
Monitoring Board, and if a safety issue arises, it will be considered and discussed among 
the Investigators. The planned sample size is 45 patients (30 treatment and 15 control). 
Subjects will be assessed daily while hospitalized. Subjects discharged from the hospital 
will be asked to attend study visits at Days 14 and 30 (telephone / telemedicine, clinic or 
inpatient ward).  


 
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The overall objective of the study is to evaluate the clinical efficacy and safety of IV bolus 
tenecteplase (TNK) and therapeutic anticoagulation compared with placebo and 
therapeutic anticoagulation in hospitalized adults diagnosed with COVID-19 infection and 
acute intermediate-risk PE. 
 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the last data point required for last follow-up is received from the last 
patient, whichever occurs later. The end of the study is expected to occur approximately 
1 month after the last patient is enrolled.   
 
3.3 
RATIONALE FOR STUDY DESIGN 
These are described in Section 1.2 and Section 1.5. 
 
3.3.1 
Rationale for Tenecteplase Dose and Schedule 
We are treating patients with intermediate-risk PE, thus, lower dose TNK is prudent.  
 
3.3.2 
Rationale for Patient Population 
COVID-19 appears to be a prothrombotic state. These patients are very susceptible to 
acute VTE and we believe they may be susceptible to a pulmonary microvascular process 
as well, which potentially could occur with or without the acute “macroscopic” PE. 
Intermediate-risk PE have a higher rate of poor outcomes than low-risk PE and could 
potentially benefit from more aggressive therapy. We believe COVID patients with acute 
intermediate-risk PE could be at even higher risk for deterioration. 
 
3.3.3 
Rationale for Double-blind, Placebo-controlled Study 
This design was chosen because of the critical importance of an accurate assessment of 
the risk/benefit. In this patient population, we are acutely aware of the bleeding risk of 
anticoagulation and while TNK could increase this risk compared with placebo, our team 
and the clinical teams will be following the patients very closely clinically. It is also 
standard of care in such patients to check a CBC daily to monitor for potential bleeding 
or thrombocytopenia.  Thus, we feel that being blinded to treatment choice will be safe. 
Based on the lack of available evidence regarding response to anticoagulation in COVID 
PE patients and the lack of proven benefit from thrombolysis in these patients, 
administration of placebo is ethical.  
 


 
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3.3.4 
Rationale for Biomarker Assessments 
Assessment of biomarkers in this study (D-dimer, ferritin, IL-6, C-reactive protein,) is 
proposed to obtain further mechanistic insights into the pathophysiology of acute COVID-
19 pneumonia that could 1) enhance understanding of disease processes, 2) assist 
development of patient risk stratification tools (via laboratory serologies), 3) aid in the 
development of novel treatments for the disease, and 4) inform potential phase 3 trial 
design, to name a few.  These biomarkers are selected for this study given the association 
with thrombosis and systemic inflammation, two hypothesized mechanisms of COVID-19 
disease progression.  The biomarkers are scheduled for assessment pre and post-
intervention.  Thromboelastography (TEG) will be tested before and after TNK/placebo 
as well, at sites that have TEG testing available. 
 
4. 
MATERIALS AND METHOODS 
4.1 
PATIENTS 
4.1.1 
Study Population / Duration 
Forty-five male or non-pregnant female adults older than 18 years of age but <75 years 
with COVID- 19 who meet all eligibility criteria will be enrolled at up to 5 sites.  Study 
participants will be randomized in a 2:1 manner to either intervention (TNK) or 
control/standard-of-care arms, respectively. The total number enrollees into each 
treatment arm will be 30 TNK and 15 control subjects.  The estimated time from screening 
(Day 1 to end of study) for an individual subject is approximately 30 days. If, based on 
initial study results, it appears appropriate to include additional sites, this can be 
considered.  
 
4.1.2 
Inclusion Criteria 
In order to be eligible to participate in this study, a patient must meet all of the following 
criteria:  
1. Male or non-pregnant female adult ≥18 years of age, but < 75 years of age at time 
of enrollment. 
2. Laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or other 
commercial or public health assay in any specimen < 28 days prior to 
randomization, OR person under investigation (PUI) of COVID-19 with pulmonary 
infiltrates and elevated ferritin and CRP level. 
3. Acute intermediate-risk pulmonary embolism defined as: 
• Presence of acute pulmonary embolism confirmed by diagnostic imaging 
(computed tomographic angiography, ventilation-perfusion scan, or 
invasive pulmonary angiography) AND  


 
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• Presence of clot burden with at least one lobar artery involved OR bilateral 
with at least segmental branches OR unilateral clot in at least multiple 
segmental branches.  
4. Subject (or legally authorized representative) provides written informed consent 
prior to the performance of any study procedures. 
5. In the Investigator’s judgement, patient has the ability to comply with the study 
protocol, and understands and agrees to comply with planned TNK bolus versus 
placebo.  
 
4.1.3 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Anticipated transfer to another hospital (which is not a study site) within 72 hours  
2. Allergy or contraindications to TNK 
3. Contraindications to systemic anticoagulation 
4. Active bleeding 
5. Known significant bleeding risk (although recent exposure to aspirin or any other 
antiplatelet therapy is not an exclusion criterion). While there is no specific 
hemoglobin cut-off value for enrollment, Investigators will gauge the severity / 
stability of the Hgb and exclude patients deemed inappropriate. 
6. Major GI or GU bleed within the past 3 weeks 
7. History of hemorrhagic stroke 
8. History of acute ischemic stroke in the last 90 days 
9. High-risk (massive) acute PE (PE associated with hypotension (systolic BP < 90 
mmHg for > 15 min). 
10. PE associated with syncope and any degree of head trauma 
11. PE meeting criteria for intermediate-risk PE and thus for enrollment, but with 
clinical evidence of deterioration such that the Investigator deems the patient not 
appropriate for enrollment. 
12. Administration of thrombolytic agent within the previous 7 days 
13. Pulmonary thrombectomy within the previous 30 days 
14. Uncontrolled hypertension defined as systolic blood pressure >180 mm Hg 
and/or diastolic blood pressure >110 mm Hg at randomization 
15. Severe ARDS (P/F ratio < 100)  
16. Platelet count lower than 80,000/mm3  


 
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17. Known hereditary or acquired hemorrhagic diathesis, coagulation factor 
deficiency; recent oral anticoagulant therapy with INR 1.7  
18. Arterial puncture at a non-compressible site within the past 5 days 
19. Prior brain surgery 
20. Severe trauma in the prior 2 weeks  
21. Major surgery in the prior 2 weeks 
22. Brain malignancy / metastases, brain tumor in past 5 years 
23. Brain AVM or ruptured aneurysm at any time 
24. Acute myocardial infarction or history of myocardial infarction within the past 3 
weeks or cardiac arrest during hospitalization 
25. Cardiac tamponade 
26. Lumbar puncture with in past 7 days 
27. Known abdominal or thoracic aneurysm 
28. Acute or chronic renal failure requiring dialysis 
29. Chronic liver failure (acutely elevated liver function tests not an exclusion criterion) 
30. Bacterial endocarditis at time of study entry  
31. Seizure during pre-hospital course or during hospitalization for COVID-19 
32. Currently on ECMO 
33. Pregnancy, lactation or parturition within the previous 30 days 
34. Patients, in whom, in the opinion of the Investigator, are critically ill from 
concomitant comorbid cardiopulmonary disease, and unlikely to benefit. 
35. Any other condition that the Investigator felt would place the patient at increased 
risk if the investigational therapy were initiated 
36. Previous enrollment in this study 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT  
After informed consent is obtained, screening and assessment procedures will be 
completed to confirm a patient’s eligibility for participation in the study. The study site will 
obtain the patient’s medical record number/unique patient identification number, and 
treatment assignment to either interventional (TNK) or placebo arms of the study will be 
randomly determined.  Patients will be allocated to the interventional versus placebo arms 
in a 2:1 manner as per a computer generated randomization schedule. A total of 30 TNK 
subjects versus 15 placebo controls will be enrolled. Randomization will be via a central 
randomization system created in REDCap. Allocation concealment will be ensured, as 


 
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the service will not release the randomization assignment to the unblinded pharmacy 
team until the patient has been recruited into the trial, which takes place after all baseline 
measurements have been completed.  
 
4.3 
STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is tenecteplase. (See above) 
 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Tenecteplase 
Tenecteplase will be supplied by Genentech, Inc. 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.   
For information on the formulation and handling of tenecteplase, see the local prescribing 
information for tenecteplase. 
 
4.3.1.2 
Placebo or Other Assigned Treatment 
Placebo for tenecteplase will be supplied by Genentech, Inc. 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.   
The placebo arm treatment will consist of an intravenous syringe identical to that of TNK 
using the local prescribing information for tenecteplase. 
Protocol Specified Therapy/Other Study Drug(s) – NONE 
 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
Any overdose or incorrect administration of tenecteplase 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. 
ANTICOAGULATION AND TNK DOSING 
• Once a patient is diagnosed with suspected PE, therapeutic anticoagulation with 
either standard UFH or LMWH will be initiated, per the judgment of the treating 
physicians (and then the patient will be evaluated for enrollment and informed 


 
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consent obtained). The patient will be subsequently randomized to either TNK or 
placebo and both will receive continued anticoagulation. 
• The dose regimen for TNK for the PEITHO PE trial was approximately 0.5 mg/kg. 
In this study, TNK will be administered as a lower dose protocol as outlined below, 
after the patient is randomized into the TNK study arm. It will be delivered as a 
bolus over 5 seconds. In the setting of acute PE, if there is deterioration at any 
point to high-risk (massive) PE status, treatment appropriate for that setting will be 
determined and initiated by the managing team.  
Low dose Protocol 
0.25 mg/kg (10 mg / 2000 U / 2mL) (maximum dose of 25 mg) 
 
4.3.3 
Blinding and Unblinding Procedures 
Patients will receive TNK or identical-appearing placebo. At randomization, unblinded 
Pharmacy Staff will see treatment assignments via the randomization dashboard in 
REDCap. 
In the case of an emergency where, in the opinion of the Investigator, discontinuation of 
study drug bolus is not possible or sufficient and the study treatment must be unblinded 
in order to evaluate further a course of medical treatment, the Investigator can perform 
the unblinding according to site-specific procedures, consistent with DSMB 
recommendations  
 
4.3.4 
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 2 weeks 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 in REDCap.  
Patients who use oral contraceptives or maintenance therapy for comorbidities should 
continue their use. No additional anticoagulants should be administered concomitantly 
with the therapeutic anticoagulation prescribed. Antiplatelet drugs should be continued if 
deemed appropriate by the clinical team. 
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 


 
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Investigator should contact the Medical Monitor if questions arise regarding medications 
not mentioned above. 
 
4.3.5 
Additional Medication  
Any medications required for treating COVID-19 infection or any underlying comorbid 
conditions should continue to be administered as standard of care unless otherwise 
indicated. 
 
4.3.6 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
• No additional anticoagulants should be administered concomitantly with the 
therapeutic anticoagulation prescribed.  
• Antiplatelet drugs should be continued if deemed appropriate by the clinical team. 
 
4.4 
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
Patients should be assessed for toxicity prior to the dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable. Patients will be 
closely monitored for safety and tolerability throughout the study.   
 
4.4.1 
Informed Consent Forms and Screening Log 
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. 
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. 
 
4.4.2 
Medical History, Concomitant Medication, and Demographic Data 
Medical history includes clinically significant diseases and procedures.  All medication 
taken in the last 2 weeks prior to randomization (including prescription, over-the-counter, 
and herbal/homeopathic remedies and therapies) are to be recorded. 


 
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Demographic data, including age, sex, and self-reported race/ethnicity will be collected 
during screening. 
 
4.4.3 
Physical Examinations 
A complete physical examination, performed at screening, should include an evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  
Any abnormality identified at baseline should be recorded in the patient’s medical records. 
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated. Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events in the patient’s medical records and in the REDCap 
EDC. 
 
4.4.4 
Vital Signs 
Vital signs will include measurements of temperature, pulse rate, systolic and diastolic 
blood pressure, respiratory rate, and oxygen saturation. 
Vital signs should be measured within 60 minutes prior to study drug bolus, within 15 
minutes after the bolus, and 60 minutes after the bolus. In addition, vital signs should be 
measured at other specified timepoints as outlined in the schedule of activities (see 
Appendix 1). 
4.4.5 
Laboratory, Biomarkers, and Other Biological Samples 
Please reference Appendix 1 for a summary of lab collection. Samples for the laboratory 
tests referenced below will be sent to the study site's local laboratory for analysis. There 
are no samples that will be sent to a central lab in this study.  
Results from the following are required prior to enrollment (- 3 days): 
• Urine/serum pregnancy test 
o If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test. 
o A woman is considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal state ( 12 continuous 
months of amenorrhea with no identified cause other than menopause), and 
has not undergone surgical sterilization (removal of ovaries and/or uterus). 
• Complete blood count (CBC) 
• Chemistry Panel with liver function tests (LFTs)  
 


 
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Results from the following are required on Day 1 pre-bolus (- 3 days):  
• CBC 
• Chemistry panel 
• COVID-19 panel: D-dimer, C-reactive protein (CRP), Creatine Kinase (CK), Ferritin, 
Troponin, IL-6 
• Coagulation panel: PT/PTT, Fibrinogen, INR 
 
If site has the capacity to run Thromboelastography (TEG), this test should be collected 
immediately prior to administration of TNK/placebo, 10 min (+5min) after, and 24 hours 
after (encouraged, not mandatory). 
• TEG is a noninvasive test that quantitatively measures the ability of whole blood to 
form a clot. The principle of this in vitro test is to detect and quantify dynamic changes 
of the viscoelastic properties of a blood sample during clotting under low shear 
stress. In contrast to traditional, static measurements of hemostasis (e.g., PT, aPTT, 
INR, fibrinogen level, and fibrin degradation products), TEG allows for an assessment 
of near real-time, in-vivo clotting capacity, providing the interpreter information 
regarding the dynamics of clot development, stabilization, and dissolution. It is feasible 
that this test may enlighten us with regard to the DIC picture in COVID-19 infection 
and perhaps shed light on good candidates for the COVID lung injury patients who 
might benefit from thrombolysis.  
• If the pre-bolus TEG is not performed, please do not obtain follow-up TEG samples. 
 
Results from the following labs should be collected 24 hours (+/- 6 hours) post-bolus:  
• COVID-19 labs: D-dimer, CRP, Ferritin, IL-6 
 
Results from the following lab tests should be collected Days 2-7 (or discharge, if sooner): 
• CBC 
• Chemistry panel 
• Results if completed for Standard of Care: LFTs, Coagulation labs, or COVID-19 
labs 
 
If follow-up visits are in person, the following lab tests should be collected: 
• CBC 
• Chemistry panel  
o LFTs are collected only at Day 30 
• SARS-CoV-2-specific neutralizing antibody titer 
o This test is collected only at Day 30 and is strictly for those patients who 
were persons under investigation (PUIs) at time of enrollment and have 
not had any positive SARS-CoV-2 PCR or public health assay at the time 


 
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of the Day 30 visit or if they not had a positive COVID-19 antibody titer in 
the past 40 days. 
 
4.4.6 
Echocardiograms 
Echocardiogram results will be obtained at screening  and 24 +/- 6 hours after the bolus.  
 
4.5 
TREATMENT, PATIENT, AND STUDY DISCONTINUATION 
The bolus is given over 5-10 seconds. If patient has complaints within that timeframe or 
there is evidence of anaphylaxis, the clinical may attempt to discontinue the bolus, if time 
permits.  
 
4.5.1 
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: 
1. Withdrawal of consent 
2. Study termination or site closure 
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. 
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. 
 
4.5.2 
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: 
1. The incidence or severity of adverse events in this or other studies indicates 
a potential health hazard to patients 
2. 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 


 
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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 anticoagulation 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 
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. 
 
5.1.1.1 
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 


 
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Management of Bleeding  
Patients will be excluded for the presence of conditions related to risks of bleeding (as 
outlined in Section 4.1.3 Exclusion Criteria).  
Fibrin, which is part of the hemostatic plug formed at needle puncture sites, may be lysed 
during tenecteplase therapy.  In the event of serious bleeding (not controlled by local 
pressure) in a critical location (intracranial, gastrointestinal, retroperitoneal, or pericardial), 
study drug should be discontinued immediately, and any concomitant heparin or 
antiplatelet agents should be discontinued immediately and appropriate treatment 
initiated.  
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 5.2.4) and should be reported and submitted to the Sponsor 
(Section 5.4 ). 
 
5.1.1.2 
Risk of Hypersensitivity 
Hypersensitivity, including urticarial/anaphylactic reactions, have been reported after 
administration of tenecteplase (e.g., anaphylaxis, angioedema, laryngeal edema, rash, 
and urticaria).  When such reactions occur, they usually respond to conventional therapy.  
Monitor patients treated with tenecteplase during and for several hours after the bolus.  
 
Management of Hypersensitivity 
If symptoms of hypersensitivity occur, appropriate therapy should be initiated. 
 
5.1.1.3 
Thromboembolism 
The use of thrombolytics can increase the risk of thrombo-embolic events in patients with 
high likelihood of left heart thrombus, such as patients with mitral stenosis or atrial 
fibrillation.  
 
5.1.1.4 
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 


 
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infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and 
rhabdomyolysis. 
 
5.1.1.5 
Arrhythmias 
Coronary thrombolysis may result in arrhythmias associated with reperfusion.  These 
arrhythmias (such as sinus bradycardia, accelerated idioventricular rhythm, ventricular 
premature depolarizations, ventricular tachycardia) are not different from those often seen 
in the ordinary course of acute myocardial infarction and may be managed with standard 
anti-arrhythmic measures.  It is recommended that anti-arrhythmic therapy for 
bradycardia and/or ventricular irritability be available when tenecteplase is administered. 
 
5.1.1.6 
Use with Percutaneous Coronary Intervention 
In patients with large ST segment elevation myocardial infarction, physicians should 
choose either thrombolysis or percutaneous coronary intervention (PCI) as the primary 
treatment strategy for reperfusion.  Rescue PCI or subsequent elective PCI may be 
performed after administration of thrombolytic therapies if medically appropriate; however, 
the optimal use of adjunctive antithrombotic and antiplatelet therapies in this setting is 
unknown. 
 
5.1.1.7 
Other Adverse Reactions 
The following adverse reactions have been reported among patients receiving 
tenecteplase in clinical trials.  These reactions are frequent sequelae of the underlying 
disease, and the effect of tenecteplase on the incidence of these events is unknown. 
These events include cardiogenic shock, arrhythmias, atrioventricular block, pulmonary 
edema, heart failure, cardiac arrest, recurrent myocardial ischemia, myocardial 
reinfarction, myocardial rupture, cardiac tamponade, pericarditis, pericardial effusion, 
mitral regurgitation, thrombosis, embolism, and electromechanical dissociation.  These 
events can be life-threatening and may lead to death.  Nausea and/or vomiting, 
hypotension, and fever have also been reported. 
 
5.1.2 
Management of Patients Who Experience Adverse Events 
5.1.2.1 
Management Guidelines 
Guidelines for management of specific adverse events are outlined in Table 1. 


 
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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. 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
5.2.1 
Specification of Safety Variables 
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. 
5.2.2 
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: 
1. 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. 
2. Complications that occur as a result of protocol-mandated interventions (e.g., 
invasive procedures such as cardiac catheterizations). 
3. If applicable, AEs that occur prior to assignment of study treatment 
associated with medication washout, no treatment run-in, or other protocol-
mandated intervention. 


 
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4. Preexisting 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.  
 
5.2.3 
Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
1. It results in death (i.e., the AE actually causes or leads to death). 
2. 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.). 
3. It requires or prolongs inpatient hospitalization. 
4. 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). 
5. It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the IMP. 
6. 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). 
 
5.2.4 
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: 
1. Any intracranial hemorrhage event (symptomatic and/or asymptomatic), if not 
already reported as an SAE  
2. The non-drug specific AESIs: 
• 
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. 
3. 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 


 
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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 
Investigators will seek information on adverse events at each patient contact.  All adverse 
events, whether reported by the patient or noted by study personnel, will be recorded in 
the patient's medical record. 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported. 
After initiation of study treatment, all adverse events will be reported until 30 days after 
study treatment.   
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 and, if applicable, reappears upon re-challenge. 
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 the tenecteplase dose). 


 
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Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert (P.I) or current Tenecteplase Investigator Brochure (I.B.). 
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 
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?"  
 
5.4.2 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs.  Avoid colloquialisms and abbreviations. 
 
5.4.2.1 
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. 
 
5.4.2.2 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 5.3.1), 
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”. 


 
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5.4.2.3 
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”). 
 
5.4.2.4 
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: 
1. Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration)  
2. 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:  
1. Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours. 
 
5.4.2.5 
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. 
Table 2: Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE  


 
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Table 3: 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. 
 
5.4.3 
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): 
1. Temporal relationship of event onset to the initiation of study drug 


 
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2. Course of the event, with special consideration of the effects of dose 
reduction, discontinuation of study drug, or reintroduction of study drug (if 
applicable). 
3. Known association of the event with the study drug or with similar treatments 
4. Known association of the event with the disease under study 
5. 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 
 
Table 4: 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? 
YES 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. 
 
5.4.3.1 
Pregnancies 
If a female patient becomes pregnant within 9014 days after tenecteplase/placebo bolus, 
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 


 
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anomaly/birth defect in a child born to a female patient exposed to tenecteplase/placebo 
should be reported to Genentech, Inc. as an SAE. 
 
5.4.3.2 
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/placebo 
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. 
 
5.4.3.3 
Case Transmission Verification of Single Case Reports 
The Investigator agrees to conduct Case transmission Verfication for the product to 
ensure that all single case reports have been adequately received by Genentech via the 
Investigator emailing Genentech a Quarterly line-listing documenting single case reports. 
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 Investigator 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 Investigator 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 Investigator 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. 
 
5.5 
EXCHANGE OF SINGLE CASE REPORTS 
Investigators are 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.  
Investigators must report all the above mentioned single case reports adequately to 
Genentech within the timelines described below. The completed MedWatch reporting 


 
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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 call via: 
PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm PST) 
 
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. 
These single case reports will be exchanged between the parties as outlined below so 
that regulatory obligation are met.  
All SAEs, AESIs, pregnancy reports other Special Situation Reports and Product 
Complaints (with or without an AE) where the patient has been exposed to the Genentech 
Product, shall be transmitted to Genentech/Roche on a MedWatch or CIOMS I or on 
Genentech approved SAE form within one (1) business day of the awareness date. 
Serious adverse events (SAEs), AEs of Special Interest (AESIs), pregnancy reports other 
Special Situation Reports and Product Complaints (with or without an AE) where the patient 
has been exposed to the Genentech Product, will be sent on a MedWatch form or CIOMS 
I form or on Genentech approved reporting forms to  Genentech Drug Safety. 
Transmission of these reports (initial and follow-up) will be either electronically or by fax 
and within the timelines specified below: 
1. SADRs 
Serious AE reports that are related to the Product shall be transmitted to Roche within 
fifteen (15) calendar days of the awareness date. 
2. Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Roche within 
thirty (30) calendar days of the awareness date. 
3. Pregnancy Reports 
While such reports are not serious AEs or ADRs per se, as defined herein, any reports of 
pregnancy, where the fetus may have been exposed to the Product, shall be transmitted 
to Roche within thirty (30) calendar days of the awareness date. Pregnancies will be 


 
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followed up until the outcome of the pregnancy is known, whenever possible, based upon 
due diligence taken to obtain the follow-up information. 
4. 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. 
5. Special Situation Reports 
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: 
1. Data related to product usage during breastfeeding 
2. 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 
3. Lack of therapeutic efficacy 
4. Drug interaction 
5. Use of a Medicinal Product in a Pediatric and Elderly population  
6. 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. 
 


 
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5.5.1 
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: 
1. Protocol description (and number, if assigned) 
2. Description of event, severity, treatment, and outcome if known 
3. Supportive laboratory results and diagnostics 
4. Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
5.5.1.1 
Follow-up Information 
Additional information may be added to a previously submitted report by any of the 
following methods: 
1. Adding to the original MedWatch 3500A report and submitting it as follow-up 
2. Adding supplemental summary information and submitting it as follow-up with 
the original MedWatch 3500A form  
3. 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 
5.5.2 
Reporting to Regulatory Authorities, Ethics Committees and 
Investigators 
The Sponsor of the Study, Dr. Victor Tapson, 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. 
The Sponsor, Dr. Victor Tapson, will be responsible for the distribution of safety 
information to its own Investigators, where relevant. 
 


 
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5.5.2.1 
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 tenectaplase.  An unexpected adverse event is one that 
is not already described in the tenectaplase Investigator Brochure. 
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 site IRB: 
Antonina Caudill, Study Coordinator, antonina.caudill@cshs.org will communicate 
with IRB.  
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel:  (888) 835-2555 
Fax:  (650) 225-4682 or (650) 225-4630 


 
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5.6 
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  
DEVELOPMENT SAFETY UPDATE REPORT 
Dr. Victor Tapson will forward a copy of the Final Study Report to Genentech upon 
completion of the Study and any publications generated from the study.  
Dr. Victor Tapson, as the Sponsor of the Study, will be responsible for the preparation of 
their own Development Safety Update Report (DSUR) for the Study and for the 
submission of the report to the regulatory authorities and Ethics Committees of the 
concerned Member States, where applicable. Dr. Tapson agrees to share a copy of their 
own DSUR with Genentech as soon as reasonably possible after completion. Genentech 
agrees to forward to Dr. Victor Tapson an executive summary of the Genentech DSUR 
upon request. Furthermore, Genentech agrees that Dr. Victor Tapson may cross-
reference the executive summary of the Genentech DSUR, as applicable. 
Note: Investigators should also report events to their IRB as required. 
 
5.7 
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 
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 
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com  
QUERIES 
Queries related to the Study will be answered by Dr. Victor Tapson; 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.  Dr. Victor Tapson agrees that 
he 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. 


 
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SAFETY CRISIS MANAGEMENT 
In case of a safety crisis, e.g., where safety issues have a potential impact on the 
indication(s), on the conduct of the Study, may lead to labeling changes or regulatory 
actions that limit or restrict the way in which the Product is used, or where there is media 
involvement, the Party where the crisis originates will contact the other Party as soon as 
possible. 
The Parties agree that Genentech shall have the final say and control over safety crisis 
management issues relating to the Product. Dr. Victor Tapson agrees that he shall not 
answer such queries from media and other sources relating to the Product but shall 
redirect such queries to Genentech. 
 
6. 
STATISTICAL CONSIDERATIONS 
6.1 
DETERMINATION OF SAMPLE SIZE 
Our primary endpoint is shock index (heart rate / systolic blood pressure) 6 hours after 
administration of intravenous TNK or matching placebo. We will utilize a 2:1 
randomization scheme, TNK:placebo. As shock index is a continuous measure, data will 
be summarized as numbers, mean, standard deviation (SD), and median, minimum, and 
maximum. We will use the independent samples T-test to compare the two arms with a 
two-sided 0.05 (5%) significance level.  Power and sample size are based on the percent 
change in shock index from baseline to 6 hours. We assume that a clinically important 
difference between arms in mean percent shock index is 10% and that the SD of the 
changes is 12%. A total sample size of 45 (30 TNK / 15 placebo) provides 73% power to 
detect a 10% difference in the mean change in shock index from baseline to 6 hours.  We 
seek to show that the TNK therapy is promising, not to demonstrate a significant 
difference in shock index.  
 
6.2 
PLANNED EFFICACY EVALUATIONS 
The analysis population for the efficacy analyses will consist of all enrolled patients, with 
patients grouped according to their assigned treatment. 
DATA COLLECTED 
The above data used to determine primary and secondary efficacy and safety endpoints 
will be collected. Lab testing will be performed as well. Trends in Hgb and platelets will 
be followed daily as per standard of care (SOC). D-dimer, ferritin, C-reactive protein 
(CRP), IL-6 levels, and coagulation parameters will be performed as is now considered 
SOC in COVID-19 infected patients. Thromboelastography (TEG) will be performed after 
enrollment and before TNK / placebo administration. Patients will be evaluated for acute 
DVT and PE when suspected based on the standard of care. Oxygen saturation values 
and O2 requirements will be followed. The use of mechanical ventilation, ECMO, and 
vasopressors will be determined. The 7-point ordinal score will be determined daily.  (SEE 
SCHEDULE OF ASSESSMENTS). 


 
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6.3 
PRIMARY EFFICACY VARIABLES 
The primary efficacy variable is percentage change in shock index from baseline at 6 
hours after TNK/placebo. 
 
6.4 
SECONDARY EFFICACY VARIABLES 
The secondary efficacy variables are as follows:  
1. Clinical status at 24 hours after administration of TNK/placebo based upon 7-point 
ordinal scale 
2. Clinical status at Day 7 after administration of TNK/placebo based upon 7-point 
ordinal scale 
3. Clinical status at Day 28 after administration of TNK/placebo based upon 7-point 
ordinal scale 
4. O2 sat / FIO2 ratio 6 hours and 24 hours after administration of TNK/placebo 
5. Percentage change in shock index 24 hours after TNK/placebo 
6. Percentage change in RV.LV ratio 24 hours after TNK/placebo 
7. Post-enrollment days with O2 requirement < 4L/min at Day 7 
8. Post-enrollment days with no O2 requirement at Day 7 
9. Change in D-dimer level 24 hours after enrollment  
10. Change in D-dimer level at Day 7 (if obtained) 
11. Change in ferritin, C-reactive protein (CRP), IL-6 levels 24 hours after TNK/ 
placebo  
12. Post-enrollment documented new clinical thrombotic events at Day 7 
13. All-cause mortality at day 7 and day 30 
 
6.5 
SAFETY ANALYSES 
The safety analysis population will consist of all randomized patients who received study 
drug, with patients grouped according to treatment received.  
 
6.6 
EXPLORATORY ENDPOINTS  
1. We will examine characteristics of patients prior to enrollment by measuring static 
measurements of hemostasis including D-dimer, PT, aPTT, INR, fibrinogen level, 
fibrin degradation products, FVIII, antithrombin. In addition,  thromboelastography 
(TEG) will be performed (TEG 6S or 5000, depending on site’s availability).  
2. TEG will be performed immediately prior to, 10 min (+5min) after, and ideally at 24 
(+/- 6) hours after TNK/placebo administration. 
 


 
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6.7 
INTERIM ANALYSIS 
An interim analysis will be performed after 18 patients are enrolled to evaluate patient 
safety. The study will be stopped if there are two critical site bleeds in the interventional 
(TNK) study arm, as adjudicated by the DSMB. 
 
6.8 
METHOD OF ANALYSIS 
The primary and secondary endpoints will be summarized by treatment group using 
descriptive statistics. Continuous variables will be summarized by mean (standard 
deviation and/or median (range), as appropriate. Incidences will be summarized by count 
and percentages. The associated 95% confidence intervals will be provided as 
appropriate. Time to event endpoints will be analyzed by the Kaplan-Meier method with 
the median time to event estimated along with the associated 95% confidence interval. 
For the primary efficacy endpoint, improvement from baseline will be determined by the 
percentage change in shock index at 6 hours from baseline. A 10% improvement in the 
primary endpoint would be considered clinically significant.  
 
6.9 
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. 
 
6.10 
STUDY MEDICAL MONITORING REQUIREMENTS 
This clinical research study will be monitored both internally by the PI and externally by 
the Cedars-Sinai Medical Center IRB.  In terms of internal review, the PI will continuously 
monitor and tabulate AEs.  Appropriate reporting to the Cedars-Sinai Medical Center and 
additional study site IRBs will be made.  The PI of this study will also continuously monitor 
the conduct, data, and safety of this study to ensure that: 
1. Interim analyses occur as scheduled, 
2. Stopping rules for toxicity and/or response are met, 
3. Risk/benefit ratio is not altered to the detriment of the patients, 
4. Appropriate internal monitoring of AEs and outcomes is done, 


 
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5. Over-accrual does not occur, 
6. Under-accrual is addressed with appropriate amendments or actions, and 
7.  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. 
 
6.11 
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. 
 
6.12 
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 Cedars-Sinai Medical Center IRB. 
 
7. 
ETHICAL CONSIDERATIONS 
7.1 
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. 


 
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The signed consent form must remain in each patient’s study file and must be available 
for verification by study monitors at any time. 
 
7.2 
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.). 
 
7.3 
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. 


 
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8. 
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33. Paranjpe I, Fuster V, et al. Association of treatment dose anticoagulation with in-
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Berkhemer OA, Fransen PSS, Beumer D, et al. A randomized trial of intraarterial 
treatment for acute ischemic stroke. N Engl J Med 2015;372:1009−1018. 
Bivard A, Huang X, McElduff P, et al. Impact of computed tomography perfusion imaging 
on the response to tenecteplase in ischemic stroke: analysis of 2 randomized 
Controlled trials. Circulation 2017;135(5):440−448. 
Campbell BCV, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke 
with perfusion-imaging selection. N Engl J Med 2015;372:1009−1018. 


 
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Campbell BCV, Carpenter JS, Cognard C, et al. Multisociety consensus quality 
improvement revised consensus statement for endovascular therapy of acute 
ischemic stroke. Int J Stroke 2018 [Epub ahead of print]. 
Centers for Disease Control and Prevention (CDC). Stroke facts (2017). Available at: 
https://www.cdc.gov/stroke/facts.htm. 
Churilov L, Amup S, Johns H, et al. An improved method for simple, assumption-free 
ordinal analysis of the modified Rankin Scale using generalized odds ratios. Int J 
Stroke 2014;9(8):999−1005. 
Coutts SB, Dubuc V, Mandzia J, et al. Tenecteplase-tissue-type plasminogen activator 
evaluation 
for 
minor 
ischemic 
stroke 
with 
proven 
occlusion. 
Stroke 
2015;46(3):769−774. 
DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med 
1994;13(13−14):1341−1352. 
Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity 
on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: 
a meta-analysis of individual patient data from randomised trials. The Lancet 
2014;384(9958):1929−1935. 
Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular 
treatment of ischemic stroke. N Engl J Med 2015;372:1019−1030. 
Haley EC Jr, Lyden PD, Johnston KC, et al. A pilot dose-escalation safety study of 
tenecteplase in acute ischemic stroke. Stroke 2005;36(3):607−12. 
Haley EC Jr, Thompson JLP, Grotta JC, et al. Phase IIB/III trial of tenecteplase in acute 
ischemic stroke: result of a prematurely terminated randomized clinical trial. Stroke 
2010;41(4):707−11. 
Howard G, Waller JL, Voeks JH. A simple, assumption-free, and clinically interpretable 
approach for analysis of modified Rankin outcomes. Stroke 2012;43:664−669. 
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. 
Huang X, MacIsaac R, Thompson JL, et al. Tenecteplase versus alteplase in stroke 
thrombolysis: An individual patient data meta-analysis of randomized controlled 
trials. Int J Stroke 2016;11(5):534−543. 
Jovin TG, Liebeskind DS, Gupta R, et al. Imaging-based endovascular therapy for acute 
ischemic stroke due to proximal intracranial anterior circulation occlusion treated 
beyond 8 hours from time last seen well: retrospective multicenter analysis of 237 
consecutive patients. Stroke 2011;42(8):2206−2211. 
Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset 
in ischemic stroke. N Engl J Med 2015;372:2296−2306. 


 
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Kate 
M, Wannamaker 
R, Kamble 
H, 
et 
al. 
Penumbral imaging-
based thrombolysis with tenecteplase is feasible up to 2 
hours after 
symptom onset. J Stroke 2018;20(1):122−30. 
Lansberg MG, Cereda CW, Mlynash M, et al. Diffusion and Perfusion Imaging Evaluation 
for Understanding Stroke Evolution 2 (DEFUSE 2) Study Investigators. Response 
to endovascular reperfusion is not time-dependent in patients with salvageable 
tissue. Neurology 2015;85(8):708−714. 
Logallo N, Kvistad CE, Thomassen L. Therapeutic potential of tenecteplase in the 
management of acute ischemic stroke. CNS Drugs 2015;29:811−818. 
Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase for management 
of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded 
endpoint trial. Lancet Neurol 2017;16(10):781−788. 
Nogueira RG, Jadhav AP, Haussen DC, et. al. Thrombectomy 6 to 24 hours after stroke 
with mismatch between deficit and infarct. N Engl J Med 2018;378:11−21. 
Parsons MW, Levi CR. Reperfusion trials for acute ischaemic stroke. Lancet 
2012;380(9843):706−708. 
Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the Early Management 
of Patients with Acute Ischemic Stroke: A Guideline for Healthcare Professionals 
from the American Heart Association/American Stroke Association. Stroke 
2018;49(3):e46−e110. 
Saver JL, Goyal M, Bonafe A, et al. Solitaire with the Intention for Thrombectomy as 
Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME) trial: 
protocol for a randomized, controlled, multicenter study comparing the Solitaire 
revascularization device with IV tPA with IV tPA alone in acute ischemic stroke. Int 
J Stroke 2015;10(3):439−448. 
Ovbiagele B, Goldstein LB, Higashida RT, et al. Forecasting the future of stroke in the 
United States: a policy statement from the American Heart Association and 
American Stroke Association. Stroke 2013;44(8):2361−7 


 
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53 
APPENDIX 1: SCHEDULE OF ASSESSMENTS 
Schedule of Assessments  
1. 
All patients must be on prophylactic anticoagulation; enoxaparin 40 mg once-daily is preferred. 
2. 
Screening and Day 30 Chemistry panel must include liver function tests. If screening labs are performed within 3 days of Day 1, they may be used as Day 1 labs as well. 
3. 
The labs referenced are required Day 1 (pre-bolus) and 24 hours (+/- 6 hours after the bolus). For Day 1 (pre-bolus) labs, labs performed within 3 days of Day 1 may be used. On Days 2-7, data 
should be collected only if labs were performed as standard of care. 
4. 
The labs referenced are required Day 1 (pre-bolus), but labs performed within 3 days of Day 1 may be used. On Days 2-7, data should be collected only if labs were performed as standard of care. 
5. 
This test will only be obtained by sites that have the capacity to run TEG.TEG will be performed immediately prior to study drug administration and 10min(+5min) after the bolus. The 24 hour TEG is 
encouraged, but not mandatory. If the pre-bolus TEG is not performed, please do not obtain follow-up TEG samples. 
6. 
In-person visits are preferred but recognizing quarantine and other factors may limit the subject’s ability to return to the site for the visit. In this case, these visits may be conducted by phone / 
telemedicine and blood will not be collected. Labs at Day 30 are preferred but not mandatory. Any relevant exam finding (e.g., leg swelling, discoloration) will be noted by in-person exam or photo / 
telemedicine. 
7. 
This test will only be obtained for persons under investigation (PUIs) who did not otherwise have a COVID positive PCR or public health assay prior to their Day 30 visit and have not had a positive 
C19 titer within the past 40 days. 
 Timepoint 
Screening 
Study intervention period 
Follow-Up6 
Day/hour +/- window 
-3 or 1 
Day 1  
(pre-bolus) 
Day 1  
(post-bolus) 
24 hours  
(+/- 6 hours) 
Day 2-7  
or until 
discharge 
Day 14  
(+/- 2 days) 
Day 30  
(+/- 4 days)  
Informed Consent 
X 
 
 
 
 
 
 
Demographics and Medical History collection 
X 
 
 
 
 
 
 
Complete physical exam (collected from medical record) 
X 
 
 
 
 
 
 
Targeted exam (if applicable/indicated) 
 
 
 
 
X 
X 
X 
Review SARS-CoV-2 results 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Prophylactic anticoagulation1  
 
X 
 
X 
X 
 
 
Administration of TNK / placebo  
 
X 
 
 
 
 
 
Vital signs (including oxygen saturation)  
 
X 
X 
 
X 
X 
X 
Clinical data collection 
 
X 
X 
 
X 
X 
X 
Echocardiogram 
X 
 
 
X 
 
 
 
Targeted medication review  
 
X 
 
 
X 
X 
X 
Adverse event evaluation 
 
X 
X 
 
X 
X 
X 
Safety Labs: CBC, Chemistry  
X2 
X 
 
 
X 
X 
X 
Other Labs: CRP, Ferritin, IL-6, Fibrinogen, D-dimer3 
 
X 
 
X 
X 
 
 
Collection of lab results performed for standard of care 
(Liver Function Tests, PT/PTT,  Troponin, Creatinine 
Kinase, INR)4 
 
X 
 
 
X 
 
 
Pregnancy testing for females of childbearing potential 
X 
 
 
 
 
 
 
TEG (thromboelastography)5 
 
X 
X 
X 
 
 
 
SARS-CoV-2-specific neutralizing antibody titer7 
 
 
 
 
 
 
X 


  
Tenecteplase⎯Cedars-Sinai Medical Center, Los Angeles, CA 
Protocol ML42522 Version 5.0 
54 
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 
 
 


  
Tenecteplase⎯Cedars-Sinai Medical Center, Los Angeles, CA 
Protocol ML42522 Version 5.0 
55 
APPENDIX 3: FDA MEDWATCH 3500 FORM 
This form is included in the study start-up zip file to be sent to sites via email. 
 
 

ICF_001.pdf: 
STUDY00000800 CONSENT VERSION 3.1 
Page 1 of 17 
CONSENT FORM FOR RESEARCH
Title: LOW-DOSE TENECTEPLASE IN COVID-19 PATIENTS WITH ACUTE PULMONARY 
EMBOLISM: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL
STUDY SUPPORT PROVIDED BY: 
GENETECH, INC.
PRINCIPAL INVESTIGATOR: 
VICTOR TAPSON, MD
STUDY PHONE NUMBER AT CSMC: 
919-971-6441
AFTER HOURS CONTACT (24 HOURS):  
310-423-5000 (ASK FOR THE PULMONOLOGIST ON CALL)
This research study is sponsored by Genentech, Inc. Genentech, Inc. only reimburses Cedars-Sinai 
Medical Center for the costs associated with running the study; Genentech, Inc. is not providing 
additional compensation to Cedars Sinai Medical Center or the Principal Investigator for their 
participation in the study.
1.
WHAT IS THE PURPOSE OF THIS RESEARCH STUDY?
We are doing this study to examine the safety and effectiveness of adding a low dose of tenecteplase 
(TNK), a thrombolytic drug (clot buster), to standard therapy for patients with COVID-19 who have 
a blood clot. We want to know if and how much a patient’s heart rate and blood pressure can be 
improved after treatment with tenecteplase (TNK), as compared to the standard of care anticoagulant 
(blood thinning) therapy alone. TNK is a thrombolytic drug which means the drug is designed to 
dissolve dangerous clots in blood vessels to improve the blood flow and prevent damage to tissue and 
organs. The standard of care therapy for pulmonary embolism is either heparin or enoxaparin which 
are anticoagulants. Anticoagulants are commonly referred to as blood thinners. They are used to 
prevent and reduce the clotting of blood.
You are being asked to take part in this research study because you have a diagnosis of COVID-19 
and a blood clot in one or both of your pulmonary arteries (large blood vessels in your chest) that is 
interfering with blood flow through your heart and lungs.
The study will enroll up to 45 people in total.
This research study is designed to test the investigational use of tenecteplase (TNK). This drug is 
approved by the U.S. Food and Drug Administration (FDA) for breaking down blood clots found in 
the heart. However, it is not approved by the FDA for breaking down clots found in the lung at the 
low dose of the drug being administered in this study.
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STUDY00000800 CONSENT VERSION 3.1 
Page 2 of 17 
2.
WHAT WILL HAPPEN DURING THE STUDY?
This section provides a general overview of what will happen during your participation in this study.  
Information included below should be considered along with the flowchart of procedures attached as 
an Appendix.  
The flowchart shows a timeline for research-related or standard of care procedures that are involved 
in your participation in this study.  Research-related procedures are those performed solely for the 
research. They would not be performed if you did not take part in the study. Standard of care 
(routine) procedures would be performed both as part of this study and if you do not participate in 
this study.   
    
A table describing common medical procedures done solely for the purposes of monitoring and 
assessing your condition during this study is attached as an Appendix to the end of this consent form.  
Standard of care procedures that will be repeated or done at greater frequency are listed in the flow 
chart Appendix. 
 
Overview of study:

Your doctor will review your medical record, lab results and other test results to determine if 
you are able to participate in this study.

An echocardiogram will be performed once to confirm your eligibility, and once more about 
24 hours (give or take 6 hours) after bolus completion (if you proceed with study participation). 
A bolus is the very quick administration of drugs directly into your bloodstream using 
intravenous (IV) lines.

You will be randomized to one of two treatment groups. See below for more detailed 
explanation.

You will either receive TNK bolus along with standard of care or receive placebo bolus along 
with standard of care.

Your vital signs (temperature, respiratory rate, heart rate, blood pressure, and oxygen 
saturation level) and medical records data will be collected immediately prior to the bolus, 
within 15 minutes after the bolus, 60 minutes after the bolus, about 24 hours (give or take 6 
hours) after bolus completion, and each day of your hospital stay.

You will also be assessed for adverse events, including bleeding complications, during your 
hospitalization and if any occur, the information will be recorded in the study record.

A blood draw to collect biomarkers may be performed before your drug bolus, and 10 minutes, 
24 hours after study treatment administration, throughout your hospitalization, and possibly 
14/30 days after receiving study treatment.
This is a randomized, double-blind, placebo-controlled research study.

“Randomized” means that you will be assigned to a study group by chance.  You will be 
randomized into one of two study groups, and will have a one in three chance of being placed 
in the placebo group (Group 1) and a two in three chance of being placed in the intervention 
group (Group 2).

“Double-Blind” means neither you nor the researchers will know what group you are assigned 
to.

“Placebo-Controlled” means the study will compare the effects (good or bad) of tenecteplase 
(TNK) against the effects of a placebo (an inactive substance, such as, saline) on the condition 
being studied in this research.  
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STUDY00000800 CONSENT VERSION 3.1 
Page 3 of 17 
This study has 2 study groups:

Group 1 will get the usual anticoagulation therapy drug (heparin or enoxaparin) to treat 
pulmonary embolism plus a placebo injection, that will not have any active medication.

Group 2 will get the usual anticoagulation therapy drug (heparin or enoxaparin) to treat 
pulmonary embolism, plus the study drug (TNK). 
A computer will randomly assign you to a study group. This is done because no one knows if the 
results experienced by the participants in one study group are better, the same, or worse than the results 
experienced by participants in the other. Once you are put in one group, you cannot switch to another 
group. Neither you nor your doctor can choose the group in which you will be placed.
Either of these different approaches could help your condition but could also cause side effects. This 
study will allow the researchers to learn whether the different approaches are better, the same, or worse 
than the current standard of care.
In order to properly follow the study’s protocol (research plan), all participants will receive treatments 
and procedures that have been pre-determined by the protocol. In effect, the protocol describes which 
medications or procedures you will receive, rather than those decisions being made by your personal 
doctor or based on your preference. There may be options available outside of this study that you will 
not be able to receive while participating in this study.
Another purpose of this study is for researchers to learn if a biomarker test is helpful in understanding 
the process of how COVID-19 pneumonia changes over time. A biomarker is a biological molecule 
found in blood, other body fluids, or tissues that may be a sign of a condition or disease. An extra tube 
of blood will be drawn for the biomarker test, once at your baseline visit and once at your first follow-
up visit 14 days after hospital discharge. The biomarker test will not be used to make decisions about 
eligibility or treatment assignment. The researchers do not know if using the biomarker test is better, 
the same, or worse than if you were enrolled in this study without using the biomarker test.
Another way to find out what will happen to you during the study is to read the chart below. Start 
reading at the left side and read across to the right, following the lines and arrows.
Randomization
(The computer will 
randomly assign you to a 
study group)
Group (Arm) 2
Anticoagulation therapy
 + TNK
(Study group)
You agree to take 
part in the study
Group (Arm) 1
Anticoagulation therapy
+ Placebo
(Usual approach group)
If you are assigned to the control group, you will be followed as you receive the care generally 
followed for individuals with your condition.  Standard (routine) care for controls will involve IV 
infusion of heparin or injection of enoxaparin.
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STUDY00000800 CONSENT VERSION 3.1 
Page 4 of 17 
How long will you be in the study?
We think you will be in this study for about 40 days. The total time includes every day that you are 
still hospitalized and follow-up after you are discharged. After you are discharged from the hospital, 
we would like you to visit the office/clinic (in-person or via phone/telemedicine) 2 times at Day 14 
and Day 30.
3.
WHAT ARE THE POSSIBLE RISKS?
Risks of common medical procedures performed solely for research purposes are described in a table 
attached to the end of this consent form as an Appendix. Side effects and risks of standard of care 
procedures are not described in this consent form. 
This section describes the possible risks and/or discomforts we anticipate you could experience that 
are related to the study procedures. 
Unknown Risks
There may be other side effects or risks that we cannot predict.  Many side effects may go away shortly 
after the study medication or procedure is stopped.  However, in some cases they can be serious, long-
lasting, permanent, and/or fatal.
Risks of heparin
Likely, Some May Be Serious (Occurs in greater than 20% and up to 100 % of people)

None
Less Likely, Some May Be Serious (Occurs in >3% - 20 % of people)

Bleeding in various parts of the body

Allergic reaction such as itching or hives, swelling in your face or hands, swelling or tingling in 
your mouth or throat, chest tightness, trouble breathing

Decreased platelet count

Abnormal blood clotting
Rare AND Serious (Occurs in 3% or less of people and may require hospitalization or may be 
irreversible, long-term, life-threatening or fatal)

Major bleeding
Heparin-induced Thrombocytopenia (HIT) is an immune system reaction from heparin which may 
cause a decrease of platelet counts and blood clots.  HIT may occur up to several weeks after heparin 
therapy completion.  You will not be enrolled in this study if you have a known history of HIT.
Risks of enoxaparin
Likely, Some May Be Serious (Occurs in greater than 20% and up to 100% of people)
In the list below, “Serious,” refers to those side effects that 
may require hospitalization, may be irreversible, long-term, 
life-threatening or fatal.
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STUDY00000800 CONSENT VERSION 3.1 
Page 5 of 17 

None
Less Likely, Some May Be Serious (Occurs in >3% - 20% of people)

Bleeding in various parts of the body

Allergic reaction such as itching or hives, swelling in your face or hands, swelling or tingling in 
your mouth or throat, chest tightness, trouble breathing 
Rare AND Serious (Occurs in 3% or less of people and may require hospitalization or may be 
irreversible, long-term, life-threatening or fatal)

Decreased platelet count, which may cause abnormal blood clotting

Major bleeding
In addition to the risks summarized above, the FDA has issued the following warning for 
enoxaparin:
Risks of tenecteplase 
Likely, Some May Be Serious (Occurs in greater than 20% and up to 100% of people)

Minor bleeding in parts of the body other than the brain
Less Likely, Some May Be Serious (Occurs in >3% - 20% of people)

Major bleeding in parts of the body other than the brain

Minor bruising 
Rare AND Serious (Occurs in 3% or less of people and may require hospitalization or may be 
irreversible, long-term, life-threatening or fatal)

Stroke and brain bleeds

Major bleeding in the urinary tract, the gut tract, and/or at the site of catheter puncture

Cholesterol embolization syndrome, which includes features such as gangrene in toes and fingers, 
heart attack, and acute kidney failure. This condition is also associated with other thrombolytic 
therapies and with invasive vascular procedures, such as vascular surgery and cardiac 
catheterization 
FDA Blackbox warning: Spinal/Epidural Hematoma
Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular 
weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal
puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when 
scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or 
spinal hematomas in these patients include:
• Use of indwelling epidural catheters
• Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs 
(NSAIDs), platelet inhibitors, other anticoagulants
• A history of traumatic or repeated epidural or spinal punctures
• A history of spinal deformity or spinal surgery.
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological 
compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial 
intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.
CSMC IRB No: STUDY00000800 / MOD00002717
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STUDY00000800 CONSENT VERSION 3.1 
Page 6 of 17 

Allergic reaction such as itching or hives, swelling in your face or hands, swelling or tingling in 
your mouth or throat, chest tightness, trouble breathing
Reproductive and Lactation Risks 
Taking part in this research study can affect an unborn baby. Therefore, you should not become 
pregnant or father a baby while on this study. If you or your partner is capable of becoming pregnant 
you will need to use birth control. Check with the researcher about approved birth control methods to 
use while participating in this study.   
Women should not breastfeed a baby while on this study.  
Collection of Pregnancy Outcomes 
If you become pregnant during the study, or if you are a male subject whose female partner becomes 
pregnant, we will collect information on the outcome of the pregnancy including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
abnormalities, or complications, and the health status of your child. By signing this consent, you are 
agreeing to have this information about you and your child collected from your medical records in the 
rare case that you or your female partner become pregnant during your participation in this research 
study, however, you are always free to withdraw your consent to participate in any research procedure. 
Study Design Risks
Participation in a double-blind study means that you may not be able to participate in other, similar 
trials since unblinding would generally only occur for emergent, life-threatening situations. We might 
not be able to tell you if you received the study drug or placebo in a situation where you would like to 
qualify for another research study. Because you may not know the study group to which you were 
assigned, in the future should you wish to participate in a different study that requires knowing what 
drug you received in this study, you may not be eligible to participate in the different study.
Follow-up Visit for Discontinuing Participants
While you are free to discontinue your participation at any time, we encourage you to complete a Final 
Study Visit.  During this visit, we will conduct tests to collect safety data, and discuss any information 
that may be important to share with your treating physician.
4.
ARE THERE BENEFITS IN TAKING PART IN THE STUDY?
If you agree to take part in this research study, there may or may not be direct medical benefit to you.  
The possible benefit of taking part in the research study is that your medical status, as measured by 
your heart rate and blood pressure, may improve with a low dose, clot-busting medication when given 
alongside your standard of care treatment for your condition. However, no benefit is guaranteed. It is 
possible that your condition may remain unchanged or even get worse.
We hope the information learned from this research study will benefit other individuals who have 
COVID-19 and pulmonary embolism in the future by helping us to learn whether or not tenecteplase 
can help improve recovery.  
5.
WILL I BE INFORMED OF RESEARCH RESULTS?
CSMC IRB No: STUDY00000800 / MOD00002717
CSMC Date Effective: 1/14/2021


STUDY00000800 CONSENT VERSION 3.1 
Page 7 of 17 
  
The imaging procedure(s) in this study are for research purposes only. However, the techniques used 
are the same as those used in standard clinical imaging procedures. The imaging results may be shared 
with you and may be placed in your Cedars-Sinai medical record. 
Some of the research tests done in this study follow standard clinical procedures and are performed in 
certified clinical labs. These test results may be shared with you and may be placed in your Cedars-
Sinai medical record. Other research tests done in this study are for research purposes only and are 
performed in a research only lab where the results are not intended for clinical use. These research-
only results will not be shared with you or included in your Cedars-Sinai medical record. 
Unanticipated Incidental Findings
If, unexpectedly, we find that results of your research procedures could suggest important medical 
information and we determine there is something you or your doctors can do in response to this finding, 
we will contact you using the last contact information provided by you. If necessary, we may 
recommend additional clinical testing to confirm the research finding. The cost of any additional 
testing and any related treatment will be your responsibility.
6.
WHY WOULD MY PARTICIPATION BE STOPPED?
Your participation in this study may be stopped at any time by the researcher or the sponsor without 
your consent for any reason, including:

The study is stopped or suspended;

Funding for the study is reduced, stopped or withdrawn;

If it is in your best interest;

You do not consent to continue in the study after being told of changes in the research that may 
affect you;

You do not follow the study procedures;

The incidence or severity of adverse events in this or other studies indicates a potential health 
hazard to patients;

Patient enrollment is unsatisfactory.
You may choose (or you may be required) to withdraw from certain parts of the study, but invited to 
continue with other parts.  For example, you might stop taking a study drug, but continue with follow-
up visits or allow us to continue to collect data from your medical records.  Separate written consent 
will be requested if your continued participation will involve procedures not described in this consent 
form. If you withdraw from the study, the data collected to the point of withdrawal remains part of the 
study database and may not be removed.
7.
ARE THERE ANY OTHER OPTIONS?
Your participation is voluntary, so you have the right to decline to participate or to withdraw from this 
research study at any time without any penalty or loss of benefits to which you would be entitled 
outside of the study.  Choosing not to participate will not affect the care you receive at Cedars-Sinai 
Health System.
If you decide not to take part in this study, you have other choices. For example:
CSMC IRB No: STUDY00000800 / MOD00002717
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STUDY00000800 CONSENT VERSION 3.1 
Page 8 of 17 

you may choose to be treated following the usual clinical approach, which is receiving heparin IV 
infusions or enoxaparin injections. 

you may choose to take part in a different study at CSMC or elsewhere, if one is available

you could decide not to be treated.

you may choose to pursue supportive or palliative care for your condition. Such care is focused on 
reducing suffering and improving the quality of life of individuals with chronic or life-threatening 
illnesses.  The primary intent of palliative care is not to cure a disease or to prolong life. Palliative 
therapy is focused primarily on managing symptoms. 
The researcher will discuss these options and their risks and benefits with you.
8.
WILL MY INFORMATION BE KEPT CONFIDENTIAL?
We will do our best to make sure that the personal information collected as part of this study is kept 
private. However, we cannot guarantee total privacy. A copy of your research consent and 
authorization forms may be filed in your electronic medical record at CSMC. Your personal 
information may be given out if required by law. If information from this study is published or 
presented at scientific meetings, your name and other identifiable personal information will not be 
used. Organizations that may look at and/or copy your medical records for research oversight, quality 
assurance, and data analysis include: accrediting agencies, government and regulatory groups (such as 
Food and Drug Administration (FDA), Office for Human Research Protections (OHRP), etc.), safety 
monitors, companies that sponsor the study, and authorized representatives of the sponsor. 
Attached to this consent form is an “Authorization Form” that outlines with whom your information 
may be shared for the purposes of this research and under what circumstances.  
We might share your information and/or research samples collected in this study with other researchers 
at Cedars-Sinai, other academic institutions, or third party commercial entities for future research 
without additional informed consent from you. Information that identifies you will be removed and 
will not be shared with other researchers or anyone outside of Cedars-Sinai. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Website will not include information that can identify you.  At most, the Website will 
include a summary of the results.  You can search this Website at any time.
9.
WHAT IF I BECOME ILL OR INJURED BECAUSE OF TAKING PART IN THIS STUDY?
Contact your study doctor at once if you feel that you are ill or have been injured because of taking 
part in this study.  If it is a medical emergency, call 911 or go to an emergency room.  Promptly notify 
your study doctor of your situation at the phone number listed on page 1 of this consent form.
Who pays for my research related illness or injury?
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STUDY00000800 CONSENT VERSION 3.1 
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Cedars-Sinai has no plans to pay for costs associated with the treatment of research-related injury or 
illness.  We will make every effort to seek reimbursement from your health plan.  However, you will 
be responsible for any deductibles and co-payments required under your health plan and for any claims 
ultimately denied by your health plan.  Financial assistance may be available under Cedars-Sinai’s 
Charity Care Policy and Procedure.  If you feel that you have had a research-related injury and need 
financial assistance, please contact the IRB Office at 310-423-3783.  You do not waive any of your 
legal rights by signing this form.
10.
FINANCIAL CONSIDERATIONS
Costs of Participation
Please review the attached Appendix flowchart for a listing of items, drugs and services that will be 
billed to you and/or your insurance and those that will be covered by the study sponsor.
Only items, drugs and services that are reasonable and necessary for your medical care throughout the 
study will be billed to your insurance. You remain responsible for all deductibles, co-pays, and 
balances under your health benefit plan. If your insurance company does not pay, you will be billed 
for those charges.  You should check with your health benefit plan if you have questions or concerns 
about your insurance coverage.
Compensation for Participating
You will be paid $50 for each research study visit.  The total amount you will receive if you complete 
the whole study is $100. If you do not complete the entire research study, you will only be paid for 
those visits and procedures you do complete.
You may be required to complete a W-9 Form in order to receive payment.  The W-9 Form will be 
maintained by our accounting department at Cedars-Sinai.  Although any amount of payment may be 
reportable (check with a tax professional if you have questions about your obligations), if total 
payment by Cedars-Sinai is $600 or more in a calendar year, a 1099 Form will be filed with the IRS 
in accordance with federal tax law.
If you are a Cedars-Sinai employee, you should provide your employee identification number to the 
research team so that your payment can be appropriately processed through Payroll.  For your own 
protection and to comply with tax laws, your payment for participation will be reported to the IRS 
together with other compensation you receive from Cedars-Sinai.
Financial Interest in the Research
The PI and institution have no potential financial conflict of interest with respect to this study.
11.
WHAT IF I HAVE QUESTIONS OR PROBLEMS?
Please contact the investigator listed on the first page of this form for questions or concerns about the 
research.  
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STUDY00000800 CONSENT VERSION 3.1 
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If you have questions, problems, or concerns that you want to discuss with someone who is not 
associated with this study, or want to offer suggestions or feedback, please contact:
Cedars-Sinai Human Research Protection Program (HRPP)
Phone: (310) 423-3783
Email: ResearchConcerns@cshs.org
The Cedars-Sinai HRPP has been established to protect the rights and welfare of research participants.  
You may also contact the Cedars-Sinai HRPP if you want to offer input or obtain information 
regarding the study.
12.
CONSENT PROVISIONS 
If you sign this form below, it means that:  
(1) You have taken the time to carefully read and understand the information presented in this 
informed consent form; you should discuss it with others, and if appropriate seek a second opinion 
to make an informed decision;
(2) The information concerning the research study and its involved procedures has been fully 
explained to you and your questions have been answered to your satisfaction; 
(3) You have received and understand all of the information you desire regarding your participation 
in the research study; 
(4) You have considered the potential risks, any anticipated benefits and alternatives (and their 
relative risks and benefits) of participation;
(5) You are voluntarily agreeing to participate in this research study;
(6) You understand that by consenting to participate in the research you are not giving up any of your 
legal rights; 
(7) You understand that you have the right to be informed of significant new findings related to this 
research study which may affect your willingness to continue participating in this study; and
(8) You have been provided with a copy of the “Experimental Subject’s Bill of Rights”, if applicable 
to this research study, and have been provided with an opportunity to ask questions regarding the 
Bill of Rights.
We will give you a copy of this signed and dated consent form and the Experimental Subject’s Bill of 
Rights.
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STUDY00000800 CONSENT VERSION 3.1 
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SIGNATURE PAGE
Consent Form for Research and 
Authorization for Use and Disclosure of Identifiable Health Information 
(Research)
SIGNATURE BY THE PARTICIPANT OR LEGAL REPRESENTATIVE:
Main Research Study: I hereby agree to participate in the research study described 
to me during the informed consent process and described in this informed consent 
form.  You will be given a signed copy of this form.
Name of Participant (Print)
Signature of Participant
Date of Signature
If participant is unable to sign the form, please state the reason below:
Signature of Legal Representative   Relationship to the Participant      Date of Signature
Authorization for Use and Disclosure of Identifiable Health Information 
(Research): I hereby agree that my identifiable health information may be used 
and/or disclosed in accordance with the “Authorization for Use and Disclosure of 
Identifiable Health Information (Research)” form attached as an Appendix to this 
form.
Name of Participant (Print)
Signature of Participant
Date of Signature
If participant is unable to sign the form, please state the reason below:
Signature of Legal Representative   Relationship to the Participant      Date of Signature
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STUDY00000800 CONSENT VERSION 3.1 
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SIGNATURE BY THE INVESTIGATOR: I attest that all the elements of informed 
consent described in this form have been discussed fully in non-technical terms with 
the participant.  I further attest that all questions asked by the participant were 
answered to the best of my knowledge.   
Name of Investigator (Print)
Signature
Date Signed
SIGNATURE BY THE INTERPRETER/WITNESS (if applicable)
(Signature of an interpreter is only required when a non-English speaking subject is 
consented with the assistance of an interpreter. The interpreter may be any person 
who is conversant in both English and the language of the Non-English speaking 
subject, such as the interpreter (the certified hospital interpreter), study staff, a 
family member, or other person. The interpreter signs the consent forms to confirm 
that the oral interpretation occurred.)
Signature of Interpreter/Witness                                                   Date of Signature
SIGNATURE BY THE IMPARTIAL WITNESS (if applicable)
Signature of an impartial witness is required when an English-speaking subjects 
who has been determined to have capacity to consent is unable to read or physically 
sign the consent form, but choses to indicate via a “mark” or verbally that he/she 
agrees to participate. The impartial witness signs the consent form to confirm that 
an oral consent process occurred and that the individual verbally consented to 
participate in the research.
Signature of Impartial Witness                                           
Date of Signature
TO BE MARKED AT TIME OF SIGNATURE:  
Consent obtained:
☐ From non-English speaking individual with assistance of interpreter
☐ From individual who is not physically able to sign the consent document
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STUDY00000800 CONSENT VERSION 3.1 
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APPENDIX: EXPERIMENTAL SUBJECT’S BILL OF RIGHTS
In accordance with California Health and Safety Code 24172, any person who is required to consent 
to participate as a subject in a research study involving a medical experiment or who is requested to 
consent on behalf of another has the right to:
1.
Be informed of the nature and purpose of the experiment.
2.
Be given an explanation of the procedures to be followed in the medical experiment, and any 
drug or device to be utilized.
3.
Be given a description of any attendant discomforts and risks to the subject reasonably to be 
expected from the experiment.
4.
Be given an explanation of any benefits to the subject reasonably to be expected from the 
experiment, if applicable.
5.
Be given a disclosure of any appropriate alternative procedures, drugs or devices that might be 
advantageous to the subject, and their relative risks and benefits.
6.
Be informed of the avenues of medical treatment, if any, available to the subject after the 
experiment if complications should arise.
7.
Be given an opportunity to ask any questions concerning the experiment or the procedure 
involved.
8.
Be instructed that consent to participate in the medical experiment may be withdrawn at any 
time and the subject may discontinue participation in the medical experiment without 
prejudice.
9.
Be given a copy of any signed and dated written consent form used in relation to the 
experiment.
10.
Be given the opportunity to decide to consent or not to consent to a medical experiment without 
the intervention of any element of force, fraud, deceit, duress, coercion, or undue influence on 
the subject’s decision.
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AUTHORIZATION FOR USE AND DISCLOSURE OF
IDENTIFIABLE HEALTH INFORMATION FOR RESEARCH

USE AND DISCLOSURE OF HEALTH INFORMATION
If you agree to this Authorization, you give permission to the Sponsor, Principal 
Investigator, other investigators and their research team described in the Consent 
Form for Research (“Research Team”) to use or disclose your identifiable health 
information (“private information”) for the research study titled “LOW-DOSE 
TENECTEPLASE IN COVID-19 PATIENTS WITH ACUTE PULMONARY 
EMBOLISM” which is described in the Consent Form for Research (“Consent 
Form”) to which this Authorization is attached. In particular, you authorize the 
research team acting under the direction of the Principal Investigator to review your 
medical records and collect your private information from the following sources: 
☒ Laboratory tests
☐ Pathology reports
☒ Imaging reports (e.g., x-rays or scans)
☐ Photographs or videos of your image
☒ Doctor/clinic records  
☒ Hospital/medical records
☐ Mental health records
☐ Billing records
☐ Other tests or other types of medical information:  

WHO WILL HAVE ACCESS TO YOUR PRIVATE INFORMATION?
Your private information will be used by and/or shared with the Research Team.  
In addition to the research team, if applicable, the following parties may receive your 
private information and inspect your records: 

The reviewing Institutional Review Boards and Cedars-Sinai offices with authority 
to oversee research compliance.

U.S. government agencies, such as the Food and Drug Administration and the 
Department of Health and Human Services. 

Researchers at other organizations who are participating in this research study.

The Study Sponsor, its business partners, and Cedars-Sinai’s business partners for 
matters related to research study oversight, data analysis and use of research results 
in product development, and payment or reimbursement. 

Representatives from regulatory agencies in other countries may join in the review 
of your research records, including research-related medical reports and 
information, with the Sponsor and/or the FDA.
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Cedars-Sinai is required by law to protect your private information. However, the 
recipients described above may re-disclose (or share) your information with other 
parties unless such sharing is prohibited by law.

WHEN WILL MY AUTHORIZATION EXPIRE? 
By signing this document, you authorize the use and sharing of your private 
information until the end of the research study and any related optional sub-study you 
choose to participate in. 

REVOKING AUTHORIZATION 
You may change your mind and revoke (take back) this Authorization at any time.  
Even if you revoke this Authorization, the research team may still use or disclose 
private information they already have obtained about you as necessary to maintain the 
integrity or reliability of the current research. To revoke this Authorization, you must 
write to the Principal Investigator of the research study by writing to the Office of 
Research Compliance and Quality Improvement, 6500 Wilshire Blvd, Suite 1800, Los 
Angeles, Calif. 90048 and/or emailing to ResearchConcerns@cshs.org.  

NOTICE OF RIGHTS AND OTHER INFORMATION
You do not have to agree to this Authorization, but if you do not agree, you may not 
participate in the research study. The Research Team may not condition (withhold or 
refuse) treating you on whether you agree to this Authorization.
If you agree to this Authorization, please sign on the appropriate signature line on the 
Signature Page. You will receive a copy of this Authorization. 
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STUDY00000800 CONSENT VERSION 3.1 
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APPENDIX:  Detailed Description of Common Medical Procedures Performed 
for Research Purposes and Associated Risks
The procedures listed below are often performed as part of routine care for a person with your 
condition.  They are being repeated, or performed more frequently as part of this research.  
However, the risks associated with each procedure should be comparable to what you would 
experience even if you were undergoing the procedure outside this research study.
Study Procedure
Related Risks
Blood draw: A needle is placed in the vein in 
your arm to draw blood.
Blood drawing may cause some pain and has a 
small risk of bleeding, bruising, or infection at the 
puncture site.  There is also a small risk of 
fainting.
Bolus Procedure: A bolus is the very quick 
administration of drugs directly into your 
bloodstream using intravenous (IV) lines. For 
this study, the study drug will be 
administered as a 5 second bolus. 
Occasionally, people have allergic reactions 
(including life-threatening reactions) when taking 
any medication.  Symptoms of any allergic 
reaction can include a rash, hives, itching, and/or 
difficulty breathing, closing of the throat, swelling 
of the lips, tongue or face, and rarely death.  If 
you experience any difficulty breathing, closing 
of the throat, swelling of the lips, tongue or face, 
or hives, you should stop taking your study drug 
and immediately seek emergency medical 
attention.
In general, allergic reactions to medicines are 
more likely to occur in people who have allergies 
to other drugs, foods, or things in the 
environment, such as dust or grass. If you have 
allergies to other medicines, foods, or other things 
in the environment, or if you have asthma, you 
should let your researcher know.
Physical Exam: Includes height, weight, 
vital signs (heart rate and blood pressure).
There are no physical risks associated with these 
procedures.
Concomitant Medications: You will be 
asked about your previous and current 
medications that you take. 
There are no physical risks associated with these 
procedures.
Medical History Review: You will be asked 
about your medical and surgical history with 
attention to smoking and alcohol habits, 
menopausal history (females only) and your 
physical activity.
There are no physical risks associated with this 
procedure.
Echocardiogram: a test that uses ultrasound 
waves to create a moving picture that shows 
how strong your heart muscle is pumping or 
if there are areas not pumping normally. The 
picture is much more detailed than an x-ray 
image and involves no radiation exposure.
You may feel some discomfort similar to pulling 
off an adhesive bandage when the technician 
removes the electrodes placed on your chest 
during the procedure.
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STUDY00000800 CONSENT VERSION 3.1 
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Urine Sample: If you are a woman who is 
able to become pregnant, we will collect a 
urine sample in a collection cup to run a 
pregnancy test.
There are no physical risks associated with this 
procedure.
Pregnancy Test: If you are a woman who is 
able to become pregnant, urine samples will 
also be used to do a pregnancy test. If the 
urine pregnancy test is positive, a blood 
pregnancy test will be conducted.
If your test is positive, you will be told and at that 
point you should discuss options available with 
your primary physician.  
Demographic Information: You will be 
asked about your age, gender, race, whether 
you are a fraternal or identical twin, and 
ethnicity.
There are no physical risks associated with these 
procedures.
CSMC IRB No: STUDY00000800 / MOD00002717
CSMC Date Effective: 1/14/2021