Pulmonary Embolism, Pulmonary Embolism Subacute Massive, Pulmonary Embolism With Acute Cor Pulmonale, Pulmonary Embolism With Pulmonary Infarction, Right Ventricular Dysfunction, Right Ventricular Failure
Conditions
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.
Interventions
DRUGAlteplase
Lyophilized powder for reconstitution in 50mg vials
DRUGUnfractionated heparin
Heparin sodium in 0.45% sodium chloride injection for intravenous use
DRUGPlacebo
Saline solution reconstituted to mimic Alteplase 50mg vial
DRUGApixaban
Apixaban tablet
Sponsors
Bristol-Myers Squibb
Victor Tapson, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Extent of Clot Lysis in the Experimental Arm | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in Extent of Clot Lysis Between the Experimental Arm and the Active Comparator Arm | 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). |
| Change in Right Ventricular to Left Ventricular Diameter (RV/LV) Ratio | 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. |
| Change in RV/LV Ratio From Baseline Echocardiogram | 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. |
| Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) From Baseline Echocardiogram | 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. |
| Change in Right Ventricular Systolic Pressure (RVSP) From Baseline Echocardiogram | 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. |
| Change in the Collapse of the Inferior Vena Cava (IVC) From Baseline Echocardiogram | 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. |
| Change in the Requirement for Oxygen Therapy After 6 Minute Walk Test (6MWT) | 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. |
| Change in Borg Dyspnea Scale Score After 6 Minute Walk Test (6MWT) | 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. |
| Change in Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Questionnaire | 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. |
| Change in Pulmonary Embolism Quality of Life (PEmb-QOL) Questionnaire | 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. |
| Number of Recurrent Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) Events | 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. |
Countries
United States
Participant flow
Pre-assignment details
The study was terminated early and never unblinded. Arm/Group randomization information is not available.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants were randomly assigned to either:
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.
Alteplase: Lyophilized powder for reconstitution in 50mg vials Unfractionated heparin: Heparin sodium in 0.45% sodium chloride injection for intravenous use Apixaban: Apixaban tablet OR 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.
Unfractionated heparin: Heparin sodium in 0.45% sodium chloride injection for intravenous use Placebo: Saline solution reconstituted to mimic Alteplase 50mg vial Apixaban: Apixaban tablet | 4 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Age, Continuous | 62.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Gender Female | 3 Participants |
| Gender Male | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Region of Enrollment United States | 4 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 4 |
| other Total, other adverse events | 1 / 4 |
| serious Total, serious adverse events | 2 / 4 |
Outcome results
Primary
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).
Time frame: Baseline, 24 hours
Population: The study was terminated early and never unblinded. Data was not analyzed.
Secondary
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.
Time frame: 30 days, 60 days, and 1 year
Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.
Secondary
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).
Time frame: Baseline, 24 hours
Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.
Secondary
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.
Time frame: 30 days, 6 months, and 1 year
Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.
Secondary
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.
Time frame: 30 days, 6 months, and 1 year
Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.
Secondary
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.
Time frame: Baseline, 24 hours and 30 days
Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.
Secondary
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.
Time frame: Baseline, 24 hours
Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.
Secondary
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.
Time frame: Baseline, 24 hours and 30 days
Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.
Secondary
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.
Time frame: Baseline, 24 hours and 30 days
Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.
Secondary
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.
Time frame: 30 days, 60 days, and 1 year
Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.
Secondary
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.
Time frame: Baseline, 24 hours and 30 days
Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.
Secondary
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.
Time frame: 30 days, 60 days, 6 months, and 1 year
Population: Data analysis not done because study closed early due to COVID-19 and there were only 4 subjects enrolled. With only 4 subjects, we decided not to unblind due to the sample size being so small that statistical significance could never be demonstrated.