Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Standard-dose Apixaban AFtEr Very Low-dose ThromboLYSis for Acute Intermediate-high Risk Acute Pulmonary Embolism (SAFE-LYSE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03988842
Recruitment Status : Terminated (COVID-19 pandemic)
First Posted : June 18, 2019
Results First Posted : May 18, 2021
Last Update Posted : June 11, 2021
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Victor Tapson, MD, Cedars-Sinai Medical Center

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.

Condition or disease Intervention/treatment Phase
Pulmonary Embolism With Acute Cor Pulmonale Pulmonary Embolism Pulmonary Embolism With Pulmonary Infarction Pulmonary Embolism Subacute Massive Right Ventricular Dysfunction Right Ventricular Failure Drug: Alteplase Drug: Unfractionated heparin Drug: Placebo Drug: Apixaban Phase 4

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Standard-dose Apixaban AFtEr Very Low-dose ThromboLYSis for Acute Intermediate-high Risk Acute Pulmonary Embolism
Actual Study Start Date : July 25, 2019
Actual Primary Completion Date : April 5, 2020
Actual Study Completion Date : April 5, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Alteplase & Unfractionated Heparin & Apixaban
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.
Drug: Alteplase
Lyophilized powder for reconstitution in 50mg vials
Other Names:
  • Activase
  • tissue-type plasminogen activator

Drug: Unfractionated heparin
Heparin sodium in 0.45% sodium chloride injection for intravenous use
Other Name: Heparin sodium

Drug: Apixaban
Apixaban tablet
Other Name: Eliquis

Active Comparator: Placebo & Unfractionated Heparin & Apixaban
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.
Drug: Unfractionated heparin
Heparin sodium in 0.45% sodium chloride injection for intravenous use
Other Name: Heparin sodium

Drug: Placebo
Saline solution reconstituted to mimic Alteplase 50mg vial
Other Name: Placebo (for Alteplase)

Drug: Apixaban
Apixaban tablet
Other Name: Eliquis




Primary Outcome Measures :
  1. Change in Extent of Clot Lysis in the Experimental Arm [ Time Frame: Baseline, 24 hours ]
    Change in percentage of clot lysis in the experimental arm only as measured using the Refined Modified Miller Score (RMMS) from the baseline CTA to the 24 hour CTA after 24mg of systemic (IV) tPA + standard anticoagulation therapy (experimental arm).


Secondary Outcome Measures :
  1. Change in Extent of Clot Lysis Between the Experimental Arm and the Active Comparator Arm [ Time Frame: Baseline, 24 hours ]
    Change in percentage of clot lysis between the experimental arm and the active comparator arm as measured using the Refined Modified Miller Score (RMMS) from the baseline CTA to the 24 hour CTA after 24mg of systemic (IV) tPA + standard anticoagulation therapy (experimental arm) compared to 24mg of systemic (IV) placebo + standard anticoagulation therapy (active comparator arm).

  2. Change in Right Ventricular to Left Ventricular Diameter (RV/LV) Ratio [ Time Frame: Baseline, 24 hours ]
    RV/LV ratio as measured by chest CTA from baseline to 24 ± 6 hours after the infusion of very low dose systemic (IV) tPA in patients with acute intermediate-high risk PE compared with placebo.

  3. Change in RV/LV Ratio From Baseline Echocardiogram [ Time Frame: Baseline, 24 hours and 30 days ]
    Change from baseline in echocardiographic parameters as measured by the RV/LV ratio within 24 hours ± 6 hours and at 30 ± 5 days after the end of the systemic (IV) tPA infusion compared with placebo.

  4. Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) From Baseline Echocardiogram [ Time Frame: Baseline, 24 hours and 30 days ]
    Change from baseline in echocardiographic parameters as measured by the tricuspid annular plane systolic excursion (TAPSE) within 24 hours ± 6 hours and at 30 ± 5 days after the end of the systemic (IV) tPA infusion compared with placebo.

  5. Change in Right Ventricular Systolic Pressure (RVSP) From Baseline Echocardiogram [ Time Frame: Baseline, 24 hours and 30 days ]
    Change from baseline in echocardiographic parameters as measured by the estimated right ventricular systolic pressure (RVSP) within 24 hours ± 6 hours and at 30 ± 5 days after the end of the systemic (IV) tPA infusion compared with placebo.

  6. Change in the Collapse of the Inferior Vena Cava (IVC) From Baseline Echocardiogram [ Time Frame: Baseline, 24 hours and 30 days ]
    Change from baseline in echocardiographic parameters as measured by the collapse of the inferior vena cava (IVC) with respiration within 24 hours ± 6 hours and at 30 ± 5 days after the end of the systemic (IV) tPA infusion compared with placebo.

  7. Change in the Requirement for Oxygen Therapy After 6 Minute Walk Test (6MWT) [ Time Frame: 30 days, 60 days, and 1 year ]
    6MWT distance as measured by the requirement for oxygen therapy at 30 day, 60 day and one year ± 14 days clinic follow-up compared with placebo.

  8. Change in Borg Dyspnea Scale Score After 6 Minute Walk Test (6MWT) [ Time Frame: 30 days, 60 days, and 1 year ]
    6MWT distance as measured by the Borg Dyspnea Scale score (Borg score) at 30 day, 60 day and one year ± 14 days clinic follow-up compared with placebo. The Borg Scale measures self-reported intensity and severity of breathlessness (dyspnea) and fatigue before, during, and after a 6MWT. Each item is scored 0 - 10 (0 = no breathlessness at all; 10 = most severe breathlessness that you have ever experienced), yielding a total between 0 and 20.

  9. Change in Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Questionnaire [ Time Frame: 30 days, 6 months, and 1 year ]
    Quality of life (QOL) as measured by the PROMIS PF-6at 30 days, 6 months and one year ± 14 days clinic follow-up compared with placebo. The PROMIS PF-6 measures self-reported physical function for everyday tasks (i.e., yard work, shopping, walking up/down stairs). Each item is score 1 - 5 (1 = unable to do/cannot do; 5 = without any difficulty/not at all), yielding a total between 6 and 30.

  10. Change in Pulmonary Embolism Quality of Life (PEmb-QOL) Questionnaire [ Time Frame: 30 days, 6 months, and 1 year ]
    Quality of life (QOL) as measured by the PEmb-QOL at 30 days, 6 months and one year ± 14 days clinic follow-up compared with placebo. The PEmb-QOL measures self-reported QOL after a Pulmonary Embolism. The PEmb-QOL has nine sub-scales with higher scores indicating worse outcomes. Each item is score 1 - 5 (1 = unable to do/cannot do; 5 = without any difficulty/not at all), yielding a total between 6 and 30.

  11. Number of Recurrent Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) Events [ Time Frame: 30 days, 60 days, 6 months, and 1 year ]
    Measured as the number of recurrent DVT and/or PE events in patients at 30 days, 60 days, 6 months, and 1 year compared to placebo.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Chest CT angiogram (CTA) evidence of proximal Pulmonary Embolism (PE) with a filling defect in at least one main pulmonary artery or lobar artery
  • PE symptom duration ≤14 days
  • Intermediate-high risk PE: defined as RV dysfunction with an RV/LV diameter ≥ 0.9, sPESI > 0, and either troponin > 0.05ng/mL or BNP > 100 pg/mL, and hemodynamically stable (systolic blood pressure > 90mmHg without the use of vasopressor support)
  • Randomization within 24 + 4 hours of anticoagulation
  • Signed and dated informed consent obtained from subject or legally authorized representative before initiation of any study procedures

Exclusion Criteria:

  • Weight > 130kg or < 40 kg on day of randomization
  • 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 90mmHg and/or use of vasopressors for greater than 15 minutes
  • Severe hypertension as defined as SBP greater than 180mmHg
  • 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 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 clearances < 60 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03988842


Locations
Layout table for location information
United States, California
Cedars-Sinai Medical Center
Los Angeles, California, United States, 90048
Sponsors and Collaborators
Victor Tapson, MD
Bristol-Myers Squibb
Investigators
Layout table for investigator information
Principal Investigator: Victor F Tapson, MD Cedars-Sinai Medical Center
Principal Investigator: Aaron S Weinberg, MD Cedars-Sinai Medical Center
  Study Documents (Full-Text)

Documents provided by Victor Tapson, MD, Cedars-Sinai Medical Center:
Informed Consent Form  [PDF] September 24, 2019

Publications:
Rigby RA, Stasinopoulos DM. (2005) Generalized additive models for location, scale and shape. Journal of the Royal Statistical Society: Series C (Applied Statistics). 54(3):507-54.
R Core Team (2018). A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.

Layout table for additonal information
Responsible Party: Victor Tapson, MD, Director, Clinical Research for the Women's Guild Lung Institute; Director, Venous Thromboembolism and Pulmonary Vascular Disease Research Program; Associate Director, Pulmonary and Critical Care Division, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier: NCT03988842    
Other Study ID Numbers: Pro00054951
First Posted: June 18, 2019    Key Record Dates
Results First Posted: May 18, 2021
Last Update Posted: June 11, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Pulmonary Embolism
Pulmonary Infarction
Embolism
Ventricular Dysfunction
Ventricular Dysfunction, Right
Pulmonary Heart Disease
Infarction
Ischemia
Pathologic Processes
Necrosis
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Heart Diseases
Heparin
Calcium heparin
Tissue Plasminogen Activator
Plasminogen
Apixaban
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors