Pulmonary Embolism With Acute Cor PulmonalePhase 4SAFE-LYSENCT03988842
Standard-dose Apixaban AFtEr Very Low-dose ThromboLYSis for Acute Intermediate-high Risk Acute Pulmonary Embolism
A Phase 4 study testing Alteplase, Unfractionated heparin and Apixaban in people with Pulmonary Embolism With Acute Cor Pulmonale and Pulmonary Embolism, run by Victor Tapson, MD at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Pulmonary Embolism With Acute Cor Pulmonale, Pulmonary Embolism, Pulmonary Embolism With Pulmonary Infarction
- What is being tested?
- Alteplase, Unfractionated heparin and Apixaban
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 4 participants
- Where
- 1 siteUnited States
- Study dates
- 25 Jul 2019to 5 Apr 2020
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 31Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Cedars-Sinai Medical Center
Los Angeles, California, 90048
About this study
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.
Read the 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.
- Conditions
- Pulmonary Embolism With Acute Cor Pulmonale, Pulmonary Embolism, Pulmonary Embolism With Pulmonary Infarction, Pulmonary Embolism Subacute Massive, Right Ventricular Dysfunction, Right Ventricular Failure
- Being tested
- Alteplase, Unfractionated heparin, Placebo, Apixaban
- Medical subject headings
- Pulmonary Embolism, Ventricular Dysfunction, Right, Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AlteplaseDrug
Also called Activase, tissue-type plasminogen activator
Lyophilized powder for reconstitution in 50mg vials
Unfractionated heparinDrug
Also called Heparin sodium
Heparin sodium in 0.45% sodium chloride injection for intravenous use
PlaceboDrug
Also called Placebo (for Alteplase)
Saline solution reconstituted to mimic Alteplase 50mg vial
ApixabanDrug
Also called Eliquis
Apixaban tablet
| Study group | Role | What they receive |
|---|---|---|
| Alteplase & Unfractionated Heparin & Apixaban | Experimental | 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. Receives: Drug: Alteplase; Drug: Unfractionated heparin; Drug: Apixaban |
| Placebo & Unfractionated Heparin & Apixaban | Active comparator | 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. Receives: Drug: Unfractionated heparin; Drug: Placebo; Drug: Apixaban |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Extent of Clot Lysis in the Experimental Arm
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).
Measured: Baseline, 24 hours
Secondary outcomes (11)
Change in Extent of Clot Lysis Between the Experimental Arm and the Active Comparator Arm
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).
Measured: Baseline, 24 hours
Change in Right Ventricular to Left Ventricular Diameter (RV/LV) Ratio
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.
Measured: Baseline, 24 hours
Change in RV/LV Ratio From Baseline Echocardiogram
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.
Measured: Baseline, 24 hours and 30 days
Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) From Baseline Echocardiogram
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.
Measured: Baseline, 24 hours and 30 days
Change in Right Ventricular Systolic Pressure (RVSP) From Baseline Echocardiogram
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.
Measured: Baseline, 24 hours and 30 days
Change in the Collapse of the Inferior Vena Cava (IVC) From Baseline Echocardiogram
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.
Measured: Baseline, 24 hours and 30 days
Change in the Requirement for Oxygen Therapy After 6 Minute Walk Test (6MWT)
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.
Measured: 30 days, 60 days, and 1 year
Change in Borg Dyspnea Scale Score After 6 Minute Walk Test (6MWT)
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.
Measured: 30 days, 60 days, and 1 year
Change in Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Questionnaire
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.
Measured: 30 days, 6 months, and 1 year
Change in Pulmonary Embolism Quality of Life (PEmb-QOL) Questionnaire
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.
Measured: 30 days, 6 months, and 1 year
Number of Recurrent Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) Events
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.
Measured: 30 days, 60 days, 6 months, and 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jun 2019
- Study start25 Jul 2019
- Primary completion5 Apr 2020
- Study completion5 Apr 2020
Why it stopped: COVID-19 pandemic
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (30)Papers the sponsor has linked to this study.
- Other trials for Pulmonary Embolism With Acute Cor PulmonaleStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 4 participants (actual)
Sponsor and investigators
- Lead sponsor
- Victor Tapson, MD
- Sponsor type
- University, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Responsible party
- Sponsor-investigator, Victor Tapson, MD, Cedars-Sinai Medical Center
- Investigators
- Victor F Tapson, MD, Principal investigator, Cedars-Sinai Medical CenterAaron S Weinberg, MD, Principal investigator, Cedars-Sinai Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03988842
- Sponsor's protocol ID
- Pro00054951
- Acronym
- SAFE-LYSE
- Status last verified
- Apr 2021
- First submitted
- 24 May 2019
- Last updated
- 11 Jun 2021
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation. 2012 Jan 3;125(1):e2-e220. doi: 10.1161/CIR.0b013e31823ac046. Epub 2011 Dec 15. No abstract available.
PubMed 22179539Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous thromboembolism: a public health concern. Am J Prev Med. 2010 Apr;38(4 Suppl):S495-501. doi: 10.1016/j.amepre.2009.12.017.
PubMed 20331949Layish DT, Tapson VF. Pharmacologic hemodynamic support in massive pulmonary embolism. Chest. 1997 Jan;111(1):218-24. doi: 10.1378/chest.111.1.218. No abstract available.
PubMed 8996020Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999 Apr 24;353(9162):1386-9. doi: 10.1016/s0140-6736(98)07534-5.
PubMed 10227218Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galie N, Gibbs JS, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Vonk Noordegraaf A, Zamorano JL, Zompatori M; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014 Nov 14;35(43):3033-69, 3069a-3069k. doi: 10.1093/eurheartj/ehu283. Epub 2014 Aug 29. No abstract available.
PubMed 25173341Kohn CG, Mearns ES, Parker MW, Hernandez AV, Coleman CI. Prognostic accuracy of clinical prediction rules for early post-pulmonary embolism all-cause mortality: a bivariate meta-analysis. Chest. 2015 Apr;147(4):1043-1062. doi: 10.1378/chest.14-1888.
PubMed 25317677Dalla-Volta S, Palla A, Santolicandro A, Giuntini C, Pengo V, Visioli O, Zonzin P, Zanuttini D, Barbaresi F, Agnelli G, et al. PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2. J Am Coll Cardiol. 1992 Sep;20(3):520-6. doi: 10.1016/0735-1097(92)90002-5.
PubMed 1512328Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, Bluhmki E, Bouvaist H, Brenner B, Couturaud F, Dellas C, Empen K, Franca A, Galie N, Geibel A, Goldhaber SZ, Jimenez D, Kozak M, Kupatt C, Kucher N, Lang IM, Lankeit M, Meneveau N, Pacouret G, Palazzini M, Petris A, Pruszczyk P, Rugolotto M, Salvi A, Schellong S, Sebbane M, Sobkowicz B, Stefanovic BS, Thiele H, Torbicki A, Verschuren F, Konstantinides SV; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11. doi: 10.1056/NEJMoa1302097.
PubMed 24716681Chatterjee S, Chakraborty A, Weinberg I, Kadakia M, Wilensky RL, Sardar P, Kumbhani DJ, Mukherjee D, Jaff MR, Giri J. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014 Jun 18;311(23):2414-21. doi: 10.1001/jama.2014.5990.
PubMed 24938564Marti C, John G, Konstantinides S, Combescure C, Sanchez O, Lankeit M, Meyer G, Perrier A. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J. 2015 Mar 7;36(10):605-14. doi: 10.1093/eurheartj/ehu218. Epub 2014 Jun 10.
PubMed 24917641Daley MJ, Murthy MS, Peterson EJ. Bleeding risk with systemic thrombolytic therapy for pulmonary embolism: scope of the problem. Ther Adv Drug Saf. 2015 Apr;6(2):57-66. doi: 10.1177/2042098615572333.
PubMed 25922654Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JRE, Wells P, Woller SC, Moores L. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-352. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7.
PubMed 26867832Sors H, Pacouret G, Azarian R, Meyer G, Charbonnier B, Simonneau G. Hemodynamic effects of bolus vs 2-h infusion of alteplase in acute massive pulmonary embolism. A randomized controlled multicenter trial. Chest. 1994 Sep;106(3):712-7. doi: 10.1378/chest.106.3.712.
PubMed 8082346Goldhaber SZ, Agnelli G, Levine MN. Reduced dose bolus alteplase vs conventional alteplase infusion for pulmonary embolism thrombolysis. An international multicenter randomized trial. The Bolus Alteplase Pulmonary Embolism Group. Chest. 1994 Sep;106(3):718-24. doi: 10.1378/chest.106.3.718.
PubMed 8082347Wang C, Zhai Z, Yang Y, Wu Q, Cheng Z, Liang L, Dai H, Huang K, Lu W, Zhang Z, Cheng X, Shen YH; China Venous Thromboembolism (VTE) Study Group. Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest. 2010 Feb;137(2):254-62. doi: 10.1378/chest.09-0765. Epub 2009 Sep 9.
PubMed 19741062
Study at a glance
From the registry record, last updated by the sponsor on 11 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Standard-dose Apixaban AFtEr Very Low-dose ThromboLYSis for Acute Intermediate-high Risk Acute Pulmonary Embolism
- ClinicalTrials.gov ID
- NCT03988842
- Acronym / sponsor ID
- SAFE-LYSE / Pro00054951
- Conditions
- Pulmonary Embolism With Acute Cor Pulmonale, Pulmonary Embolism, Pulmonary Embolism With Pulmonary Infarction, Pulmonary Embolism Subacute Massive, Right Ventricular Dysfunction, Right Ventricular Failure
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: COVID-19 pandemic
- Enrolment
- 4 participants (actual)
- Lead sponsor
- Victor Tapson, MDUniversity, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Study start
- 25 Jul 2019 (actual)
- Primary completion
- 5 Apr 2020 (actual)
- Study completion
- 5 Apr 2020 (actual)
- First posted
- 18 Jun 2019 (actual)
- Results
- Posted 18 May 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Alteplase & Unfractionated Heparin & Apixaban | Experimental | Drug: Alteplase, Drug: Unfractionated heparin, Drug: ApixabanAlteplase 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. |
| Placebo & Unfractionated Heparin & Apixaban | Active comparator | Drug: Unfractionated heparin, Drug: Placebo, Drug: ApixabanAlteplase 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. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (31 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AlteplaseAlso: Activase, tissue-type plasminogen activatorLyophilized powder for reconstitution in 50mg vials | Drug | Alteplase & Unfractionated Heparin & Apixaban |
| Unfractionated heparinAlso: Heparin sodiumHeparin sodium in 0.45% sodium chloride injection for intravenous use | Drug | Alteplase & Unfractionated Heparin & Apixaban, Placebo & Unfractionated Heparin & Apixaban |
| PlaceboAlso: Placebo (for Alteplase)Saline solution reconstituted to mimic Alteplase 50mg vial | Drug | Placebo & Unfractionated Heparin & Apixaban |
| ApixabanAlso: EliquisApixaban tablet | Drug | Alteplase & Unfractionated Heparin & Apixaban, Placebo & Unfractionated Heparin & Apixaban |
Primary outcome
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).
11 secondary outcomes
Change in Extent of Clot Lysis Between the Experimental Arm and the Active Comparator Arm
Time frame: Baseline, 24 hours
Change in Right Ventricular to Left Ventricular Diameter (RV/LV) Ratio
Time frame: Baseline, 24 hours
Change in RV/LV Ratio From Baseline Echocardiogram
Time frame: Baseline, 24 hours and 30 days
Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) From Baseline Echocardiogram
Time frame: Baseline, 24 hours and 30 days
Change in Right Ventricular Systolic Pressure (RVSP) From Baseline Echocardiogram
Time frame: Baseline, 24 hours and 30 days
Change in the Collapse of the Inferior Vena Cava (IVC) From Baseline Echocardiogram
Time frame: Baseline, 24 hours and 30 days
Change in the Requirement for Oxygen Therapy After 6 Minute Walk Test (6MWT)
Time frame: 30 days, 60 days, and 1 year
Change in Borg Dyspnea Scale Score After 6 Minute Walk Test (6MWT)
Time frame: 30 days, 60 days, and 1 year
Change in Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Questionnaire
Time frame: 30 days, 6 months, and 1 year
Change in Pulmonary Embolism Quality of Life (PEmb-QOL) Questionnaire
Time frame: 30 days, 6 months, and 1 year
Number of Recurrent Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) Events
Time frame: 30 days, 60 days, 6 months, and 1 year
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Jun 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 22179539Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation. 2012 Jan 3;125(1):e2-e220. doi: 10.1161/CIR.0b013e31823ac046. Epub 2011 Dec 15. No abstract available.
- Background: PubMed 20331949Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous thromboembolism: a public health concern. Am J Prev Med. 2010 Apr;38(4 Suppl):S495-501. doi: 10.1016/j.amepre.2009.12.017.
- Background: PubMed 8996020Layish DT, Tapson VF. Pharmacologic hemodynamic support in massive pulmonary embolism. Chest. 1997 Jan;111(1):218-24. doi: 10.1378/chest.111.1.218. No abstract available.
- Background: PubMed 10227218Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999 Apr 24;353(9162):1386-9. doi: 10.1016/s0140-6736(98)07534-5.
- Background: PubMed 25173341Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galie N, Gibbs JS, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Vonk Noordegraaf A, Zamorano JL, Zompatori M; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014 Nov 14;35(43):3033-69, 3069a-3069k. doi: 10.1093/eurheartj/ehu283. Epub 2014 Aug 29. No abstract available.
- Background: PubMed 25317677Kohn CG, Mearns ES, Parker MW, Hernandez AV, Coleman CI. Prognostic accuracy of clinical prediction rules for early post-pulmonary embolism all-cause mortality: a bivariate meta-analysis. Chest. 2015 Apr;147(4):1043-1062. doi: 10.1378/chest.14-1888.
- Background: PubMed 1512328Dalla-Volta S, Palla A, Santolicandro A, Giuntini C, Pengo V, Visioli O, Zonzin P, Zanuttini D, Barbaresi F, Agnelli G, et al. PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2. J Am Coll Cardiol. 1992 Sep;20(3):520-6. doi: 10.1016/0735-1097(92)90002-5.
- Background: PubMed 24716681Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, Bluhmki E, Bouvaist H, Brenner B, Couturaud F, Dellas C, Empen K, Franca A, Galie N, Geibel A, Goldhaber SZ, Jimenez D, Kozak M, Kupatt C, Kucher N, Lang IM, Lankeit M, Meneveau N, Pacouret G, Palazzini M, Petris A, Pruszczyk P, Rugolotto M, Salvi A, Schellong S, Sebbane M, Sobkowicz B, Stefanovic BS, Thiele H, Torbicki A, Verschuren F, Konstantinides SV; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11. doi: 10.1056/NEJMoa1302097.
- Background: PubMed 24938564Chatterjee S, Chakraborty A, Weinberg I, Kadakia M, Wilensky RL, Sardar P, Kumbhani DJ, Mukherjee D, Jaff MR, Giri J. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014 Jun 18;311(23):2414-21. doi: 10.1001/jama.2014.5990.
- Background: PubMed 24917641Marti C, John G, Konstantinides S, Combescure C, Sanchez O, Lankeit M, Meyer G, Perrier A. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J. 2015 Mar 7;36(10):605-14. doi: 10.1093/eurheartj/ehu218. Epub 2014 Jun 10.
- Background: PubMed 25922654Daley MJ, Murthy MS, Peterson EJ. Bleeding risk with systemic thrombolytic therapy for pulmonary embolism: scope of the problem. Ther Adv Drug Saf. 2015 Apr;6(2):57-66. doi: 10.1177/2042098615572333.
- Background: PubMed 26867832Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JRE, Wells P, Woller SC, Moores L. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-352. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Victor F Tapson, MD principal investigator
Cedars-Sinai Medical Center
Aaron S Weinberg, MD principal investigator
Cedars-Sinai Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Alteplase, Unfractionated heparin and Apixaban in people with Pulmonary Embolism With Acute Cor Pulmonale and Pulmonary Embolism, run by Victor Tapson, MD at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 11 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 May 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Extent of Clot Lysis in the Experimental Arm (time frame: Baseline, 24 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03988842, which also lists 30 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jun 2021.