Conditions: Pulmonary Embolism With Acute Cor Pulmonale Pulmonary Embolism Pulmonary Embolism With Pulmonary Infarction Pulmonary Embolism Subacute Massive Right Ventricular Dysfunction Right Ventricular Failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 4
Healthy volunteers: no

Brief summary:
The purpose of this study is to examine the degree to which pulmonary embolism (clot) can be dissolved when treated with a very low dose of a systemic thrombolytic drug (clot buster) along with standard anticoagulant therapy as compared to the standard of care anticoagulant therapy alone.

Detailed description:
The OVERALL OBJECTIVE of this investigation is to determine whether very low-dose intravenous tissue-type plasminogen activator \[tPA\] (24 mg) + standard anticoagulation therapy (intravenous heparin) for treatment of acute PE (pulmonary embolism) in intermediate-high risk patients will have superior clot lysis (breakdown of clot) by chest CTA (computed tomography angiography) at 24 ± 6 hours post infusion compared to standard of care treatment alone. Acute intermediate-high risk PE patients are those with acute symptoms \<14 days), simplified Pulmonary Embolism Severity Index (sPESI)\>0, normal systemic arterial blood pressure (\>90mmHg) without vasopressor support, elevated biomarkers (troponin or BNP), and evidence of RV dysfunction (right ventricular to left ventricular ratio\>0.9).The study is planned to evaluate the reduction in clot burden based on the obstruction index using the Refined Modified Miller Score (RMMS), improvement in right ventricular (RV) function, and overall safety in the two treatment groups. 40 Subjects with intermediate-high risk PE (hemodynamically stable PE with a RV/LV ratio ≥ 0.9, elevated biomarkers, and sPESI\>0) will be recruited and randomized to one of two treatment groups: 24mg of systemic (IV) tPA + IV unfractionated heparin versus saline placebo + IV unfractionated heparin. After delivery of the systemic (IV) tPA/placebo, patients will continue IV unfractionated heparin therapy for at least 24 hours. If there is no evidence of active bleeding nor significant hemoglobin drop (i.e., ≥ 2 mg/dL), patients will be transitioned to standard dose apixaban, 10 mg twice-daily x one week followed by 5 mg twice-daily for at least 6 months. Some patients will require indefinite apixaban therapy based on patient-specific factors, including unprovoked nature of PE event, and/or persisting DVT/PE risk factors. Finally, consideration will be given for decreasing the apixaban dose to 2.5 mg twice-daily after 6 months. Apixaban was selected as the anticoagulant of choice due to its very favorable bleeding profile in large clinical trials, which is an important consideration when prescribing an anticoagulant following systemic thrombolysis. Within 24 ± 6 hours post study drug infusion, a repeat chest CTA and echocardiogram will be performed. sPESI will also be calculated at this timepoint.At Day 30, 180 and 365, all subjects will have clinic visits which will include a physical exam, repeat echocardiogram if previous echo was abnormal, 6 minute walk test (6MWT), quality of life questionnaires, assessment of adverse and bleeding events and a review of concomitant medications including compliance with apixaban. At Days 3, 7, 90 and 270, a remote health check will occur via telephone or email assessing adverse and bleeding events, alongside a review of concomitant medications (including an assessment of compliance with apixaban).The standard of care for patients with submassive PE is to either receive anticoagulant therapy, EKOS (Catheter Assisted Thrombolysis) or thromboectomy. tPA is given at the FDA approved dose (100mg) occasionally at doses much higher than our study proposes. PatientS with PE will have the initial CTA, echocardiogram and lab work as standard of care. The follow up CTA is usually standard of care at Day 30 and the follow up echocardiograms are considered standard of care if the previous echocardiogram was abnormal.The study is being done as a proof of concept that low dose tPA is effective in clot lysis and will result in far less risk than the FDA dose. If our study achieves its aims, the research will advance clinical practices in treating pulmonary embolism by reporting the safety of lower dose tPA and opening opportunities to further explore the use of lower dose tPA to improve patient safety and outcomes.

Arms:
arm 1: Alteplase 24mg intravenous infusion for 20 minutes followed by unfractionated heparin intravenous infusion over 24 hours followed by apixaban 10mg tablet twice-daily for one week followed by apixaban 5mg tablet twice-daily for at least 6 months. arm 2: Alteplase placebo solution 24mg intravenous infusion for 20 minutes followed by unfractionated heparin intravenous infusion over 24 hours followed by apixaban 10mg tablet twice-daily for one week followed by apixaban 5mg tablet twice-daily for at least 6 months.

Interventions: intervention 1: Alteplase intervention 2: Unfractionated heparin intervention 3: Placebo intervention 4: Apixaban
Intervention descriptions: intervention 1: Lyophilized powder for reconstitution in 50mg vials intervention 2: Heparin sodium in 0.45% sodium chloride injection for intravenous use intervention 3: Saline solution reconstituted to mimic Alteplase 50mg vial intervention 4: Apixaban tablet

Protocol document:
Prot_SAP_000.pdf: 
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1 
 
Title:  
Standard-dose Apixaban AFtEr Very Low-dose ThromboLYSis 
for Acute Intermediate-high Risk Acute Pulmonary Embolism 
Short Title: 
SAFE-LYSE 
Protocol Version: 
Issue Date: 28/AUG/2019 
Principal 
Investigators:  
Victor Tapson1,2, Aaron Weinberg1,2 
Sub Investigators: 
Sam Torbati1, Susan Jackman1, Niree Hindoyan1, Joseph Meza1 
Affiliations: 
1Cedars-Sinai Medical Center 
8700 Beverly Blvd 
Los Angeles, CA 90048 
 
2Cedars-Sinai Medical Group 
200 N. Robertson Blvd.  
Beverly Hills, CA 90211 
 
Primary Contact:  
Victor Tapson 
8730 Alden Drive, W155 
Los Angeles, CA 90048 
(919) 971-6441 
Investigator-Initiated 
Study Funded By: 
Bristol-Myers Squibb Company (BMS) 


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2 
STUDY SYNOPSIS 
Funding Provided by BMS/Pfizer Alliance 
Protocol Title 
Standard-dose Apixaban AFtEr Very Low-dose ThromboLYSis for 
Acute Intermediate-high Risk Acute Pulmonary Embolism (SAFE-LYSE) 
Background 
Pulmonary embolism (PE) is a major cause of mortality in the United States, 
with an estimated 100,000 deaths annually and up to 30% of patients dying 
within the first month of diagnosis. Recent guidelines now risk-stratify 
intermediate-risk PE patients to intermediate-low and intermediate-high risk 
categories, but consensus on treatment for those patients are controversial, 
as compared to that of high or low-risk patients. 
Because of an increased risk of major, non-major, and intracranial bleeding 
and an uncertain effect on survival and post-thrombotic complications, 
thrombolysis is not routinely recommended in the guidelines for intermediate-
risk patients. However, studies have evaluated half-dose (50 mg dose) tissue 
plasminogen activator (tPA) and this appears to be effective for treating PE 
with a reduced yet still significant risk of bleeding. Catheter-directed 
thrombolysis studies have used even lower dose tPA (24mg) with significant 
reduction in clot burden, right ventricle to left ventricle ratios, and less 
bleeding; however, catheter-directed therapy requires a procedure which is 
time consuming, costly, center dependent, and introduces other potential 
complications. Based on our extensive clinical experience in treating acute 
PE, we believe that even lower doses of systemic (intravenous) tPA may be 
effective and safe, as well as simpler and more accessible than any form of 
catheter-directed thrombolysis (CDT). In addition, usage of the direct oral 
anticoagulant (DOAC), apixaban, after completion of anticoagulation therapy 
for PE has been shown to be effective in preventing recurrent VTE in patients 
while having a very low risk of major bleeding. 
To understand ways to improve PE patient outcomes while reducing risk of 
major bleeding, our proposed trial will compare a baseline CTA to a 24 hour 
CTA after administration of a 24 mg dose of systemic, (intravenous) tPA 
(treatment A) for intermediate-high risk PE patients. As a secondary endpoint 
we will compare treatment A to conventional anticoagulant therapy (treatment 
B). Patients with a low risk of bleeding will then receive standard dose 
apixaban. In addition to our primary endpoint analysis, we will follow patients 
after discharge to evaluate long-term efficacy and safety of the thrombolytic 
therapy on endpoints such as right ventricular (RV) function, residual clot 
burden, and long-term mortality.  
Diagnosis and Main 
Criterion 
for 
Inclusion 
Adult individuals with intermediate-high risk (submassive) PE. 
Primary 
Study 
Objective 
To determine whether very low 24 mg dose systemic thrombolytic therapy is 
effective and safe in treating intermediate-high risk PE compared to 
anticoagulation alone. 


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Primary Endpoint 
Mean change in percentage of Refined Modified Miller Score (RMMS) 
(measurement of extent of clot lysis) between baseline CTA and 24 hour CTA 
after 24 mg of systemic (intravenous; IV) tPA. 
Primary Hypothesis 
Very low-dose intravenous tissue-type plasminogen activator (24 mg) + 
standard anticoagulation therapy (intravenous heparin) for treatment of acute 
PE in intermediate risk patients will have clot lysis of at least 15% by chest 
CTA  at 24 ± 6 hours post infusion compared with baseline CTA. All patients 
will be treated with oral apixaban at the approved dose of 10 mg twice-daily 
starting at least 24 hours after completion of the IV study drug for seven days 
followed by 5 mg twice-daily for at least 6 months, with the potentiality of 
decreasing the apixaban dose again to 2.5 mg twice-daily after 6 months.   
Study Design and 
Methodology 
This is a randomized, double-blinded, placebo-controlled, single-center study 
intended to investigate very low dose systemic (IV) tPA along with standard 
anticoagulation 
therapy 
as 
a 
treatment 
for 
intermediate-high 
risk 
(submassive) PE. The study is planned to evaluate the reduction in clot 
burden based on the obstruction index using the Refined Modified Miller Score 
(RMMS), improvement in right ventricular (RV) function, and overall safety in 
the two treatment groups.  Subjects with intermediate-high risk PE 
(hemodynamically stable PE with significant clot burden a RV dysfunction an 
at least one elevated biomarkers,will be randomized to one of two treatment 
groups: 24mg of systemic (IV) tPA + IV unfractionated heparin versus saline 
placebo + IV unfractionated heparin.   
 
Approximately 40 subjects will be enrolled. These subjects will be randomized 
in a 1:1 ratio (approximately 20 per treatment arm) to receive 24 mg tPA 
[Activase (alteplase)] + standard anticoagulation therapy (intravenous 
heparin) vs placebo + standard anticoagulation (intravenous heparin) therapy. 
 
Upon enrollment, the standard of care labwork, chest contrast-enhanced 
computed tomographic angiogram (chest CTA), echocardiogram and duplex 
ultrasound of lower extremities will be reviewed The  sPESI core will be 
calculated.  
 
After delivery of the systemic (IV) tPA/placebo, patients will continue IV 
unfractionated heparin therapy for at least 24 hours. If there is no evidence of 
active bleeding nor significant hemoglobin drop (i.e., ≥ 2 mg/dL), patients will 
be transitioned to standard dose apixaban, 10 mg twice-daily x one week 
followed by 5 mg twice-daily for at least 6 months. Some patients will require 
indefinite apixaban therapy based on patient-specific factors, including 
unprovoked nature of PE event, and/or persisting DVT/PE risk factors. Finally, 
consideration will be given for decreasing the apixaban dose to 2.5 mg twice-
daily after 6 months.   Apixaban was selected as the anticoagulant of choice 
due to its very favorable bleeding profile in large clinical trials, which is an 
important consideration when prescribing an anticoagulant following systemic 
thrombolysis.  
 
Within 24 ± 8 hours post study drug infusion, a repeat chest CTA and 
echocardiogram will be performed. sPESI will also be calculated at this 
timepoint. 


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At Day 30, 180 and 365, all subjects will have clinic visits which will include a 
physical exam, repeat echocardiogram (at Day 30 & 180), 6 minute walk test 
(6MWT), quality of life questionnaires, assessment of adverse and bleeding 
events and a  review of concomitant medications including compliance with 
apixaban. At Day 3, 7, 90 and 270, a remote health check will occur via 
telephone or email assessing adverse and bleeding events, alongside a 
review of concomitant medications (including an assessment of compliance 
with apixaban). 
 
If any subject experiences an adverse event (AE), the investigator may, at his 
or her discretion, decrease or discontinue the study drug or apixaban. 
 
The DMC will meet after 10 subjects are enrolled; bleeding and other 
complications will be reviewed.  An interim analysis will occur after 20 subjects 
have completed Day 30. The DMC will meet again after 30 subjects have 
completed Day 30. Because it is a single-center study, the investigators and 
study coordinators will be acutely aware of all adverse events.  
 
The primary analyses will compare the clot lysis on CTA in treatment A at 24 
hours post study drug infusion. See Section 7 for a complete discussion of the 
statistical analysis. 
Inclusion Criteria 
• Male or female 18-75 years in age 
• Chest CT angiogram evidence of proximal PE with a filling defect in at least 
one main pulmonary artery or lobar artery 
• PE symptom duration ≤14 days  
• Intermediate-high risk PE: significant clot buden with RV dysfunction, an 
elevation in  troponin > 0.05 ng/mL and/or brain natriuretic peptide (BNP) 
> 100 pg/mL, and hemodynamically stable (systolic blood pessure>90mm 
Hg without the use of vasopressor support)  
• Randomization within 36 hours of anticoagulation 
• Signed and dated informed consent obtained from subject or legally 
authorized representative before initiation of any study procedures 
Exclusion Criteria 
• Stroke or transient ischemic attack (TIA), head trauma, or other active 
intracranial or intraspinal disease within one year 
• Recent (within one month) or active bleeding from a major organ  
• Major surgery within 14 days 
• Clinician deems the subject too high-risk for bleeding using HAS-BLED 
criteria. 
• History of any hematologic disease or coagulopathy  
• Cirrhosis  (as determined by Child-Pugh B or C) 
• History of heparin-induced thrombocytopenia (HIT) 
• Hemodynamic instability defined as systolic blood pressure (SBP) less 
than 90 mm Hg and/or use of vasopressors for greater than 15 minutes 
• Severe hypertension as define as systolic blood pressure (SBP) greater 
than 180 mm Hg 
• Cardiac arrest or active cardiopulmonary resuscitation (CPR) 
• Receiving neuraxial anesthesia or undergoing spinal puncture 


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• Patient with prosthetic heart valves 
• Evidence of irreversible neurological compromise 
• Evidence of poor functional status 
• History of major gastrointestinal bleed within the last month 
• Active gastric or duodenal ulcers 
• Use of thrombolytics or glycoprotein IIb/IIIa antagonists within 3 days prior 
to diagnosis 
• Lovenox administration within 12 hours of randomization  
• Direct-acting oral anticoagulant use (dabigatran, rivaroxaban, apixaban, or 
edoxaban) with last known  dose within 48 hours 
• Hemoglobin < 10 g/dL 
• creatinine clearance < 30 mL/min 
• platelets < 100 thousand/μL 
• INR > 1.4 
• Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 2 times 
upper limit of normal (ULN) 
• Total bilirubin (TBL) ≥ 1.5 times ULN (except due to confirmed Gilbert’s 
syndrome) 
• Patient is pregnant (positive pregnancy test; women of childbearing 
capacity must be tested prior to enrollment) or breast feeding 
• Patient who is a prisoner, or if subject who becomes compulsory detained 
• Active cancer defined as diagnosis of cancer within six months before the 
study inclusion, or receiving treatment for cancer at the time of inclusion 
or any treatment for cancer during 6 months prior to randomization, or 
recurrent locally advanced or metastatic cancer. 
• Known allergy, hypersensitivity or thrombocytopenia from heparin, tPA,  or 
apixaban or iodinated contrast except for mild-moderate contrast allergies 
for which steroid pre-medication can be administered within 12 hours prior 
to the CTA.  
• HIV/AIDS  
• Weight >130 kg or < 40 kg on day of randomization  
. 
Sample Size 
In this trial, 40 subjects (20 per arm) will be randomized into two treatment 
arms, 1) 24 mg IV PA + standard anticoagulation therapy (IV heparin) vs 2) 
saline placebo + standard anticoagulation therapy (IV heparin), using a 
computer program at Cedars-Sinai Medical Center in Los Angeles, California.  
Additional subjects may be consented to compensate for screening failures 
and/or treated patients who lack sufficient data. 
 
Approximately 40 subjects will be enrolled into the study, with approximately 
20 subjects in each arm.  A subject will be deemed evaluable if he/she has 
valid CTA imaging evaluations at both baseline and < 24h + 8 hours post-end 
of infusion and successfully completed administration of study drug infusion. 
Randomized subjects who do not complete blinded study drug administration 
(i.e., subjects who stop the IV infusion early due to AEs) will still be followed 
for safety through Day 30. 
 


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The planned sample size is based on a two-sided two-sample equal-variance 
t-test. A previous study [19] showed that the mean and standard deviation of 
percentage change in RV/LV ratio from baseline to 48 hours are 26 and 22.7, 
respectively. Assuming these hold for our study , data from 17 patients per 
group (34 total) achieve 90% power to detect a mean difference of 26 
percentage units between the two treatments with 5% significance level using 
a two-sided two-sample equal-variance t-test.  
Statistical Analyses 
The main objective is to determine the mean change in percentage clot lysis 
via chest CTA from baseline to 24 hours in treatment A (IV tPA + IV 
unfractionated heparin). Data will be presented as frequency (percentage, %) 
for categorical variables and mean (± SD, standard deviation) for continuous 
variables. Profile plots with mean Refined Modified Miller Score (RMMS) (± 
SE, standard error) at baseline and 24 hours will be displayed. The post-
treatment RMMS score at 24 hours as an outcome variable will be modeled 
using a generalized additive model for location, scale and shape after 
adjusting for the treatment group and the baseline RMMS score [24] to 
examine if there is a difference in the change in RMMS from baseline to 24 
hours in treatment group A. The underlying assumptions will be checked using 
residuals so that the most adequate response distribution and the regression 
functional form can be chosen. Statistical analyses will be conducted using R 
package version 3.4.1 with two-sided tests and a significance level of 0.05. 
Safety 
All recorded AEs will be listed and summarized. Vital signs and clinical 
laboratory tests will be listed and summarized by treatment. Any significant 
physical examination findings and results of clinical laboratory tests will be 
listed. Recurrent DVT and PE at 30 days, 60 days, 6 months, and 1 year 
compared with placebo. Since all patients will be on apixaban, we will 
compare DVT and PE recurrence rates with historic controls The Data 
Monitoring Committee (DMC) will meet and review safety data after the first 
10 subjects are enrolled and Day 30 assessments have been completed. A 
maximum of 3 additional subjects may be enrolled before the DMC approves 
study continuation. 


SAFE-LYSE | STUDY PROTOCOL  
 
7 
TABLE OF CONTENTS 
STUDY SYNOPSIS ................................................................................................................................................................................... 2 
1.1. BACKGROUND AND RATIONALE ..................................................................................................................................................... 9 
1.2. OBJECTIVES .................................................................................................................................................................................. 12 
1.2.1. PRIMARY ENDPOINT 
12 
1.2.2. SECONDARY ENDPOINTS 
12 
1.2.3 SAFETY ENDPOINTS 
13 
2. ETHICAL CONSIDERATIONS 
13 
2.1 GOOD CLINICAL PRACTICES ......................................................................................................................................................... 13 
2.2. INSTITUTIONAL REVIEW BOARD ............................................................................................................................................... 14 
2.3. INFORMED CONSENT ................................................................................................................................................................... 14 
2.4. PROTOCOL AMENDMENTS ............................................................................................................................................................ 15 
2.5. CONFIDENTIALITY ........................................................................................................................................................................ 15 
3. INVESTIGATIONAL PLAN 
15 
3.1. STUDY SETTING ............................................................................................................................................................................ 15 
3.2 STUDY DESIGN ............................................................................................................................................................................... 16 
3.3. STUDY POPULATION ..................................................................................................................................................................... 18 
3.3.1. INCLUSION CRITERIA ................................................................................................................................................................ 18 
3.3.2. EXCLUSION CRITERIA 
19 
3.3.3  WOMEN OF CHILDBEARING POTENTIAL 
20 
3.4. CONCOMITANT TREATMENTS ....................................................................................................................................................... 20 
3.4.1 PROHIBITED AND/OR RESTRICTED TREATMENTS 
20 
3.4.2 OTHER RESTRICTIONS AND PRECAUTIONS ................................................................................................................................ 20 
3.5. DISCONTINUATION OF SUBJECTS FROM TREATMENT .................................................................................................................. 20 
4. TREATMENTS ................................................................................................................................................................................... 22 
4.1. STUDY TREATMENTS .................................................................................................................................................................... 22 
4.1.2.. HANDLING AND DISPENSING .................................................................................................................................................... 22 
4.2. METHOD OF ASSIGNING SUBJECT IDENTIFICATION ..................................................................................................................... 22 
4.3. BLINDING AND UNBLINDING ........................................................................................................................................................ 22 
4.4. TREATMENT COMPLIANCE ........................................................................................................................................................... 23 
4.5. DESTRUCTION OF STUDY DRUG ................................................................................................................................................... 23 
THE RESEARCH PHARMACY WILL FOLLOW THE CSMC DRUG DESTRUCTION INSTITUTIONAL POLICIES. ....................................... 23 
5. STUDY ASSESSMENTS AND PROCEDURES ........................................................................................................................................ 23 
5.1. SCREENING PROCEDURES ............................................................................................................................................................. 23 
5.1.1. INFORMED CONSENT 
23 
5.2 ENROLLMENT 
24 
5.2.1. SCREENING ASSESSMENTS 
24 
5.3. RANDOMIZATION TO TREATMENT 
24 
5.3.1. SEQUENCE GENERATION 
25 
5.3.2. CONCEALMENT MECHANISM 
25 
5.4. STUDY INTERVENTIONS 
25 


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5.4.1. TREATMENTS AND TIMING ....................................................................................................................................................... 25 
5.5. RESCUE TREATMENT 
28 
6. DATA COLLECTION, MANAGEMENT AND ANALYSIS ........................................................................................................................... 29 
6.1. DATA COLLECTION METHODS ...................................................................................................................................................... 29 
6.1.2. WITHDRAWAL 
29 
6.2. DATA MANAGEMENT ..................................................................................................................................................................... 30 
6.2.1. DATA FORMS AND DATA ENTRY 
30 
6.2.2 DATA TRANSMISSION AND EDITING 
30 
6.2.3 DATA DISCREPANCY INQUIRIES AND REPORTS TO CORE COORDINATING CENTERS 
30 
6.2.4 SECURITY AND BACK-UP OF DATA 
30 
6.3. DATA MONITORING ...................................................................................................................................................................... 30 
6.3.1. FORMAL COMMITTEE 
30 
6.3.2. HARMS ...................................................................................................................................................................................... 31 
6.3.3. AUDITING .................................................................................................................................................................................. 31 
7. STATISTICAL CONSIDERATIONS 
31 
7.1. SAMPLE SIZE DETERMINATION .................................................................................................................................................... 31 
7.1.1. EFFICACY 
31 
7.1.2. SAFETY 
32 
7.1.3. ATTRITION 
32 
8.1.SERIOUS ADVERSE EVENTS ........................................................................................................................................................... 33 
8.1.1.ADVERSE EVENT COLLECTION AND REPORTING INFORMATION: 
34 
9. STUDY MANAGEMENT 
37 
9.1 COMPLIANCE .................................................................................................................................................................................. 37 
9.1.1 COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS 
37 
9.1.2 MONITORING 
37 
9.1.3 INVESTIGATIONAL SITE TRAINING 
37 
9.2 RECORDS ....................................................................................................................................................................................... 37 
9.2.1 RECORDS RETENTION 
38 
9.2.2 STUDY DRUG RECORDS 
38 
9.3. CLINICAL STUDY PUBLICATIONS .................................................................................................................................................. 38 
9.4. REVIEW PROCESS ......................................................................................................................................................................... 39 
9.5. ACCESS TO DATA ........................................................................................................................................................................... 39 
9.6. ANCILLARY AND POST-TRIAL CARE ............................................................................................................................................... 39 
9.7. CLOSE-OUT PROCEDURES 
39 
9.8. INTERIM 
39 
9.9. DATABASE LOCK 
39 
9.10. REPORTING OF STUDY RESULTS 
40 
10. REFERENCES 
41 
 
 
 
 


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1. INTRODUCTION AND STUDY RATIONALE 
1.1. BACKGROUND AND RATIONALE 
Venous thromboembolic (VTE) disease is a common condition with over a million cases in the United 
States per year [1]. Pulmonary embolism (PE) is a potentially deadly consequence of deep vein 
thrombosis with an estimated 100,000 deaths annually in the United States and up to 30% dying within 
the first month of diagnosis [2].   
 
The detrimental effects of an acute PE are understood through the pathophysiologic increase in 
pulmonary vascular resistance (PVR).  The emboli directly obstruct the pulmonary capillary bed but 
also indirectly induce hypoxic/acidotic vasoconstriction through the release of vasoactive mediators 
thus increasing the overall PVR.  The acute increase in PVR causes an elevation in pulmonary artery 
pressures, which overwhelms the thin walled RV leading to RV dilation and decreased contractility and 
function.  The dilated RV also causes septal bowing into the left ventricle.  The net result is 
compromised left ventricular filling, decreased cardiac output, hemodynamic instability, cardiogenic 
shock, and ultimately death [3].  
 
Risk stratification of acute pulmonary embolism 
The clinical classification of the severity of acute PE is generally based on the estimated early mortality 
risk defined by in-hospital or 30-day mortality. High-risk (massive) PE is defined by the presence of 
shock or persistent arterial hypotension. Patients with high-risk PE represent less than 5% of all patients 
with acute PE [4]. This is a life-threatening situation in which prompt reperfusion treatment (often 
systemic thrombolysis) is recommended to increase the chances of survival [5].  
 
More than 95% of patients with acute PE do not present with hypotension or cardiogenic shock and are 
thus not considered to be at high risk. Within this group, prediction scores derived from clinical variables 
reliably select patients with a low 30-day mortality. Both the Pulmonary Embolism Severity Index (PESI) 
and its simplified version (sPESI) have a high negative predictive value for ruling out an adverse early 
outcome [6]. Thus, a substantial proportion of all patients with acute PE can be classified as being at 
low risk based on a PESI risk class of I or II, or a sPESI of 0. These patients generally have small 
embolic burdens and are not severely tachypneic, tachycardic or hypoxemic, unless they have other 
underlying concomitant pulmonary or cardiovascular comorbidities affecting their reserve. Such 
patients are treated with anticoagulation alone.  
 
Clinically stable patients not classified into the low-risk category are classified as intermediate-risk. The 
most recent European Society of Cardiology (ESC) guidelines have further risk-stratified these patients 
into intermediate-low and intermediate high-risk categories. Intermediate-low-risk patients are defined 
by a sPESI score > 0 with either right ventricular (RV) dysfunction or elevated cardiac biomarkers 
(troponin or BNP). The patients with sPESI score > 0 and both RV dysfunction and elevated cardiac 
biomarkers are classified in the intermediate-high risk category [5]. Therapy for these patients has been 
much more controversial than therapy for high or low-risk patients.  
 
Systemic thrombolysis at standard doses for acute PE 
Thrombolytic treatment achieves a faster improvement in hemodynamic parameters in acute PE than 
IV unfractionated heparin with a significant decrease in the mean pulmonary artery pressure and a 
significant increase in the cardiac index observed two hours after the start of the infusion whereas no 
difference is observed with heparin alone [7].  Thus, in PE patients for whom the risk of deterioration or 
mortality is higher, more aggressive therapy such as systemic thrombolysis is often considered.  


SAFE-LYSE | STUDY PROTOCOL  
 
10 
In the most important therapeutic clinical trial involving intermediate-risk acute PE patients to date, the 
PEITHO trial [8], tenecteplase plus heparin was compared with placebo plus heparin. The trial was a 
randomized, double-blind trial, and eligible patients had RV dysfunction on echocardiography or chest 
computed tomographic angiography (chest CTA), as well as myocardial injury as indicated by positive 
troponin test (i.e., intermediate-high risk patients). The primary outcome was death or hemodynamic 
decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major 
extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. In the 
PEITHO trial, it was demonstrated for the first time that thrombolysis not only improves pulmonary 
vascular obstruction and right heart function, but also improves clinical end-points in intermediate-risk 
patients with PE [8].  
 
However, in these intermediate-risk PE patients, thrombolytic therapy increased the risk of major 
hemorrhage and stroke; 6.3% and 1.2% of patients had major extracranial bleeding in the tenecteplase 
and placebo groups, respectively (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase 
group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which 
was hemorrhagic (P = 0.003) [8]. This increase in the risk of bleeding was confirmed in a recent meta-
analysis, showing that in the subset of studies including patients with intermediate-risk PE, thrombolysis 
was associated with an odds ratio (OR) for major bleeding of 3.19 (95% CI: 2.07-4.92) [9].  
 
In the PEITHO trial, no difference was observed in the risk of death; by day 30, a total of 12 patients 
(2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P = 0.42) [8]. 
It is important to realize that while there was no overall difference in mortality, it is likely that the 
population was not sufficiently enriched based on severity to demonstrate a difference.  
 
Two meta-analyses have reported conflicting results. In one, a prespecified analysis performed of 8 
trials enrolling patients who were hemodynamically stable with objective assessments of RV function, 
thrombolysis was associated with a lower mortality (odds ratio, 0.48; 95% CI: 0.25-0.92) [9]. In the other 
meta-analysis, the reduction in the risk of death for intermediate-risk PE patients receiving thrombolytic 
therapy was not significant (OR: 0.42; 95% CI: 0.17–1.03) [10].   
 
The uncertain effect of thrombolytic therapy on survival and the increased risk of major and intracranial 
bleeding observed with the use of thrombolytic therapy in patients with intermediate-risk PE [11] 
prompted the recent guidelines issued by the ESC and the American College of Chest Physician to 
recommend against the use of thrombolysis in these patients [5, 11].  
 
Lower (half)-dose systemic thrombolysis 
A newer approach has been to consider lower doses of thrombolytic therapy in hopes of improving 
outcomes with a low risk of major bleeding including intracranial hemorrhage (ICH). In patients with PE, 
three small randomized trials compared a reduced dose of systemic (IV) tPA administered to 162 
patients with the conventional 100 mg dose given over 2 hours in 99 patients [12-14]. The reduced 
dose was similar in the different studies: in one trial, 50 mg given over two hours, and in the other two 
trials, 0.6mg/kg up to 50 mg given over 15 minutes [12-14]. No significant difference was observed in 
either trial regarding the different efficacy end-points including pulmonary artery pressure, cardiac 
index, residual vascular obstruction at 24h or recurrent PE [12-14]. However, the low-dose regimen 
was associated with a significant reduction in the risk of major bleeding (OR: 0.33; 95% CI: 0.12 to 
0.91) [15]. Thus, lower dose therapy appears effective, but also safer than conventional dose systemic 
(IV) tPA. The improved safety of this regimen has also been demonstrated in patients with ischemic 
stroke with a significant 50% relative reduction in the risk of major symptomatic ICH as compared to 
the standard dose  (1.0% in the low-dose group vs 2.1% in the standard-dose group; P = 0.01) [16]. In 


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11 
patients with PE, the efficacy of the reduced dose regimen is further supported by two studies 
comparing tPA given as a 0.6 mg/kg or 0.5 mg/kg and heparin in patients with PE, showing a larger 
improvement of vascular obstruction with tPA in one study [17] and a reduction in the combined end-
point of persistent pulmonary hypertension or recurrent PE in the second study [18].  Based on our 
extensive clinical experience in acute PE, we believe even lower doses of systemic (IV) tPA are 
effective and even safer.  
 
Catheter-directed thrombolysis (CDT) 
Catheter-directed thrombolysis (CDT) has been studied in intermediate-risk patients. Localizing the 
systemic (IV) tPA infusion directly into the pulmonary artery, and using lower doses of tPA, may improve 
the risk/benefit ratio. Doses of tPA have ranged from 8 to 24 mg total. Improvement in RV/LV ratio has 
been demonstrated, with more substantial improvement in clot burden using doses in the higher range 
[20-22]. However, there is only one randomized trial evaluating CDT to date, and while it demonstrated 
improvement in RV/LV ratio at 24 hours with a low risk of major bleeding, it was too small to (and did 
not intend to) demonstrate a difference in mortality [19]. Furthermore, CDT is not available at most 
smaller hospitals and the precise patients who benefit the most is not clear. Specialists in interventional 
cardiology or radiology must be available. Many hospitals around the U.S. and the world simply do not 
have access to CDT, and this practice has still not proven superior to (IV) tPA at similar doses. Thus, 
our approach is much simpler and more accessible than any form of CDT.  
 
Trials evaluating the use of a DOAC after thrombolysis for acute PE 
This trial will compare systemic (IV) tPA at a lower dose than has ever been previously studied and the 
use of apixaban after thrombolysis There are almost no data evaluating the use of apixaban after 
thrombolysis, despite the obvious logic of utilizing a short-acting oral anticoagulant with excellent safety 
data. One trial evaluated 98 consecutive patients with symptomatic PE over a 12-month period [23]. 
These patients were treated with a combination of systemic thrombolysis at a lower dose than 
traditionally prescribed, followed by rivaroxaban. The tPA was given over 2 hours. Heparin was 
administered for a total of 24 hours and rivaroxaban then started at the standard therapeutic dose. 
However, no randomized trials have examined thrombolysis followed by a DOAC. A number of PE 
systemic thrombolysis trials have been conducted in which anticoagulation has followed thrombolytic 
therapy, thus offering historical controls for comparison (7-10). Furthermore, the catheter-directed 
thrombolysis trials which have been conducted also offer potential control data [20-22]. We chose 
transitioning to apixaban based on the low risk of bleeding with apixaban in prior trials [24-25].  
Apixaban was shown to be effective for the prevention of recurrent VTE in patients who had completed 
6 to 12 months of anticoagulation for acute DVT or PE, with rates of major bleeding similar to placebo 
[24].   
 
Furthermore, in the AMPLIFY trial [25],  among patients who had PE at enrollment, the primary efficacy 
outcome occurred in only 21 of 900 patients (2.3%) in the apixaban group compared with 23 of 886 
(2.6%) in the conventional-therapy group (relative risk, 0.90; 95% CI, 0.50 to 1.61; difference in risk, 
−0.3 percentage points; 95% CI, −1.7 to 1.2). Even more impressive, for all randomized patients with 
VTE (i.e. PE and/or DVT), major bleeding occurred in only 15 of 2676 patients (0.6%) in the apixaban 
group compared with 49 of 2689 (1.8%) in the conventional-therapy group, for a relative risk of 0.31 
(95% CI: 0.17 to 0.55; P<0.001 for superiority) [25]. 
 
Very-low dose systemic thrombolysis followed by apixaban– our proposal 
This trial is comparing an even lower dose of systemic (IV) tPA than has previously been studied. We 
hypothesize that this dose of 24 mg will be effective at decreasing clot burden as measured on chest 
CTA by Refined Modified Miller Score (RMMS), as well as significantly improving RV function as 


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12 
measured by RV/LV ratio. We also expect a very low risk of major bleeding, particularly when followed 
at 24 hours by apixaban which has been associated with a very low risk of major bleeding  [24-25].  
 
While even lower doses of systemic (IV) tPA have proven effective for acute PE when delivered by 
CDT [22], we are concerned that doses in the range of 8 to 12 mg, when delivered systemically, might 
be too low to confer benefit.  
 
Patients with chest CTA-documented acute intermediate-high-risk PE (abnormal RV function by 
echocardiogram combined with an elevated troponin or BNP), who have no evidence of significant 
bleeding risk will receive systemic (IV) tPA (24 mg) combined with IV unfractionated heparin, or saline 
placebo and IV unfractionated heparin.  After delivery of the systemic (IV) tPA, patients will continue IV 
unfractionated heparin therapy for 24 hours, and if the bleeding risk remains low, all patients will be 
subsequently transitioned to standard dose apixaban, 10 mg twice-daily x one week followed by 5 mg 
twice-daily at least 6 months (some patients will require indefinite apixaban therapy based on patient-
specific factors, including unprovoked nature of PE event, and/or persisting DVT/PE risk factors). 
Finally, consideration will be given for decreasing the apixaban dose to 2.5 mg twice-daily after 6 
monthsIf bleeding suggests that a shorter acting anticoagulant (IV unfractionated heparin) should be 
continued longer, then it will be. Importantly, andexanet has now been FDA-approved for reversal of 
bleeding caused by apixaban, and will be available when our study is initiated [26]. After discharge, 
patients will be seen and followed in the Cedars-Sinai Pulmonary Embolism Response Team clinic. 
 
We have specifically chosen to transition to apixaban based upon thevery low risk of major bleeding 
seen in large randomized clinical trials [24-25]. Finally, we will obtain long-term efficacy data including 
the effects of thrombolysis followed by apixaban on RV dysfunction, dyspnea and long-term mortality. 
Safety will be assessed by examining major and minor bleeding rates in all patients at 30 days, 60 
days, and 6 and 12 months. Thus, will have data on apixaban in PE patients treated with 
thrombolysis. 
1.2. OBJECTIVES 
The OVERALL OBJECTIVE of this investigation is to determine whether very low-dose intravenous 
tissue-type plasminogen activator (24 mg) + standard anticoagulation therapy (intravenous heparin) for 
treatment of acute PE in intermediate-high risk patients will have superior clot lysis by chest CTA at 24 
± 6 hours post infusion compared to standard of care treatment alone. Acute intermediate-high risk PE 
patients are those with acute symptoms (<14 days), simplified Pulmonary Embolism Severity Index 
(sPESI)>0, normal systemic arterial blood pressure (>90mmHg) without vasopressor support, elevated 
biomarkers (troponin or BNP), and evidence of RV dysfunction (right ventricular to left ventricular 
ratio>0.9).  
1.2.1. PRIMARY ENDPOINT 
Change in percentage of clot lysis by chest computed tomographic angiography (chest CTA) (Refined 
Modified Miller Score; RMMS) after 24 mg of systemic (intravenous; IV) tPA compared with baseline 
CTA RMMS.  
1.2.2. SECONDARY ENDPOINTS 
• Change in percentage of clot lysis by chest computed tomographic angiography (chest CTA) 
(Refined Modified Miller Score; RMMS) from baseline to 24 hours for treatment A compared with 
treatment B. 
• Change in right ventricular to left ventricular diameter ratio (RV/LV) as measured by chest CTA  from 
baseline to 24 ± 8 hours after the infusion of very low dose systemic (IV) tPA in patients with acute 
intermediate-high risk (submassive) PE compared with placebo.   


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13 
• Change from baseline in echocardiographic parameters including RV/LV ratio, tricuspid annular 
plane systolic excursion (TAPSE), estimated right ventricular systolic pressure (RVSP), and 
collapse of the inferior vena cava (IVC) with respiration within 24 hours ± 8 hours and at 30 ±5 days 
after the end of the systemic (IV) tPA infusion compared with placebo. 
• 6 Minute Walk Test (6MWT) distance with the Borg Dyspnea Scale score (Borg score) and 
requirement for oxygen therapy at Day 30, 180 and Day 365 clinic follow-up compared with placebo. 
• Quality of life (QOL) as measured by the PROMIS PF-6 and Pulmonary Embolism Quality of Life 
(PEmb-QOL) at Day 30, 180, and 365 clinic follow-up compared with placebo. 
• Recurrent DVT and PE at Day 30, 180 and 365 compared with placebo. Since all patients will be 
on apixaban, we will compare DVT and PE recurrence rates with historic controls. 
1.2.3 SAFETY ENDPOINTS 
Primary Safety Endpoints 
The primary safety endpoint is major bleeding within 72 hours after initiating systemic tPA infusion. 
Major bleeding events will be defined by Global Use of Strategies to Open Occluded Arteries (GUSTO) 
criteria for severe or life threatening bleed. This includes: 
• Intracerebral hemorrhage 
• Resulting in a substantial hemodynamic compromise requiring treatment 
 
Secondary Safety Endpoints 
• GUSTO severe or life threatening bleeding within 30, 180 and 365 days 
• Need for rescue therapies such as full dose systemic thrombolysis, catheter-directed 
thrombolysis, catheter directed embolectomies, or surgical embolectomy within 30 days 
• Ischemic or hemorrhagic stroke within 30 days 
• All-cause mortality at Day 365 
• Symptomatic PE recurrence: The patient must have signs and symptoms of recurrent PE in 
addition to objective confirmation such as a new filling defect on chest CTA or pulmonary 
arteriogram at Day 365 
• Hemodynamic decompensation within 30 days as defined as a systolic blood pressure 
<90mmHg and/or need for vasopressor support. 
2. ETHICAL CONSIDERATIONS 
 
This protocol and the template informed consent forms will be reviewed and approved by the Office of 
Research Compliance and Quality Assurance with respect to scientific content and compliance with 
applicable research and human subjects regulations. 
 
The protocol, site-specific informed consent forms, subject education and recruitment materials, and 
other requested documents — and any subsequent modifications — will also be reviewed and approved 
by the Cedars-Sinai IRB Board. 
 
The Investigators will make safety and progress reports to the IRB at least annually and within three 
months of study termination or completion. These reports will include the total number of subjects 
enrolled and summaries of each DMC review of safety and/or efficacy. 
2.1 GOOD CLINICAL PRACTICES 
This study will be conducted in compliance with the protocol, the ethical principles that have their origin 
in the Declaration of Helsinki and the International Conference on Harmonisation (ICH) consolidated 


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14 
Guideline E6 for Good Clinical Practices (CPMP/ICH/135/95) and the United States Code of Federal 
Regulations (CFR), Title 21, Part 50 (21CFR50). 
 
The study and any future amendments, the informed cosent forms, HIPAA authotization and all 
recruitment materials will be submitted to the Cedars-Sinai Medical Center Institutional Review Board 
and will be approved by the IRB before the study or amendment is intiatied. All study personnel have 
been trained in Human Subject’s Protection, Good Clinical Practices and HIPAA. 
 
Study tasks will be delegated by either Co-PI. No study personnel for whom sanctions have been 
invoked or where there has been scientific misconduct or fraud will be utilized in this study. The 
Investigators will assure that all staff are qualified by education, training, and experience to perform 
their respective tasks delegated to them. 
 
All study records will be made available to the BMS/Pfizer Alliance and the FDA. 
2.2. INSTITUTIONAL REVIEW BOARD 
Before study initiation, we will obtain a written and dated approval letter from the Cedars-Sinai Medical 
Center IRB for the protocol, consent form, HIPAA Authorization form and all recruitment materials. The 
investigator will provide the IRB approval letter, stamped approved consents and recruitment materials 
to the BMS/Pfizer Alliance. 
 
The investigator will provide the BMS/Pfizer Alliance and Cedars-Sinai Medical Center IRB with Serious 
Adverse Events (SAEs), protocol deviations and Data Safety Monitoring Board correspondences.  
2.3. INFORMED CONSENT 
The Investigators will: 
a) Provide a copy of the IRB approved consent form, HIPAA form and recruitment materials written 
in an easily understood language. 
b) Obtain an interpretor to help facilitate the informed consent discussion for non-English speaking 
patients. 
c) Emphasize that the study is voluntary and the potential subjects care will not be affected by 
declining participation.  
d) Explain the study in detail including purpose of the study, study prcedures, potential risks, 
benefits, and alternatives to study participation. 
e) Allow the potential subject/legal representative to ask questions.  
f) Allow the potential subject/legal representative time to consider the study.  
g) Obtain an informed consent signed and personally dated by the participant or the subject’s 
legally acceptable representative, and by the person who conducted the informed consent 
discussion before any study procedures are initiated. 
h) For non-English speaking subjects, obtain the English informed consent with the signatures 
mentioned above, along with the interpretor’s signature as witness and obtain the short form 
consent in the subject’s native language.  
i) If the informed consent is initially given by a legal representative and the subject becomes 
capable of providing their own consent, the informed consent process will take place again with 
the subject to assure they still wish to proceed with the study. 
j) Write a note in the medical record detailing the informed consent process. 
 
 
 


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15 
2.4. PROTOCOL AMENDMENTS 
Any modifications to the protocol which may impact the conduct of the study, potential benefit of the 
patient or may affect patient safety, including changes of study objectives, study design, patient 
population, sample sizes, study procedures, or significant administrative aspects will require a formal 
amendment to the protocol. Such amendment will be agreed upon by the BMS/Pfizer Alliance and 
approved by the IRB prior to implementation. 
2.5. CONFIDENTIALITY 
All study-related data will be stored securely at study sites. The data will be coded with a unique study-
specific identifier. Data will be stored on secured server, behind CSMC’s firewall and only accessible 
to select study investigators. 
3. INVESTIGATIONAL PLAN 
 
3.1. STUDY SETTING  
Cedars-Sinai is a full-service, acute tertiary care hospital and the largest nonprofit academic medical 
center in the Western United States. The Medical Center is located on a 24-acre site, which includes a 
1.6 million square foot main complex and 12 other structures, for a total of more than 4.1 million sq. ft. 
This tertiary care facility contains over 800 beds for Internal Medicine, Obstetrics, Gynecology, 
Pediatrics and Surgery; a 28-bed rehabilitation and outpatient surgery unit; a 29-bed Skilled Nursing 
and Assessment Unit; the 150-bed Saperstein Critical Care Tower; and the new Advanced Health 
Sciences Pavilion. CSMC is a major teaching facility of the David Geffen School of Medicine at UCLA, 
with over 250 full-time faculty members in ten different departments. As a part of the DGSOM, most of 
the full-time staff hold full academic titles at UCLA, are active in the governance and committee 
structure of UCLA Academic Senate (graduate and undergraduate schools alike), and participate in the 
training of medical students, interns, residents and fellows. Cedars-Sinai marked its transition to a 
degree-granting institution June 11, 2013 by awarding doctorates to seven students in its own Graduate 
Program in Biomedical Sciences and Translational Medicine. At present, a total of 32 students have 
been awarded their doctorates. CSMC boasts a world-renowned faculty and over 60 highly competitive 
graduate medical education programs for more than 350 residents and fellows. Biomedical research is 
an integral function of the Medical Center’s commitment to developing excellent patient care. 
Translational and clinical research at CSMC falls under the purview and oversight of the Burns and 
Allen Research Institute, ranked among the top ten non-university biomedical research institutions in 
the nation in terms of funding from the National Institutes of Health. The scope of research conducted 
at CSMC encompasses a broad spectrum of disease-related investigations, ranging from molecular 
genetics, biochemical analysis, comparative animal research to clinical investigation, therapeutic trials, 
and patient care outcomes research. Over 1,888 projects involve more than 341 principal investigators. 
New federal funding for research at CSMC has increased by more than 74.3% from FY 16. As of June 
2017, there were 1,398 IRB-approved studies conducted by more than 341 unique PIs and 450 new 
studies approved with 128 unique PIs. Federal support as of June 2017 at CSMC for 425 federal 
projects reached a total of 65 million/yr that produce an average of approximately one peer-reviewed 
publication per working day. There is over 440,000 square feet of laboratory and laboratory support 
space, including the seven-story, 218,000 square foot, Barbara and Marvin Davis Research Building, 
adjacent to the main hospital, and the new state of the art Advanced Health Sciences Pavilion (AHSP) 
which opened in May 2013. Cedars-Sinai has a multi-disciplinary and comprehensive PE response 
team (PERT) program consisting of both acute care as well as long term follow-up. More than 600 
acute PE patients are seen and evaluated at Cedars-Sinai, each year.  
 


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16 
Scientific Environment: Cedars-Sinai Medical Center 
As the largest non-profit academic medical center in the Western United States and the largest teaching 
hospital affiliated with the David Geffen School of Medicine at UCLA, CSMC boasts a world-renowned 
faculty and over 60 highly competitive graduate medical education programs for more than 350 
residents and fellows. A major expansion of research infrastructure has recently increased existing wet 
lab space to 400,000 sq. ft. with the completion of the new Advanced Health Sciences Pavilion (AHSP). 
The AHSP houses clinical programs, research laboratories, and expanded vivarium space, and is 
specifically intended to stimulate translational medicine by providing an environment that fosters 
interaction between translational scientists and clinicians. In addition, intensive recruitment efforts 
during the last five years have added over two dozen outstanding faculty investigators. 
 
The scope of research conducted at CSMC encompasses a broad spectrum of disease-related 
investigations ranging from molecular genetics, biochemical analysis, comparative animal research to 
clinical investigation, therapeutic trials, and patient care outcomes research. Over 1,280 projects 
involve more than 310 principal investigators.  
 
Victor Tapson, MD: In the field of venous thromboembolism, Dr. Tapson has served on the ACCP 
Consensus Statement for Venous Thromboembolism a number of times. He served as Chairman for 
the ATS Consensus Statement and Clinical Practice Guidelines for the Diagnostic Approach to Acute 
Venous Thromboembolism.  He has cared for thousands of patients with acute PE. He has served as 
world-wide principal investigator (PI) or co-PI for several venous thromboembolism registries including 
DVT-FREE, IMPROVE, NABOR, ENDORSE. He is currently PI for the OPTALYSE PE study, the BiO2 
IVCF study, and is co-PI for the world-wide TAFIa clinical trial in acute PE, as well as for the FLARE 
clot-extraction study.  In 2014, he left Duke for an outstanding opportunity at Cedars-Sinai Medical 
Center where he continues this work. 
 
Aaron Weinberg, MD, MPhil: Dr. Weinberg is a triple board certified (Internal Medicine, Pulmonary 
Disease, Critical Care) Pulmonologist at Cedars-Sinai Medical Center, specializing in the treatment and 
prevention of venous thromboembolic disease. He is a founding member of the Pulmonary Embolism 
Response Team (PERT) at Cedars-Sinai, and on a global scale, serves as the Communications Co-
Chairmain of the national PERT consortium. Dr. Weinberg is actively involved as Co- or Principal 
Investigator on over nine research studies. He is also a member of the teaching faculty for the 
Pulmonary and Critical Care Fellowship at Cedars-Sinai.  
3.2 STUDY DESIGN 
This is a randomized, double-blinded, placebo-controlled, single-center study intended to investigate 
very low dose systemic (IV) tPA along with standard anticoagulation therapy followed by standard dose 
oral apixaban as a treatment for intermediate-high risk (submassive) PE. To date, studies have 
demonstrated that full dose (100 mg) and half-dose (50mg) systemic (IV) tPA are effective for lysing 
clot; however, at the expense of clinically significant bleeding.  Catheter-directed trials have shown that 
24mg of tPA can be administered through a pulmonary artery catheter with clinical improvement in 
obstructive index and RV/LV ratio without an increased risk of bleeding.  However, such procedures 
are time consuming, expensive, and there is the concern for clinical decompensation during the 
intervention. To date, no study has tested whether the same low dose (24mg) of systemic (IV) tPA 
could be delivered systemically with equally favorable results. 
 
In this trial, 40 patients (20 per arm) will be randomly assigned using a computer program at Cedars-
Sinai Medical Center in Los Angeles, California.  Additional subjects may be consented to compensate 
for screening failures and/or treated patients who lack sufficient data.   
 


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17 
The study is planned to evaluate the reduction in clot burden (obstruction index using the Refined 
Modified Miller Score), improvement in RV dysfunction, and overall safety in the two treatment groups.  
Subjects with intermediate-high risk PE (hemodynamically stable PE with a RV dysfunction and an, 
elevation in Troponin and/or BNP) will be randomized to one of two treatment groups: 24mg of systemic 
(IV) tPA + IV unfractionated heparin followed by the oral anticoagulant, apixaban, versus saline placebo 
+ IV unfractionated heparin followed by oral apixaban.   
 
Apixaban was chosen as the anticoagulant of choice due to its favorable bleeding profile in initial 
studies, which is an important consideration when using an anticoagulant following systemic 
thrombolysis.   
 
Bleeding, recurrent PE and serious adverse events will be collected and reported throughout the study. 
Specific reporting for the primary safety (major bleeding) events will occur during the first 72 hours. We 
will continue monitoring for bleeding (secondary safety endpoints) for up to 30 days. 
 
All imaging studies will be sent to the Syntactx core imaging laboratory for evaluation. Procedures for 
transfer of images from study site to Syntactx will be provided and we will maintain patient HIPAA 
confidentiality. Results of the assessments will be blinded and entered into the clinical database.  All 
data from the study will be blinded and exclude information regarding the drug administered.  Subjects 
will return for follow-up clinic evaluations at Day 30, 180 and 365 ± 15 days.  It is anticipated that the 
clinical study duration will be up to 24 months including first subject enrolled through to last subject 
completed or until the study is formally terminated. An individual subject’s participation will be 
approximately 1 year. 
 
The figure below shows the schematic summary of the trial design: 


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18 
 
3.3. STUDY POPULATION 
3.3.1. INCLUSION CRITERIA 
Patients eligible for the trial must comply with the following at randomization: 
• Male or female 18-75 years in age 
• Chest CT angiogram evidence of proximal PE with a filling defect in at least one main pulmonary 
artery or lobar artery 
• PE symptom duration ≤14 days  


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19 
• Intermediate-high risk PE: defined as PE with significant clot burden, RV dysfunction elevation in 
either troponin and/or BNP. and hemodynamically stable (systolic blood pressure>90mm Hg without 
the use of vasopressor support)  
• Randomization within 36 hours of anticoagulation  
• Signed and dated informed consent obtained from subject or Legally Authorized Representative 
before initation of any study procedures 
 
3.3.2. EXCLUSION CRITERIA 
Patients with any one of the following will be excluded from participation in this clinical trial: 
• Stroke or transient ischemic attack (TIA), head trauma, or other active intracranial or intraspinal 
disease within one year 
• Recent (within one month) or active bleeding from a major organ  
• Major surgery within seven days 
• Clinician deems the subject too high-risk for bleeding using HAS-BLED criteria 
• History of any hematologic disease or coagulopathy  
• Cirrhosis (as determined by Child-Pugh B or C) 
• History of heparin-induced thrombocytopenia (HIT) 
• Hemodynamic instability defined as systolic blood pressure (SBP) less than 90 mm Hg and/or use 
of vasopressors for greater than 15 minutes 
• Severe hypertension as define as systolic blood pressure (SBP) greater than 180 mm Hg 
• Cardiac arrest or active cardiopulmonary resuscitation (CPR) 
• Receiving neuraxial anesthesia or undergoing spinal puncture 
• Patient with prosthetic heart valves 
• Evidence of irreversible neurological compromise 
• Evidence of poor functional status 
• History of a major gastrointestinal bleed 
• Active gastric or duodenal ulcers 
• Use of thrombolytics or glycoprotein IIb/IIIa antagonists within 3 days prior to diagnosis 
• Lovenox administration within 12 hours of randomization  
• Direct-acting oral anticoagulant use (dabigatran, rivaroxaban, apixaban, or edoxaban) with last 
known  dose within 48 hours. 
• Hemoglobin < 10 g/dL 
• platelets < 100 thousand/μL 
• INR > 1.4  
• Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 2 times upper limit of normal (ULN) 
• Total bilirubin (TBL) ≥ 1.5 times ULN (except due to confirmed Gilbert’s syndrome) 
• creatinine clearance < 30 mL/min 
• Patient is pregnant (positive pregnancy test; women of childbearing capacity must be tested prior 
to enrollment) or breast feeding 
• Patient who is a prisoner, or if subject who becomes compulsory detained 
• Active cancer defined as diagnosis of cancer within six months before the study inclusion, or 
receiving treatment for cancer at the time of inclusion or any treatment for cancer during 6 months 
prior to randomization, or recurrent locally advanced or metastatic cancer  
• Known allergy, hypersensitivity or thrombocytopenia from heparin, tPA, apixaban, or iodinated 
contrast except for mild-moderate contrast allergies for which steroid pre-medication can be be 
administered within 12 hours prior to the CTA. 
• HIV/AIDS  


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20 
• Weight>130 kg or < 40 kg.on day of randomization 
3.3.3  WOMEN OF CHILDBEARING POTENTIAL 
Women of childbearing potential is defined as any female who has experienced menarche and who 
has not been surgically sterilized or is not postmenopausal. Menopause is as 12 months of amenorrhea 
in a woman over age 45 in the absence of other physiological causes. Serum beta human chorionic 
gonadotropin (β-hCG) pregnancy test will be performed at the Screening Visit on all women of 
childbearing potential. 
 
During the duration of the study, women of childbearing potential must agree to use two effective birth 
control methods (for example: birth control pills, condoms, etc) at the same time, and be able to comply 
with effective contraception without interruption during the study therapy (including dose interruptions). 
3.4. CONCOMITANT TREATMENTS 
3.4.1 PROHIBITED AND/OR RESTRICTED TREATMENTS 
The following systemic medications may increase the risk of bleeding and will not be concurrently 
administered during the study: 
• Other antithrombotic agents such as vitamin K antagonists (i.e., warfarin) 
• Other factor Xa inhibitor oral anticoagulants (e.g. rivaroxaban, edoxaban, or betrixaban) 
• Fondaparinux or low molecular weight heparins 
• direct thrombin inhibitors (dabigatran, argatroban, bivalirudin, lepirudin, etc.) 
• glycoprotein IIb/IIIa antagonists during the thrombolytic infusion 
• NSAIDS 
3.4.2 OTHER RESTRICTIONS AND PRECAUTIONS 
None 
3.5. DISCONTINUATION OF SUBJECTS FROM TREATMENT 
Discontinuation of alteplase 
If a subject develops the following adverse events the alteplase infusion will be permanently 
discontinued: 
• SAE or other safety concern that is related to study drug treatment  
• New onset of neurological symptoms 
• New onset of severe headache 
• Major life-threatening bleeding (per GUSTO criteria) 
• Initiating or continuing study drug places the subject at undue hazard as determined by the 
Investigator 
 
The subject will continue to be followed for the remainder of the study. The subject will be assessed 
immediately after the infusion and appropriate clinical treatment will be instituted. 
One of the PIs will use his clinical judgment to determine the treatment needed and this may include 
imaging studies, blood transfusions and IVC filter placement. Once the subject is stabilized, if 
anticoagulant therapy is considered a clinical option, the subject will be started on apixaban per 
protocol. 
 
Discontinuation of Apixaban 
If a subject must be discontinued from apixaban before the end of the study, this will not result in 
automatic withdrawal of the subject from the study, and the subject should continue to be followed for 
efficacy and safety outcomes. 


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21 
 
 
A subject should be discontinued from apixaban if: 
• The investigator believes that for safety reasons (ie, adverse event) it is in the best interest of 
the subject to stop apixaban. 
• The subject develops any condition which requires anticoagulation or thromboprophylaxis (ie, 
atrial fibrillation, VTE). 
• The subject becomes pregnant. 
• The subject requests to discontinue apixaban permanently 
• The subject has a major life-threatening bleed (per GUSTO criteria); 
 
If the subject permanently discontinues apixaban before the 6-month visit, he/she should be instructed 
to complete an unscheduled visit and the remaining scheduled visits. The investigator will provide a 
narrative to describe any adverse events that occur up to apixaban discontinuation. The appropriate 
adverse event or serious adverse event sections of the eCRF are to be completed.  
A subject should have apixaban administration interrupted if the following conditions occur: 
• Bleeding that is significant that does not fit GUSTO criteria 
• Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 2 times upper limit of 
normal (ULN) 
• Total bilirubin (TBL) ≥ 1.5 times ULN (except due to confirmed Gilbert’s syndrome) 
• Subjects with a significant drop in hemoglobin 
• Consider discontinuation / follow if Hgb < 10  
 
The PI will use clinical judgment to determine course of action (labs, imaging studies, etc.) and decide 
when and if the apixaban can be restarted. 
 
Withdrawal from the Study 
A subject will be withdrawn from the study for any of the following reasons:  
• Lost to follow-up (only after all means of all subsequent contact, including locator services where 
permitted by law) or,  
• Withdrawal of consent (unless specifically refused by the subject. Subject contact will be made 
to obtain vital status and other outcomes at the 3, 6- and 12-month visit). 
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel to 
contact the subject and determine the reason for discontinuation/withdrawal. The measures taken to 
follow up must be documented. 
 
If a subject withdraws consent from study or is lost to follow-up, his or her vital status and other 
outcomes will be collected at the Day 30, 180 and 365 visits either by telephone or in person, or if 
applicable, by a review of the subject’s medical or public records unless this contact is not allowed by 
local regulations. 
 
Stopping rules at the interim analysis for the treatment (tPA) group would involve: 
• Severe bleeding in the first 72 hours: 
-One fatal intracranial hemorrhage (ICH) 
-Two ICH of any kind 
-Severe or life-threatening bleed rate of 15%; i.e., three patients (GUSTO criteria) 


SAFE-LYSE | STUDY PROTOCOL  
 
22 
• Two cases of death from acute PE (in either group), if occurring during hospitalization 
(deterioration in a patient who survives will not be considered in stopping rules). 
• Any other issue that the DMC believes merits discontinuing the trial. 
4. TREATMENTS 
4.1. STUDY TREATMENTS 
4.1.1. Investigational Product and Apixaban Administration 
Tissue Plasminogen Activator (tPA) is a commercially available drug approved for fibrinolysis of PE by 
systemic infusion at the dose of 100mg. tPA [Activase (alteplase)] (24mg) or placebo will be prepared 
by the research pharmacy. 
 
Apixaban is an oral anti-Xa anticoagulant approved by the FDA for the treatment and prevention of 
venous thromboembolic disease. Study subjects will take 10mg by mouth twice a day for 7 days and 
5mg by mouth twice a day thereafter for 12 months. 
4.1.2.. HANDLING AND DISPENSING 
 
Systemic (IV) tPA  
Systemic (IV) tPA used in the study will be procured from the research pharmacy and prepared 
following pharmacy procedures and manufacturer instructions.      
 
IV unfractionated heparin (Standard of Care) 
Unfractionated heparin will be administered intravenously and is approved by the FDA for the treatment 
and prevention of venous thromboembolic disease. Unfractionated heparin will be procured from the 
main hospital pharmacy and prepared following pharmacy procedures and manufacturer instructions. 
 
Apixaban anticoagulant 
Apixaban will be provided by BMS for the duration of the study. It will be stored and dispensed by the 
research pharmacy. Atter completion of the study, the treating physician will determine if apixaban 
should be continued based on current guidelines and expert opinion.  If the treating physician desires 
continuation of treatment, the subject will obtain this medication via usual channels. 
4.2. METHOD OF ASSIGNING SUBJECT IDENTIFICATION 
A subject who has signed informed consent and meets all eligibility criteria will be randomized by 
computer to receive either very low dose systemic (IV) tPA (24mg) + anticoagulation vs normal saline 
placebo (of same volume as systemic [IV] tPA) + anticoagulation. Subjects will be transitioned to 
apixaban 24 hours after study drug administration if subject has no evidence of active bleeding nor 
significant hemoglobin drop (i.e. ≥ 2 mg/dL).  
4.3. BLINDING AND UNBLINDING 
All study personnel except the research pharmacy team will be blinded to intervention groups. The 
treatment medication and placebo will be prepared in similar IV bags and volumes. Assessments 
regarding clinical recovery will be conducted by an assessor blind to treatment allocation.  
To maintain the overall quality and legitimacy of the clinical trial, unblinding should occur only in 
exceptional circumstances when knowledge of the actual treatment is absolutely essential for further 
management of the patient. 
 


SAFE-LYSE | STUDY PROTOCOL  
 
23 
The Investigator is encouraged to maintain the blind as far as possible. The actual allocation must NOT 
be disclosed to the patient and/or other study personnel including other site personnel, monitors, 
BMS/Pfizer Alliance or project office staff; nor should there be any written or verbal disclosure of the 
code in any of the corresponding patient documents. 
4.4. TREATMENT COMPLIANCE 
The Investigator(s) or designee(s) is responsible for accounting for apixaban that is issued to and 
returned by the subject during the course of the study. Accurate recording of all apixaban 
administration (including dispensing and dosing) will be made in the appropriate section of the 
subject’s CRF and source documents. Study personnel will review the instructions printed on the 
package with the study subjects prior to dispensing the study drug. The apixaban will be dispensed as 
noted in the Flowchart of Procedures. The subjects will be instructed to return the apixaban containers, 
including any unused apixaban, to the study site at each visit for tablet counts and reconciliation. 
Subjects will be asked whether they have taken their apixaban as instructed at each study visit. Any 
problems with apixaban compliance will be reviewed with the subject. If a subject misses 4 or more 
consecutive days of dosing, the investigator will decide whether dosing should resume or whether the 
subject should be terminated from the study drug and entered into the Posttreatment Observational 
Follow-up Phase. 
 
Study drug compliance will be calculated at each visit as: 
Compliance (%) = Number of tablets actually taken between visits                                X 100 
                              Number of tablets that should have been taken between visits 
4.5. DESTRUCTION OF STUDY DRUG 
The research pharmacy will follow the CSMC drug destruction institutional policies. 
5. STUDY ASSESSMENTS AND PROCEDURES 
5.1. SCREENING PROCEDURES 
All subjects presenting for evaluation and treatment of intermediate-high risk PE will be considered for 
the study.  All subjects that meet the study’s inclusion criteria and do not meet any exclusion criteria 
are eligible for randomization into the study. 
 
Potential subjects will be referred to the Pulmonary Embolism Response Team (PERT) by their treating 
physician. We will also identify potential patients through the Deep 6 AI Cohort Builder. Deep 6 will be 
the primary method of screening. If this primary method is not successful, then the study team is 
requesting a waiver of consent and HIPAA in order to conduct an additional secondary review of the 
patients’ medical records. For the potential subjects identified via these methods, an investigator will 
discuss the study with their treating physician and seek permission to discuss the study with his/her 
patient. For patients referred by their treating physician or for patients who were identified by chart 
review and physician approval was granted, the informed consent process discussed in section 2.3 will 
be followed. 
5.1.1. INFORMED CONSENT 
The Cedars-Sinai Medical Center informed consent template will be used to create the SAFE-LYSE 
informed consent form. This template includes all elements required by ICH, GCP, and applicable 
regulatory requirements. The informed consent form will adhere to the ethical principles that have their 
origins in the Declaration of Helsinki. The consent will also include a statement that the Bristol-Myers 
Squibb Company will not continue to supply study drug to enrolled patients after conclusion of the 


SAFE-LYSE | STUDY PROTOCOL  
 
24 
study. The study participant’s treating physician will be responsible to ensure that they receive 
appropriate standard of care or other treatment for their condition.   
 
The consent form, HIPAA Authorization and all recruitment materials will be approved by the Cedars-
Sinai Medical Center Institutional Review Board (FWA 00000468). The informed consent form will be 
revised if new safety information becomes available or if there are any new additions to the protocol. 
Subjects currently enrolled in the study who may be affected by the new information will be re-
consented. 
5.2 ENROLLMENT 
Subjects will be considered enrolled in the study at the time informed consent is obtained. 
5.2.1. SCREENING ASSESSMENTS 
The following assessments will be performed at Screening: 
• Informed consent  
• Medical history and demographics  
• Inclusion/exclusion criteria 
• Pregnancy test if the subject is female and of child-bearing potential. 
• Vital signs and physical exam including blood pressure, respiratory rate, heart rate, and SpO2. 
• Electrocardiogram (ECG; 12 lead) 
• CT Angiogram to evaluate the anatomic location of PE (at least pulmonary or lobar artery 
involvement). The RV/LV ratio at end-diastole and the initial Refined Modified Miller obstruction 
index score will be determined from this image by a third party blinded radiologist.  
• Echocardiogram to measure: RV dysfunction, RV/LV ratio, TAPSE, estimated RVSP, and collapse 
of the IVC with respiration.  
• Laboratory testing including hemoglobin (Hgb), hematocrit (Hct), platelet count, blood urea nitrogen 
(BUN), creatinine, aPTT, PT and INR, liver function tests (ALP, ALT, AST), troponin I, and B-type 
natriuretic peptide and (BNP). 
• Simplified Pulmonary Embolism Severity Index (sPESI) score calculation 
• Lower extremity duplex ultrasound 
5.3. RANDOMIZATION TO TREATMENT 
A subject who has signed informed consent and meets all eligibility criteria will be randomized by 
computer to receive either very low dose systemic (IV) tPA (24mg) + anticoagulation vs normal saline 
placebo (of same volume as systemic [IV] tPA) + anticoagulation. Subjects will be transitioned to 
apixaban 24 hours after study drug administration if subjects have no evidence of active bleeding nor 
significant hemoglobin drop (i.e. ≥ 2 mg/dL).  
 
All patients who give consent for participation and who fulfill the inclusion/exclusion criteria will be 
randomized. Randomization will be requested by the staff member responsible for recruitment from 
Randomize.net. 
 
In return, Randomize.net will send an answer form to the research pharmacy, who are not involved in 
assessing outcome of the study. This form will include a randomization number. A closed envelope with 
printed randomization numbers on it are available on-site. For every randomization number, the 
corresponding code for the therapy group of the randomization list will be found inside the envelopes. 
The research pharmacy will open the envelope and will find the treatment condition to be conducted. 
Treatment medication will be prepped according to the randomization assignment. Staff responsible for 
recruitment and symptom ratings is not allowed to receive information about the group allocation. 


SAFE-LYSE | STUDY PROTOCOL  
 
25 
5.3.1. SEQUENCE GENERATION 
Subjects will be randomly assigned to either control or experimental group with a 1:1 allocation as per 
a computer generated randomization schedule using permuted blocks of random sizes. The block sizes 
will not be disclosed to ensure concealment. 
5.3.2. CONCEALMENT MECHANISM 
Subjects will be randomized using Randomize.net, which is an online, central randomization service. 
Allocation concealment will be ensured, as the service will not release the randomization code until the 
patient has been recruited into the trial, which takes place after all baseline measurements have been 
completed. 
5.4. STUDY INTERVENTIONS 
Eligible patients will be randomized in equal proportions between very low dose systemic (IV) tPA 
(24mg) + IV unfractionated heparin or saline placebo + IV unfractionated heparin. Study drug will be 
infused as follows: 4mg bolus IV push over 1 minute followed by 20mg infused IV over 19 minutes.  
 
The study drug will be purchased from Genentech in its commercially available recombinant form. The 
study drug and placebo will be relabelled by the Cedars-Sinai Medical Center Research Pharmacy 
according to MHRA (Medicines and Healthcare Regulatory Agency) guidelines. 
 
Study drug will be administered within 36 hours of anticoagulant administration. Study drug or placebo 
will be administered to the patient by a study-trained nurse while the patient is in hospital. All personnel 
will be blinded to the identity of the IV bag contents. 
5.4.1. TREATMENTS AND TIMING 
 
SAFE-LYSE Flowchart of Procedures 
Procedures 
Baseline  
up to 48 
hours pre 
study 
medication 
Day 0 
Day 1 
Day 2 
Day 3 & 
Day 7 
Day 30 
+15 days 
(Clinic 
Visit) 
Day 90    
+15 days 
(Phone 
contact) 
Day 180 
+15 days 
(Clinic 
contact) 
Day 270    
+15 days 
(Phone 
contact) 
Day 
365 +15 
days 
(Clinic 
Visit) 
ET1 
Informed consent 
x 
  
  
  
 
  
  
  
  
  
  
Inclusion/Exclusion 
x 
  
  
  
 
  
  
  
  
  
  
Randomization 
  
x 
  
  
 
  
  
  
  
  
  
Heparin 
anticoagulation 
therapy2 
x 
x 
x 
  
 
  
  
  
  
  
  
Pregnancy test (if 
applicable) 
x 
  
  
  
 
  
  
  
  
  
  
Medical and 
demographic history 
x 
  
  
  
 
  
  
  
  
  
  
Physical exam 
x 
  
x 
  
 
x 
  
x 
  
x 
x 
Vital signs including 
pulse ox  
x 
x 
x 
x 
 
x 
  
x 
  
x 
x 


SAFE-LYSE | STUDY PROTOCOL  
 
26 
SAFE-LYSE Flowchart of Procedures 
Procedures 
Baseline  
up to 48 
hours pre 
study 
medication 
Day 0 
Day 1 
Day 2 
Day 3 & 
Day 7 
Day 30 
+15 days 
(Clinic 
Visit) 
Day 90    
+15 days 
(Phone 
contact) 
Day 180 
+15 days 
(Clinic 
contact) 
Day 270    
+15 days 
(Phone 
contact) 
Day 
365 +15 
days 
(Clinic 
Visit) 
ET1 
Chest contrast-
enhanced computed 
tomographic 
angiogram (chest 
CTA) 
x 
  
x 
  
 
  
  
  
  
  
  
Echocardiogram 
x 
  
x 
  
 
x 
  
x 
  
 
x 
Ultrasound of lower 
expremities to rule 
out DVT 
x 
 
 
 
 
 
 
 
 
 
 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
Hemoglobin, 
hematocrit, platelet 
count 
x 
x 
x 
x 
 
x 
  
  
  
  
  
BUN, creatinine 
x 
x 
 x 
  
 
x 
  
  
  
  
  
Liver Function Tests 
x 
  
  
  
 
x 
  
  
  
  
  
aPTT, PT and INR 
x 
x 
  
  
 
 
  
  
  
  
  
Troponin I (or 
Troponin T) 
x 
  
  
  
 
 
  
  
  
  
  
BNP 
x 
  
  
  
 
 
  
  
  
  
  
sPESI 
x 
  
x 
  
 
  
  
  
  
  
  
Quality of life 
questionnaires 
  
  
  
  
 
x 
  
x 
  
x 
x 
Administration of 
tPA/placebo 
  
x 
  
  
 
  
  
  
  
  
  
Administration of 
apixaban3 
  
  
x 
x 
x 
x 
 
x 
 
 
  
6 Minute Walk and 
Borg Dyspnea scale 
  
  
  
  
 
x 
  
x 
  
x 
x 
Remote health 
checks (phone and 
email) 
  
  
  
  
 
  
x 
  
x 
  
  
Review of 
medications and 
adverse events, 
bleeding events and 
VTE events 
x 
x 
x 
x 
x4 
x 
x 
x 
x 
x 
x 
1Early Termination: Obtain if subject withdraws early 
2Heparin duration up to clinician discretion but patient must be on for at least 24 hours after infusion of study drug.  
3Could start as early as soon as 24 hours post treatment, contingent upon clinician discretion.  
472-hour assessment of AE will be conducted either in person or if discharged via telephone call. Day 7 follow up will be 
telephone call. 


SAFE-LYSE | STUDY PROTOCOL  
 
27 
Anticoagulation 
All subjects will receive unfractionated IV heparin per standard of care with a goal of aPTT of 1.5 - 2 
times control which is approximately 50-70 seconds, upon established diagnosis of PE.    
 
Twenty-four hours after study drug administration, when the bleeding risk is determined to be low by 
the treating physician (i.e. no active bleeding nor significant hemoglobin drop ≥ 2 mg/dL), post-
intervention evaluations are complete, the patient is tolerating oral medications, and the patient’s 
creatinine clearance is >30 mL/min, the IV unfractionated heparin will be stopped.  Provided bleeding 
risk is deemed acceptable, they will be immediately started on apixaban (Eliquis) 10 mg twice-daily x 
one week followed by 5 mg twice-daily for at least 6 months. Based on patient-specific factors, including 
unprovoked nature of PE event, and/or persisting DVT/PE risk factors, consideration will be given for 
decreasing the apixaban dose to 2.5 mg twice-daily after 6 months for the remainder of the study.   The 
duration of total anticoagulation will be determined by the treating physician based on clinic judgement, 
risk of recurrence, and whether the initial PE was provoked. Apixaban will be dispensed on Day 1, 30, 
and 180. 
 
Timing of Thrombolytic Intervention 
The subject will receive 24 mg of systemic (IV) tPA vs normal saline placebo within 24 hours of initiaition 
of anticoagulation therapy.  
 
Systemic (IV) tPA 
Commercially available formulation of systemic (IV) tPA (Genentech) may be used and all instructions 
for reconstitution provided in the package insert should be followed. tPA will be specially labeled for the 
study. The systemic (IV) tPA will be infused as follows: 4mg bolus followed by infusion at a rate of 20mg 
over 19 minutes for a total of 24mg. 
 
Normal Saline Placebo 
The pharmacy will prepare a normal saline placebo packaged in the same fashion as the systemic (IV) 
tPA. The saline will be infused as follows: 4mg bolus followed by infusion at a rate of 20mg over 19 
minutes for a total of 24mg. 
 
Day 0 Assessments: Pre-Infusion and Post-Infusion 
• Vital signs including temperature, respiratory rate, heart rate, blood pressure, and oximetry will be 
obtained.  
• Assessment of adverse events and bleeding events. 
 
Day 1 Assessments 
• Vital signs including temperature, respiratory rate, heart rate, blood pressure, and oximetry will be 
obtained.  
• Physical Examination will be completed. 
• Within 24 ± 8 hours of discontinuing treatment, the subject will be assessed for improvement in PE 
signs and symptoms including sPESI score, repeat CT angiogram for determination of thrombus 
burden as measured by a Refined Modified Miller Score and RV/LV ratio, and an echocardiogram.  
• Laboratory tests for Hgb, Hct, platelet count, aPTT, PT and INR, BNP, troponin, BUN and creatinine 
will also be obtained. 
• Adverse events, VTE recurrence, and bleeding events will be recorded. 
 
 
 


SAFE-LYSE | STUDY PROTOCOL  
 
28 
Day 2 Assessments 
• Vital signs including temperature, respiratory rate, heart rate, blood pressure, and oximetry will be 
obtained.  
• Laboratory tests for Hgb, Hct, platelet count, aPTT, PT and INR, BUN and creatinine will also be 
obtained. 
• Adverse events, VTE recurrence, and bleeding events will be recorded. 
 
Follow-up Clinic Visits and Subject Contact 
• The subjects will be followed until Day 365 ± 15 days. 
• A 72-hour follow-up assessment of Adverse Events will be conducted either in-person if the subject 
is still admitted at CSMC, or via telephone call if the subject is discharged. 
• A Day 7 follow-up assessment of Adverse Events will be conducted via telephone call. 
• The subject will return to the clinic Day 30, 180 and 365. 
• The following assessments will be performed at follow-up clinic visits: 
o Echocardiogram at Day 30 and Day 180. Echocardiogram will be repeated at Day 365/EOT 
if last echocardiogram was abnormal. 
o Blood draw for laboratory tests, including hemoglobin, hematocrit, platelet count, BUN, 
creatinine, and liver function tests at Day 30. 
Physical exam and vital signs including respiratory rate, heart rate, blood pressure, 
temperature, and sPO2  
o 6MWT with Borg score and requirement for oxygen therapy 
o Quality of life (QOL) as measured by the PROMIS PF-6 and Pulmonary Embolism Quality of 
Life (PEmb-QOL) 
o Adverse Events through 1 year follow-up. 
o Signs or symptoms of recurrent VTE  
o Changes in anticoagulant medications 
o Evidence of chronic thromboembolic disease or chronic thromboembolic pulmonary 
hypertension 
• Phone calls for remote health checks will be conducted at Day 7, Day 90 ± 15 days and Day 270 ± 
15 days.  
5.5. RESCUE TREATMENT 
In the event of hemodynamic collapse, the following emergency supportive and therapeutic measures 
can be provided at the discretion of the investigator and responsible clinical team:  
 
• Inotropic or vasopressor agents  
• Additional rescue peripherally-administered systemic fibrinolytic therapy  
• Surgical pulmonary embolectomy  
• Catheter-assisted embolectomy including catheter directed thrombolysis and embolectomy 
• IVC filters: The insertion of IVC filters is discouraged unless the subject develops a contraindication 
to therapeutic dose systemic anticoagulation or if the subject suffers recurrent PE despite 
therapeutic levels of anticoagulation.  
• ECMO 
 
5.6 
SAFETY ASSESSMENTS 
Adverse events/SAEs, vital signs, significant physical examination findings, and results of clinical 
laboratory tests will be assessed throughout the study. A local laboratory will perform the laboratory 


SAFE-LYSE | STUDY PROTOCOL  
 
29 
analyses and will provide reference ranges for these tests. The following clinical laboratory tests will be 
performed: 
 
Hematology 
Hemoglobin 
Hematocrit 
Platelet count 
 
Liver Function Tests 
ALT 
AST 
Total Bili 
 
Chemistry 
Creatinine 
 
Other Analyses 
Pregnancy test (WOCBP only: screening) 
6. DATA COLLECTION, MANAGEMENT AND ANALYSIS 
6.1. DATA COLLECTION METHODS 
After obtaining consent, all subjects are assigned a study-specific ID upon enrollment, which will be 
used in lieu of PHI to obtain patient data for SAFE-LYSE. The study-specific ID will be linked to the 
subject’s medical record number. The information will be stored in a password protected file on a secure 
server, behind CSMC’s firewall and only accessible to select study investigators.  
 
When a physician refers patients to the SAFE-LYSE study, study staff will pre-screen the patient for 
eligibility. If the patient qualifies, the PI or sub-investigator will introduce the study and review the 
informed consent with the patient. If the patient agrees to participate, the consent form will be signed 
and the patient will be randomized. The research pharmacy is notified and will begin to prepare study 
drug or placebo as assigned. In the meantime, appropriate study staff will collect necessary labs, 
administer questionnaires, and complete case report forms at certain timepoints per protocol. All 
imaging will be de-identified and transferred to the Syntactx imaging core laboratory for evaluation. 
Upon discharge, study staff will coordinate attendance at Day 30, 180 and 365 follow-up visits. Study 
staff will also conduct interim phone calls to assess for AE’s and administer questionnaires per protocol 
at Day 90 and 270.  
6.1.2. WITHDRAWAL 
Subjects may withdraw from the study for any reason at any time. The investigator also may withdraw 
subjects from the study in order to protect their safety and/or if they are unwilling or unable to comply 
with required study procedures. Subjects also may be withdrawn if BMS/ Pfizer Alliance or government 
or regulatory authorities terminate the study prior to its planned end date.  
 
All data collected prior to withdrawal will remain part of the study. Every effort will be made to have the 
subject return to the clinic to obtain final study assessments.  
 
 


SAFE-LYSE | STUDY PROTOCOL  
 
30 
6.2. DATA MANAGEMENT 
The Investigator will ensure that the records and documents pertaining to the conduct of the study and 
the distribution of the investigational product are complete, accurate, filed and retained. Examples of 
source documents include: hospital records; clinic and office charts; laboratory notes; memoranda; 
subject’s diaries or evaluation checklists; dispensing records; recorded data from automated 
instruments; copies or transcriptions certified after verification as being accurate copies; CTA reports; 
and records kept at the pharmacy and the laboratories, as well as copies of CRFs. 
6.2.1. DATA FORMS AND DATA ENTRY 
Data will be collected via case report forms (CRF) and entered into a research database maintained 
in REDCap (Research Electronic Data Capture). This data will be electronically verified through use 
of programmed edit checks specified by the clinical team. Discrepancies in the data will be flagged in 
REDCap and corrected by the study team. An audit trail within REDCap will track all changes made 
to the data. 
 
CT and Echo DICOM images will be transmitted to the imaging core laboratory, Syntactx. A central 
reader will review the images and complete a case report form. Syntactx will read the images in bulk at 
the end of the study. 
6.2.2 DATA TRANSMISSION AND EDITING 
The data entry fields in REDCap will resemble the CRFs used to capture study data. Data integrity will 
be enforced through a variety of mechanisms. Referential data rules, valid values, range checks, and 
consistency checks against data already stored in the database will be supported. Checks will be 
applied at the time of data entry into a specific field and/or before the data is written into the database. 
Modifications to the data written to the database will be documented through either the data change 
system, an inquiry system, and/or the electronic audit trail created in REDCap for entries and changes. 
Data entered into the database will be retrievable for view in REDCap. The type of activity that an 
individual user may undertake is regulated by the privileges associated with his/her user identification 
code and password. 
6.2.3 DATA DISCREPANCY INQUIRIES AND REPORTS TO CORE COORDINATING CENTERS 
Additional errors will be detected by programs designed to detect missing data or specific errors in data. 
These errors will be summarized along with detailed descriptions for each specific problem in Data 
Query Reports. The research staff who receives the inquiry will respond by checking the original forms 
for inconsistency, checking other sources to determine the correction, and/or modifying the original 
form by entering a response to the query. The CDCC will be responsible for making appropriate 
corrections to the original paper forms whenever any data item is changed. Written documentation of 
changes will be available via electronic logs and audit trails. 
6.2.4 SECURITY AND BACK-UP OF DATA 
Study-related reports, documents and trackers will be stored on a HIPAA compliant secure server on 
a password-protected computer. The research team will ensure that records and documents pertaining 
to the conduct of the study are complete, accurate, filed and retained. A complete back-up of the 
primary database will be performed once per month. 
6.3. DATA MONITORING 
6.3.1. FORMAL COMMITTEE 
A Data Monitoring Committee (DMC) will be assembled to assess safety endpoints. The Board will be 
comprised of 3 non-study personnel who are experts in the field of Pulmonary Medicine. The Board will 


SAFE-LYSE | STUDY PROTOCOL  
 
31 
meet after the first 10 patients complete Day 30. The DMC will be independent from the CSMC, BMS 
and competing interests. A charter with further details will be available.  
6.3.2. HARMS 
A rigorous screening process will be utilized to verify eligibility.  This will include reviewing the imaging 
diagnosis of PE (to ensure that subjects without acute PE are not inadvertently enrolled in the study), 
performing a detailed history and physical examination (to ensure that enrolled subjects truly fulfill all 
eligibility criteria), and carefully reviewing the results of laboratory testing (in particular, hematocrit, 
platelet count, INR, and creatinine clearance).  
 
During study drug treatment period, the subject will be monitored during the infusion and the infusion 
will be stopped if bleeding occurs. To reduce the risks associated with the CTA, we will ascertain that 
the subject has no history of allergic reaction to the contrast and we will make sure their creatinine 
clearance is adequate. 
 
During the follow-up period, changes in health status will be evaluated by the study doctor and reported 
as deemed appropriate. 
6.3.3. AUDITING 
Through the combination of our use of REDCap with its electronic error detection, QA/QC plan, and 
regular site monitoring, we will ensure the quality and completeness of data in this trial. 
7. STATISTICAL CONSIDERATIONS 
7.1. SAMPLE SIZE DETERMINATION 
7.1.1. EFFICACY 
The following information was prepared in collaboration with the Cedars-Sinai Biostatistics Department. 
The primary outcome is mean change in percentage of clot lysis by RMMS from the 24 hour CTA after 
24 mg of systemic (IV) tPA + standard anticoagulation therapy compared to the baseline CTA.  
 
• Statistical Analysis: The main objective is to determine the mean change in clot lysis by RMMS from 
baseline to 24 hours in treatment A (systemic [IV] tPA + IV unfractionated heparin). Data will be 
presented as frequency (percentage, %) for categorical variables and mean (± SD, standard 
deviation) for continuous variables. Profile plots with mean RMMS(± SE, standard error) at baseline 
and 24 hours will be displayed. The post-treatment RMMS score at 24 hours as an outcome variable 
will be modeled using a generalized additive model for location, scale and shape [26, 27] after 
adjusting for the treatment group and the baseline RMMS score [28] to examine if there is a 
difference in the change in RMMS from baseline to 24 hours between two treatment groups. The 
underlying assumptions will be checked using residuals [29]. Statistical analyses will be conducted 
using R package version 3.4.1 [30] with two-sided tests and a significance level of 0.05. 
 
• Sample Size Justification: Statistical power was estimated with a two-sided two-sample equal-
variance t-test. A mean difference of at least 15 percentage units between baseline and post- 
treatment A will be clinically meaningful. According to a previous study [22], the baseline RMMS 
was 21.14 units, thus a decrease of 15% from the amounts is 3.171 units in RMMS. Using the 
standard deviation of the difference in RMMS to 48h post-procedure from the baseline of 2.7 units 
obtained from the same study, 17 patients per group (34 total) achieve 99.5% power, to detect a 


SAFE-LYSE | STUDY PROTOCOL  
 
32 
difference of 15 percentage units (i.e., 3.171 units difference in RMMS) between the baseline CTA 
and 24 hour post-treatment CTA in treatment A with 5% significance level using a two-sided two-
sample equal-variance t-test. 
 
A secondary outcome is mean change in percentage of clot lysis by RMMS from the 24 hour CTA after 
24 mg of systemic (IV) tPA + standard anticoagulation therapy (treatment A) compared to that of the 
24 hour CTA after standard anticoagulation therapy alone (treatment B).  
 
• Statistical Analysis: We will also compare the RMMS at 24 hours for treatment A, with that of 
treatment B (saline placebo + IV unfractionated heparin) as a secondary outcome. Data will be 
analyzed and presented in the same way as the primary outcome.  
• Sample Size Justification: Statistical power was estimated in the same way as the primary outcome. 
17 patients per group achieve 91% power to detect a difference of 15 percentage units between 24 
hour post-treatment CTAs of treatments A and B. 
 
Another secondary outcome is change from baseline RV/LV ratio by chest CTA expressed as 
percentage change from baseline. 
 
• Statistical Analysis: Statistical analysis for the seconday outcome will be similar to the primary 
outcome. 
• Sample Size Justification:  Statistical power was estimated with a two-sided two-sample equal-
variance t-test. A previous study [22] showed that the mean and standard deviation of percentage 
change in RV/LV ratio from baseline to 48 hours are 26 and 22.7, respectively. Assuming these hold 
for our study , data from 17 patients per group (34 total) achieve 90% power to detect a mean 
difference of 26 percentage units between the two treatments with 5% significance level using a 
two-sided two-sample equal-variance t-test. 
7.1.2. SAFETY 
• Sample Size Justification: The main safety risk is bleeding in a critical site. The full list of primary 
and secondary safety endpoints is presented in Section 1.3.4. We expect that the incidence of 
bleeding will be 5% or less at Day 30. Table 1 shows two-sided exact confidence intervals (Clopper-
Pearson) at 95% level for selected incidences of bleeding with a sample size of 17 patients.    
 
Table 1.  95% Exact Confidence Interval 
Width, Lower Limit, and Upper Limit for 
selected incidences of bleeding 
Incidences Confidence 
Width 
Lower 
Limit 
Upper 
Limit 
0.01 
0.212 
0 
0.212 
0.02 
0.229 
0 
0.229 
0.03 
0.244 
0 
0.245 
0.04 
0.259 
0 
0.26 
0.05 
0.274 
0.001 
0.274 
7.1.3. ATTRITION 
The determined sample size is 17 subjects per arm (34 total), but we will enroll 20 per arm (40 total) 
to allow for potential attrition. 


SAFE-LYSE | STUDY PROTOCOL  
 
33 
8. ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug that does 
not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of investigational product, whether or not considered to be related to the 
investigational product. 
 
A non-serious adverse event is an AE not classified as serious.  
8.1.SERIOUS ADVERSE EVENTS 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
• results in death 
• is life-threatening (defined as an event in which the participant was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe) 
• requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below) 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect  
• is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and scientific 
judgment, may jeopardize the subject or may require intervention [e.g., medical, surgical] to prevent 
one of the other serious outcomes listed in the definition above. Examples of such events include, 
but are not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization).  
• Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
drug is an SAE.  
Although pregnancy and potential drug-induced liver injury (DILI) are not always serious by regulatory 
definition, these events must be reported within the SAEs timeline. 
Any component of a study endpoint that is considered related to study therapy should be reported as 
an SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 
The following hospitalizations are not considered SAEs:  
• a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event). 
• elective surgery, planned prior to signing consent. 
• admissions as per protocol for a planned medical/surgical procedure. 
• routine health assessment requiring admission for baseline/trending of health status (e.g., routine 
colonoscopy). 
• Medical/surgical admission other than to remedy ill health and planned prior to entry into the study. 
Appropriate documentation is required in these cases. 


SAFE-LYSE | STUDY PROTOCOL  
 
34 
• Admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver 
respite, family circumstances, administrative reason). 
• Admission for administration of anticancer therapy in the absence of any other SAEs (applies to 
oncology protocols). 
8.1.1.ADVERSE EVENT COLLECTION AND REPORTING INFORMATION: 
• 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to participate 
in the study through 30 days of discontinuation of dosing must be reported to BMS Worldwide 
Safety, whether related or not related to study drug. If applicable, SAEs must be collected that 
relate to any later protocol-specified procedure (e.g., a follow-up skin biopsy). 
• Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, are collected, including those thought to be associated with protocol-
specified procedures. The investigator should report any SAE occurring after these 
aforementioned time periods, which is believed to be related to study drug or protocol-specified 
procedure. 
• An SAE report should be completed for any event where doubt exists regarding its seriousness.  
• If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
An appropriate SAE form (e.g.,  ex-US = CIOMS form or USA = Medwatch form) should be used to 
report SAEs to BMS.  If you prefer to use your own institutional form, it must be reviewed by the BMS 
Protocol Manager prior to study initiation to ensure that, at a minimum, all of the data elements on the 
CIOMS form are present.  Note:  Please include the BMS Protocol number on the SAE form or on 
the  cover sheet with the SAE form transmission.   
• The CIOMS form is available at: http://www.cioms.ch/index.php/cioms-form-i  
• The MedWatch form is available at: MedWatch 3500 Form  
• The Sponsor will reconcile the clinical database AE cases (case level only) transmitted to BMS 
Global Pharmacovigilance (Worldwide.Safety@bms.com).  
o The Investigator will request from BMS GPV&E, aepbusinessprocess@bms.com the SAE 
reconciliation report and include the BMS protocol number every 3 months and prior to data 
base lock or final data summary. 
o GPV&E will send the investigator the report to verify and confirm all SAEs have been 
transmitted to BMS GPV&E. 
o The data elements listed on the GPV&E reconciliation report will be used for case 
identification purposes. If the Investigator determines a case was not transmitted to BMS 
GPV&E, the case should be sent immediately to BMS (Worldwide.Safety@bms.com). 
• In addition to the Sponsor Investigator’s responsibility to report events to their local HA, suspected 
serious adverse reactions (whether expected or unexpected) shall be reported by BMS to the 
relevant competent health authorities in all concerned countries according to local regulations 
(either as expedited and/or in aggregate reports). 
• In accordance with local regulations, BMS will notify sponsor investigators of all reported SAEs 
that are suspected (related to the investigational product) and unexpected (i.e., not previously 
described in the IB). An event meeting these criteria is termed a Suspected, Unexpected Serious 
Adverse Reaction (SUSAR). Sponsor investigator notification of these events will be in the form 
of either a SUSAR Report or a Semi-Annual SUSAR Report.  


SAFE-LYSE | STUDY PROTOCOL  
 
35 
o Other important findings which may be reported by BMS as an Expedited Safety Report 
(ESR) include: increased frequency of a clinically significant expected SAE, an SAE 
considered associated with study procedures that could modify the conduct of the study, 
lack of efficacy that poses significant hazard to study subjects, clinically significant safety 
finding from a nonclinical (e.g., animal) study, important safety recommendations from a 
study data monitoring committee, or sponsor or BMS decision to end or temporarily halt a 
clinical study for safety reasons. 
o Upon receiving an ESR from BMS, the investigator must review and retain the ESR with 
the IB. Where required by local regulations or when there is a central IRB/IEC for the study, 
the sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC 
will determine if the informed consent requires revision. The investigator should also comply 
with the IRB/IEC procedures for reporting any other safety information.  
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS within 
24 hours \ 1 Business Day of becoming aware of the event. SAEs must be recorded on either CIOMS, 
MedWatch, or approved site SAE form.   
Pregnancies must be reported and submitted to BMS.  BMS will perform due diligence follow-up using 
the BMS Pregnancy Form which the investigator must complete.  
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  +1 609-818-3804 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours \ 1 Business Day to BMS using the 
same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. The causal relationship to study drug is 
determined by a physician and should be used to assess all adverse events (AE). The casual 
relationship can be one of the following: 
o Related: There is a reasonable causal relationship between study drug administration and the 
AE. 
o Not related: There is not a reasonable causal relationship between study drug administration 
and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.  
Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, 
or evaluation of a subject (In order to prevent reporting bias, subjects should not be questioned 
regarding the specific occurrence of one or more AEs). 
 
Non-serious Adverse Event 


SAFE-LYSE | STUDY PROTOCOL  
 
36 
• Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or final 
study reports as specified in the agreement or, if a regulatory requirement [e.g., IND US trial] as 
part of an annual reporting requirement.  
• Non-serious AE information should also be collected from the start of a placebo lead-in period 
or other observational period intended to establish a baseline status for the subjects.  
 
Non-serious Adverse Event Collection and Reporting 
The collection of non-serious AE information should begin at initiation of study drug. All non-serious 
adverse events (not only those deemed to be treatment-related) should be collected continuously 
through week 52 visit. 
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they become 
serious. Follow-up is also required for non-serious AEs that cause interruption or discontinuation of 
study drug and for those present at the end of study treatment as appropriate.  
 
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported to BMS as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
• any laboratory test result that is clinically significant or meets the definition of an SAE 
• any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
• any laboratory abnormality that required the subject to receive specific corrective therapy.  
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value). 
 
AEs of Special Interest 
In this study, the following adverse events are to be reported to BMS, regardless of whether these 
reports are classified as serious or unexpected: 
Potential or suspected cases of liver injury including but not limited to liver test abnormalities, jaundice, 
hepatitis or cholestasis. 
Pregnancy 
If following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 5 half-lives after product administration, the investigational product will be 
permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for 
participant).  
The investigator must immediately notify Worldwide.Safety@bms.com of this event and complete one 
of the following forms within 24 hours of awareness of the event via either the CIOMS, MedWatch or 
appropriate Pregnancy Surveillance Form in accordance with SAE reporting procedures.  
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 


SAFE-LYSE | STUDY PROTOCOL  
 
37 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome 
and, where applicable, offspring information must be reported on the CIOMS, MedWatch, BMS 
Pregnancy Surveillance Form, or approved site SAE form.  A BMS Pregnancy Surveillance Form may 
be provided upon request. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to BMS. 
Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In order for 
Sponsor or designee to collect any pregnancy surveillance information from the female partner, the 
female partner must sign an informed consent form for disclosure of this information.  
 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, X-
rays, and any other potential safety assessments, whether or not these procedures are required by the 
protocol, should also be recorded as a non-serious or serious AE, as appropriate, and reported 
accordingly.  
9. STUDY MANAGEMENT 
9.1 COMPLIANCE 
9.1.1 COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS 
The study will be conducted as described in this approved protocol. All revisions to the protocol will be 
discussed with the BMS/Pfizer Alliance. The investigator will not implement any deviation or change to 
the protocol without review and documented approval from the CSMC IRB of the amendment, except 
where necessary to eliminate immediate danger to study subjects. If a deviation or change to a protocol 
is implemented to eliminate immediate danger before obtaining CSMC  IRB approval, as soon as 
possible the deviation or change will be submitted to both CSMC IRB and BMS/Pfizer Alliance for 
review and approval. 
 
Documentation of the IRB approval, consent form, HIPAA authorization and all recruitment materials 
will be sent to the sponsor. If an amendment substantially alters the study design or increases the 
potential risk to the subject: (1) the consent form will be revised and submitted to the CSMC IRB for 
review and approval; (2) particpants will be re-consented with the new revised consent form and the 
re-consenting process will be documented in the subject’s chart; and (3) the new approved cosent form 
will be used to obtain consent from new potential subjects before enrollment.  
9.1.2 MONITORING 
The study will be monitored internally. Monitoring will include the review of study records, source 
documents, a meeting with one of the investigators about the conduct of the study and a meeting with 
the research pharmacists as necessary. 
9.1.3 INVESTIGATIONAL SITE TRAINING 
All study staff will be trained by the investigators before intiation of the study. In addition to the GCP, 
HIPAA, human subjects and informed consent training discussed in Section 2 of the protocol, the staff 
will be trained on the protocol, study drug administration, AE reporting, entry into the REDCap EDC, 
and study documentation. All trainings will be documented in the regulatory binder. 
 
9.2 RECORDS 


SAFE-LYSE | STUDY PROTOCOL  
 
38 
9.2.1 RECORDS RETENTION 
Essential documents will be retained by the Investigator according to the period of time outlined in the 
Clinical Trial Agreement. The Investigator will retain these documents for the time period described 
above or according to local laws or requirements, whichever is longer. Essential documents include, 
but are not limited to, the following: 
 
• Signed ICFs for all subjects; 
• Subject identification code list, screening log (if applicable), and enrollment log; 
• Record of all communications between the Investigator and the IRB/EC; 
• Composition of the IRB/EC; 
• Record of all communications between the Investigator, BMS/Pfizer Alliance, and their authorized 
representative(s); 
• List of Sub-investigators and other appropriately qualified persons to whom the Investigator has 
delegated significant study-related duties, together with their roles in the study, curriculum vitae, 
and their signatures; 
• Copies of CRFs (if paper) and of documentation of corrections for all subjects; 
• Apixaban accountability records; 
• All other source documents (subject records, hospital records, laboratory records, etc); 
• All other documents as listed in Section 8 of the ICH consolidated guideline on GCP (Essential 
Documents for the Conduct of a Clinical Trial). 
 
The Investigator will notify BMS/Pfizer Alliance if he wishes to assign the essential documents to 
someone else or remove them to another location. The Investigator will obtain approval in writing from 
BMS/Pfizer Alliance prior to destruction of any records. 
 
All study documents will be made available if required by relevant health authorities. The Investigator 
or Cedars-Sinai Medical Center will take measures to prevent accidental or premature destruction of 
these documents. 
9.2.2 STUDY DRUG RECORDS 
The investigator will ensure that a current disposition record of investigational product is maintained in 
the research pharmacy and in the CRF. 
• Records or logs will comply with applicable regulations and guidelines and will include: 
o Amount received and placed in storage area in research pharmacy 
o Amount currently in storage area 
o Label identification number or batch number 
o Amount dispensed to and returned by each partipant, including unique subject identifiers 
o Nonstudy disposition (e.g., wasted due to expiration) 
o Amount destroyed at study site 
o Amount returned to the BMS if applicable 
o Dates and initials of person responsible for investigational product dispensing/accountability, 
as per the Delegation of Authority Log 
9.3. CLINICAL STUDY PUBLICATIONS 
The data collected during this study are confidential and proprietary to the investigators. Any 
publications or abstracts arising from this study require approval by the BMS/Pfizer Alliance before 
publication or presentation and must adhere to the BMS/Pfizer Alliance’s publication requirements as 
set forth in the approved clinical trial agreement (CTA). All draft publications, including abstracts or 
detailed summaries of any proposed presentations, must be submitted to the BMS/Pfizer Alliance at 


SAFE-LYSE | STUDY PROTOCOL  
 
39 
the earliest practicable time for review, but at any event no less than 30 days before submission or 
presentation unless otherwise set forth in the CTA. The BMS/Pfizer Alliance shall have the right to 
delete any confidential or proprietary information contained in any proposed presentation or abstract 
and may delay publication for up to 60 days for purposes of filing a patent application. 
 
The results of the SAFE-LYSE study will be disseminated via peer-reviewed journal publications, 
presentations and scientific conferences, and educational lectures nationally and internationally. Co-
investigators will have priority for publishing data. 
9.4. REVIEW PROCESS 
Each scientific manuscript or abstract must be submitted to all SAFE-LYSE investigators and 
BMS/Pfizer Alliance for review of its appropriateness and scientific merit prior to submission to a journal 
or conference. Recommended changes to the authors will be made and the manuscript will be modified 
accordingly.  A final version will be agreed upon by the study team. 
9.5. ACCESS TO DATA 
Study investigators will only be given access to the coded data sets. Project data sets will be housed 
in REDCap and other password-protected access systems. 
9.6. ANCILLARY AND POST-TRIAL CARE 
A research-related injury or illness is a direct result of the Study Drug, or a procedure performed only 
as a part of the study and that is not part of your standard clinical medical treatment.  Injury or illness 
related to an underlying medical condition or caused by non-research-related activities (such as 
treatment generally provided outside of the study) would not be considered research-related.  The 
CSMC IRB Chair will determine whether the illness or injury is research-related. If the subject is being 
treated for a research-related injury or illness, they will not pay for the costs of the appropriate medical 
or emergency room care provided so long as the IRB has determined that the illness or injury is 
research-related. CSMC has no plans to pay for losses such as lost wages.   
9.7. CLOSE-OUT PROCEDURES 
SAFE-LYSE may terminate at the planned target of 2 years after the last subject has been randomized, 
or at an earlier or later date if the circumstances warrant. Regardless of the timing and circumstances 
of the end of the study, close-out will proceed in two stages: 
• Interim period for analysis and documentation of study results 
• Debriefing of subjects and dissemination of study results. 
9.8. INTERIM 
Every attempt will be made to reduce to an absolute minimum the interval between the completion of 
data collection and the release of the study results. We expect to take about 3 to 4 months to compile 
the final results paper for an appropriate journal. 
9.9. DATABASE LOCK 
Permissions to allow data entry to the study will be removed from all persons except the Data Manager 
when all of the following are complete: 
• All requested information has been collected 
• All applicable data has been entered into REDCap 
• All data queries and discrepancies have been resolved 
A series of meetings will be held with the data and trial management teams, including the PI, to review 
the status of matters that need to be resolved before the study can be finally locked. When all standing 
issues are rectified, the study database will be put into a state such that further additions and changes 


SAFE-LYSE | STUDY PROTOCOL  
 
40 
to the data are not possible. Data extracted after the lock will be transferred, using standard practices, 
to the person responsible for data analysis. 
9.10. REPORTING OF STUDY RESULTS 
The study results will be released to the participating physicians, referring physicians, patients and the 
general medical community. 
 
 


SAFE-LYSE | STUDY PROTOCOL  
 
41 
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3. Layish, DT and VF Tapson, Pharmacologic hemodynamic support in massive pulmonary embolism. 
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4. Goldhaber SZ, Visani L, De Rosa M: Acute pulmonary embolism: clinical outcomes in the 
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7. Dalla-Volta S, Palla A, Santolicandro A, et al. PAIMS 2: Alteplase combined with heparin versus 
heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter 
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8. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary 
embolism. N Engl J Med. 2014;370:1402-11. 
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all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA 
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Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-
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and Expert Panel Report. Chest. 2016;149:315-52. 
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acute massive pulmonary embolism. A randomized controlled multicenter trial. Chest. 
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14. Goldhaber SZ, Agnelli G, Levine MN: Reduced dose bolus alteplase vs conventional alteplase 
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Bolus Alteplase Pulmonary Embolism Group. Chest. 1994;106:718-24. 
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YH: Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment 
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16. Zhang Z, Zhai ZG, Liang LR, Liu FF, Yang YH, Wang C: Lower dosage of recombinant tissue-type 
plasminogen activator (rt-PA) in the treatment of acute pulmonary embolism: a systematic review 
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in acute ischemic stroke. N Engl J Med. 2016;374:2313-23. 
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20. Kucher N, Boekstegers P, Muller O, et al. Randomized controlled trial of ultrasound assisted 
catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation 
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ICF_001.pdf: 
CSMC Combined Main ICF, HIPAA Authorization and Optional Sub-Study Template_01.16.2019
Page 1 of 20 
CONSENT FORM FOR RESEARCH
 Title: 
STANDARD-DOSE APIXABAN AFTER VERY LOW-DOSE 
THROMBOLYSIS FOR ACUTE INTERMEDIATE-HIGH RISK 
ACUTE PULMONARY EMBOLISM “(SAFE-LYSE)”  
STUDY SUPPORT PROVIDED BY: BRISTOL-MYERS SQUIBB COMPANY (BMS)
PRINCIPAL INVESTIGATOR:
VICTOR TAPSON, MD 
CO-PRINCIPAL INVESTIGATOR
AARON WEINBERG, MD
CO-PRINCIPAL INVESTIGATOR 
 
STUDY CONTACT PHONE NUMBER AT CSMC:   310-423-4765 OR 310-423-4788
AFTER HOURS CONTACT (24 HOURS):  310-423-5000 AND ASK FOR PULMONARY EMBOLISM RESPONSE 
TEAM PHYSICIAN ON CALL
This research study is funded by Bristol-Myers Squibb Company (BMS).  BMS only reimburses 
Cedars-Sinai Medical Center for the costs associated with running the study; BMS 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 see how much of the pulmonary embolism (clot) can be dissolved when 
treated with a very low dose of a thrombolytic drug (clot buster) along with standard anticoagulant 
therapy as compared to the standard of care anticoagulant therapy alone.
You are being asked to join in a clinical research study because you have 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. Your doctor has decided that you need to have the blood clot 
dissolved.
The study will enroll up to 40 people in total.
This research study is designed to test the investigational use of Alteplase, or tPA.  This drug is 
approved by the U.S. Food and Drug Administration (FDA) for breaking down blood clots.  
However, it is not approved by the FDA for the condition that is being studied at the low dose of the 
drug being administered in this study.
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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.

You will be randomized to one of two treatment groups. See below for more detailed 
explanation.

You will either receive study drug or placebo infusion along with Standard of Care heparin, a 
blood thinner drug.

Your vital signs (temperature, respiratory rate, heart rate, blood pressure, and oxygen 
saturation level) will be measured immediately prior to the infusion and at 24 ± 6 hours after 
infusion completion.

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.

Within 24 ± 6 hours of completing infusion, a CT-angiogram and an echocardiogram 
(ultrasound test) will be performed to see how much clot has been dissolved. Some blood 
tests will also be repeated. 

After at least 24 hours of your drug administration, you will transition to an oral 
anticoagulant, apixaban (Eliquis). You will start on 10 mg twice a day for the first 7 days. 
You will then transition to 5 mg twice a day for 12 months. If your risk of bleeding is high, 
your doctor may delay your transition to apixaban.

There are a total of seven (7) follow-up visits. Three visits will require a return to the 
doctor’s clinic and four (4) will be conducted by phone or e-mail. During the clinic visits at 
30 ± 15 days, 180 ± 15 days, and 365 ± 15 days after your procedure, you will be asked about 
your general health, have an echocardiogram (ECHO), a physical exam, an exercise test, and 
complete two quality of life questionnaires. At days, 3, 7, 90 ± 15 days, and 270 ± 15 days 
after your procedure, you will be contacted by phone or e-mail by study staff to review your 
general health and to complete two quality of life questionnaires.

The two quality of life questionnaires include the Patient-Reported Outcomes Measurement 
Information System Physical Function 6 (PROMIS PF-6) and the Pulmonary Embolism 
Quality of Life (PEmb-QOL) surveys.
This is a randomized, double-blind research study. 
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
“Randomized” means that you will be assigned to a study group by chance, like flipping a 
coin.  You will be randomized into one of 2 study groups, and will have an equal chance of 
being placed in one of the groups described above. 

“Double-blind” means neither you nor the researchers will know what group you are 
assigned to.
This study has 2 study groups:

Group 1 will get the usual drug to treat pulmonary embolism (heparin) plus a placebo IV 
infusion.

Group 2 will get the usual drug to treat pulmonary embolism (heparin) plus the study drug (tPA) 
IV infusion.
After initial treatment, all study participants will be transitioned to apixaban 10 mg twice a day for 7 
days, followed by 5 mg twice a day for at least 6 months. If your doctor thinks it is safe and 
appropriate, the apixaban dose may be additionally decreased to 2.5 mg twice a day for the 
remaining 6 months. 
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. 
This is a placebo-controlled study.  It will compare the effects (good or bad) of tPA against the 
effects of a placebo (an inactive substance, such as, a sugar pill) on the condition being studied in 
this research. 
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 2
Anticoagulation therapy + 
tPA (Study group)
You agree to take 
part in the study
Group 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 
infusions of heparin.
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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. We do not believe 
you should be at any increased risk due to this limitation. 
How long will you be in the study?
We think you will be in this study for/until about 1 year. The total time includes the days while you 
are in the hospital and the 7 follow-up visits (as indicated above – 3 in-clinic; 4 over the phone or by 
email) over the course of the year after your hospitalization.
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. 
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

Abnormal blood clotting

Decreased platelet count
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 
completing heparin therapy.  You will not be enrolled in this study if you have a known history of 
HIT.  
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Risks of tPA 
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 the brain

Need for blood transfusion

Bleeding in the stomach or intestinal tract

Blood in urine

Bruising

Bleeding in other parts of the body
Rare AND Serious (Occurs in 1% or less of people and may require hospitalization or may be 
irreversible, long-term, life-threatening or fatal)

Allergic reaction, which can be severe, such as swelling of the airways, rash, or shock

New case of ischemic stroke
Risks of apixaban
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

Clinically relevant non-major bleeding
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

Allergic reaction, which can be severe
In addition to the risks summarized above, the FDA has issued the following warning for 
apixaban: 
In the lists below, “Serious,” refers to those side effects that 
may require hospitalization, may be irreversible, long-term, 
life-threatening or fatal.
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Radiation Risk 
This research study involves exposure to radiation from a CT Angiogram. The amount of radiation 
exposure from each CT Angiogram is approximately 6-10 Rem, which is within the typical range 
from similar diagnostic x-ray procedures.  One of these procedures will be done as standard of care. 
and an additional one will only be done because of your participation in this research study.  This 
research CT Angiogram involves radiation exposure that is not necessary for your medical care and 
is for research purposes only. This use involves minimal radiation risk and is necessary to obtain the 
research information desired. 
CT Angiogram Contrast Risks:
The contrast (dye) solution that may be given for a CT scan may cause an allergic reaction (rare).  
Severe allergic reactions can be life threatening.  CT contrast solution can cause kidney damage, 
especially if you are diabetic, dehydrated (lost body water) or elderly.
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.  
Participation in a Double-Blind Study
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
FDA Blackbox warning:   Increased risk of thromboembolic events (blood clots such as 
stroke) upon discontinuation of apixaban. Patients are at increased risk of thrombotic 
events when apixaban is discontinued prematurely (too early). If apixaban must be 
discontinued for a reason other than bleeding or completion of therapy, your doctor may 
consider administering another anticoagulant.  Talk to your doctor before stopping apixaban.
FDA Blackbox warning: Risk of spinal/epidural hematoma: Additionally, patients on 
apixaban who receive neuraxial anesthesia (pain blockers administered into the central 
nervous system, such as the spine) or undergoing spinal puncture are at risk for spinal or 
epidural hematomas (collection of blood).  This may result in long-term or permanent 
paralysis.  Talk to your doctor about apixaban before receiving any spinal procedures. 
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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 benefits of taking part in the research study is that your clot burden may be 
reduced more quickly with a low dose, clot-busting medication when given alongside your Standard 
of Care treatment for your condition. As a study subject, you will be seen more often and followed 
more closely at the clinic than is normal for a non-study subject who have pulmonary embolism. 
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 with 
pulmonary embolism in the future by helping us to learn if clots are sufficiently dissolved by giving 
a lower dosage of tPA.
5.
WILL I BE INFORMED OF RESEARCH RESULTS?
  
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.
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;

You decide to withdraw from the study for any reason;

You become pregnant;

You lose the ability to freely provide consent through imprisonment.
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 
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consent will be requested if your continued participation will involve procedures not described in 
this consent form.
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:

you may choose to be treated following the usual clinical approach, which is receiving heparin 
IV infusions 

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.
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.
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Who pays for my research related illness or injury?
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 in-person follow-up visit. The payment will be issued after completion 
of the entire study. The total amount you will receive if you complete the whole study is $150. The 
cost of parking for Day 30, Day 180, and Day 365 visits will also be covered. 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 one of the investigators listed on the first page of this form for questions or concerns 
about the research.  
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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 (other than the postponement of your access to certain health information as 
described in this informed consent form); 
(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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CSMC Date Effective: 9/24/2019


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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
Date Signed
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 this “Authorization for Use and Disclosure of 
Identifiable Health Information (Research)” form attached as Appendix to this form.
Name of Participant (Print)
Signature
Date Signed
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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CSMC Date Effective: 9/24/2019


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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
(Signature of an interpreter is only required when a non-English speaking subject is consented 
with the assistance of an interpreter and an IRB-approved ‘short form.’  The witness 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 witness signs the consent forms to confirm that the oral interpretation occurred.)
Name of Witness (Print)
Signature
Date Signed
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CSMC Date Effective: 9/24/2019


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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 research team at Cedars-
Sinai Medical Center (“CSMC”) to use or disclose your identifiable health 
information (“private information”) for the research study titled “STANDARD-DOSE 
APIXABAN AFTER VERY LOW-DOSE THROMBOLYSIS FOR 
ACUTE INTERMEDIATE-HIGH RISK ACUTE PULMONARY EMBOLISM 
“(SAFE-LYSE)” 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: Cath lab reports

WHO WILL HAVE ACCESS TO YOUR PRIVATE INFORMATION?
Your private information will be used by and/or shared with the CSMC investigators 
listed in Section A of the Consent Form and their research staff.  
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 CSMC 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 and its business partners, for matters related to research 
study oversight, data analysis and use of research results in product development. 
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
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.
CSMC 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. 

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. The mailing address is: 8700 
Beverly Blvd., Los Angeles, CA 90048 (Attn: Dr. Victor Tapson).

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. CSMC 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. You 
will receive a copy of this Authorization. 
CSMC IRB No: Pro00054951
CSMC Date Effective: 9/24/2019


CSMC Combined Main ICF, HIPAA Authorization and Optional Sub-Study Template_01.16.2019
Page 16 of 20 
APPENDIX:  FLOWCHART OF PROCEDURES – Medicare Coverage Analysis (MCA) Review
LEGEND 
R = Research item/procedure done only for research purposes and covered by the study
SS = Standard of care item/procedure that is part of regular care, but covered by the study
S = Standard of care item/procedure that is part of regular care and billed to the patient/insurance
Procedures
Baseline up 
to 48 hours 
pre-study 
medication
Day 0
Day 1
Day 2
Day 3 & 
Day 7
Day 30       
± 15 days 
(Clinic 
Visit)
Day 90     
± 15 days 
(Phone 
Contact)
Day 180  
± 15 days 
(Clinic 
Visit)
Day 270   
± 15 days 
(Phone 
Contact)
Day 365  
± 15 days 
(Clinic 
Visit)
ET1
Informed consent
R
Inclusion/Exclusion
R
Randomization
R
Heparin anticoagulation therapy2
S
S
S
Pregnancy test (if applicable)
S
Medical and demographic history
S
Physical exam
S
S
S
S
S
S
Vital signs including pulse ox 
S
S
S
S
S
S
S
S
Chest contrast-enhanced computed 
tomographic angiogram (chest CTA)
S
R


CSMC Combined Main ICF, HIPAA Authorization and Optional Sub-Study Template_01.16.2019
Page 17 of 20 
Procedures
Baseline up 
to 48 hours 
pre-study 
medication
Day 0
Day 1
Day 2
Day 3 & 
Day 7
Day 30       
± 15 days 
(Clinic 
Visit)
Day 90     
± 15 days 
(Phone 
Contact)
Day 180  
± 15 days 
(Clinic 
Visit)
Day 270   
± 15 days 
(Phone 
Contact)
Day 365  
± 15 days 
(Clinic 
Visit)
ET1
Echocardiogram
S
S
S
S
S
Ultrasound of lower extremities to rule 
out DVT
S
ECG
S
Hemoglobin, hematocrit, platelet count
S
S
S
S
S
BUN, creatinine
S
S
S
S
Liver Function Tests
S
S
aPTT, PT and INR
S
S
Troponin I (or Troponin T)
S
BNP
S
sPESI
R
R
Quality of life questionnaires (PROMIS 
PF-6 and Pulmonary Embolism Quality 
of Life (PEmb-QOL)
R
R
R  
R
Administration of tPA/placebo 
R


CSMC Combined Main ICF, HIPAA Authorization and Optional Sub-Study Template_01.16.2019
Page 18 of 20 
Procedures
Baseline up 
to 48 hours 
pre-study 
medication
Day 0
Day 1
Day 2
Day 3 & 
Day 7
Day 30       
± 15 days 
(Clinic 
Visit)
Day 90     
± 15 days 
(Phone 
Contact)
Day 180  
± 15 days 
(Clinic 
Visit)
Day 270   
± 15 days 
(Phone 
Contact)
Day 365  
± 15 days 
(Clinic 
Visit)
ET1
Administration of apixaban3
SS
SS
SS
SS
SS
SS
SS
6 Minute Walk and Borg Dyspnea scale
S
S
S
S
Remote health checks (phone and 
email)
R
R
Review of medications and adverse 
events, bleeding events and VTE events
R
R
R
R
R4
R
R
R
R
R
R
Footnotes:
1Early Termination: Obtain if subject withdraws early
2Heparin duration up to clinician discretion but patient must be on for at least 24 hours after infusion of study drug. 
3Could start as early as 24 hours post treatment, contingent upon clinician discretion.
472-hour assessment of AE will be conducted either in person or if discharged via telephone call. Day 7 follow up will be telephone call.


CSMC Combined Main ICF, HIPAA Authorization and Optional Sub-Study Template_01.16.2019
Page 19 of 20 
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.
Electrocardiogram (ECG): abbreviated as 
EKG or ECG – is a test that measures the 
electrical activity of the heartbeat using 
electrodes (disposable adhesive discs placed 
on the skin).
There’s no pain or risk associated with having an 
electrocardiogram.  When the disposable adhesive 
discs are removed from your skin, there may be 
some minor skin discomfort or irritation.  You 
may experience temporary discomfort (pulling on 
the skin/skin hair) during removal of the patches.  
This hair may be shaved for patch placement.
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 risk factors for thromboembolism 
and bleeding.
There are no physical risks associated with this 
procedure.
6-Minute Walk Test (6MWT): You will be 
asked to walk for 6 minutes along a 
designated pathway (a track in the hospital 
hallway) while being observed by study 
personnel. You will be observed before, 
during and after the 6-minute walk by study 
personnel. Your heart rate and blood pressure 
will be recorded before and after the test. We 
will also measure the distance that you are 
able to walk during the 6 minutes. After the 
test, you will also be asked a few questions.  
The test and assessments will take about 10-
15 minutes, but no more than 30 minutes 
total.
There is a rare possibility of fainting, while you 
perform the 6 Minute walk test. Please note that 
all medical procedures will be done in the 
presence of the study Investigator and research 
team in order to minimize the occurrence of such 
untoward events.
An ultrasound called transthoracic 
echocardiogram (TTE): This is performed 
by placing a probe across the surface of your 
chest; it is used to examine and provide 
images of the heart.
If you participate in this study, when you have the 
echocardiogram (ultrasound) a solution may be 
injected into your vein to help the doctor see the 
pictures of your heart more clearly.  There are two 
types of solutions that may be used and they are 
CSMC IRB No: Pro00054951
CSMC Date Effective: 9/24/2019


CSMC Combined Main ICF, HIPAA Authorization and Optional Sub-Study Template_01.16.2019
Page 20 of 20 
DEFINITY® and OPTISON™.  If you have an 
allergy to eggs or if you have had a reaction to 
blood or blood products, or albumin in the past, 
you may have an allergic reaction to 
OPTISON™.  It is important to let the doctor 
know of any allergies or reactions you may have 
had in the past.  Please inform the doctor of any 
history of liver disease or respiratory 
difficulties/disease.  DEFINITY®, the other 
solution, may cause a change in the rhythm of 
your heart.  Please inform the doctor if you 
believe you are pregnant or if you have a 
congenital heart defect (heart problem you were 
born with).
Pregnancy Test: If you are a woman who is 
able to become pregnant, blood samples will 
also be used to do a pregnancy test
If your test is positive, you will be told and at that 
point you should discuss options available with 
your primary physician.  
Questionnaires: You will be asked to 
complete questionnaires.  We will ask you 
questions to evaluate your quality of life.  We 
think it should take about 10 minutes to 
complete the questionnaire.  Questionnaires 
will ask you to respond to questions about 
pain you are experiencing, other medical 
symptoms and how it affects the activities of 
daily living and your emotions.
If you feel uncomfortable or embarrassed 
answering any question, you may skip it. The 
questionnaire will be labeled with a unique study 
number that will link your identity so that only the 
research team can recognize you.
Demographic Information: You will be 
asked about your age, gender, race, ethnicity
There are no physical risks associated with these 
procedures.
CSMC IRB No: Pro00054951
CSMC Date Effective: 9/24/2019