Pulmonary Embolism
Conditions
Keywords
Pulmonary Embolism, Tenecteplase, Enoxaparin, Thrombosis, Fibrinolytics
Brief summary
The purpose of this study is to determine if tenecteplase plus enoxaparin is safe and effective in the treatment of patients with severe submassive pulmonary embolism.
Detailed description
This project is a phase III, six-center, randomized trial of tenecteplase to treat severe submassive (systolic blood pressure \>90 mm Hg) pulmonary embolism (PE). Severe requires one of the following predictors of a adverse outcome: right ventricular (RV) hypokinesis on echocardiography, hypoxemia (pulse oximetry reading \<95%, \<1000 feet above sea level), serum troponin I (abnormal at local threshold) or brain natriuretic peptide concentration \>90 pg/mL (or NT proBNP \>900 pg/mL). Patients from the emergency department or inpatients can be enrolled within 24 hours of a diagnostic positive CT angiography. After informed consent, eligible patients will be randomized to the study or placebo arm. All patients will a receive a 1mg/kg enoxaparin, SQ followed by a syringe prepared in pharmacy containing either a body weight-adjusted dose of tenecteplase or a 0.9% saline placebo, given IV push. Patients will be followed for five days post-treatment for composite acute adverse outcomes: PE-related (death, any ACLS intervention, circulatory shock, respiratory failure, need for vasopressors with organ dysfunction) and hemorrhage-related (intracranial or intraspinal hemorrhage and any other hemorrhage requiring transfusion, surgical or endoscopic intervention or a hemostatic drug). Survivors will return at three months for assessment of a delayed adverse outcomes of death or cardiopulmonary functional limitation (CFL): interval medical care for dyspnea + RV dysfunction or pulmonary hypertension on echo + either a NYHA score ≥3 or a 6 minute walk distance \<330 m. Together, the acute and delayed outcomes represent composite serious adverse outcomes (SAOs). We hypothesize an absolute 20% reduction in composite serious adverse outcomes in the study arm compared with the placebo arm. The six hospitals represent geographic diversity: Boston, Charlotte, Chicago, Denver, New Haven, and Springfield, MA. To help maintain balance between sites, the six sites will each enroll a maximum of 40 patients until the sample size of N=200 is reached, which allows the 20% effect size to be tested at α =0.05 and β=0.20 with 15% loss to follow-up. The study will employ an intent-to treat analysis. Secondary endpoints include recurrent venous thromboembolism within three months, scores from two validated quality of life questionnaire (VEINES-QOL and SF-36TM) at three months. Human subject safety include requirement that a study MD verify the presence of all inclusion and absence of exclusions in real-time, a method to allow unblinding to the clinical care team, an independent DSMB that will perform 6 interim analyses and will enforce predefined stopping criteria for either safety or efficacy.
Interventions
DRUGTenecteplase + Enoxaparin
Enoxaparin: 1 mg/kg within 12 hours before receiving tenecteplase.Subsequently, patients will receive 1 mg/kg enoxaparin SQ Q12 hours until discontinuation is clinically indicated. Tenecteplase:will be administered using a tiered-dosing schedule according to patient weight: \<60Kg=30mg; ≥60Kg to \<70Kg=35mg; ≥70Kg to \<80Kg=40mg; ≥80Kg to \<90Kg=45mg; ≥90Kg=50mg
DRUG0.9% Saline + Enoxaparin
Enoxaparin: 1 mg/kg within 12 hours before receiving saline.
Sponsors
Wake Forest University Health Sciences
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Pulmonary vascular imaging positive for PE within the previous 24 hours * Ability to provide written informed consent and comply with study assessments for the full duration of the study * Age \>17 years * Evidence of severe PE: RV hypokinesis on echocardiography, abnormal troponin I or T (any non-normal including indeterminate values, using local reference thresholds) or BNP measurement \>90 pg/mL or NT proBNP \>900 pg/ml (not more than 6 hours prior to CT angiography and not more than 30 hours before enrollment) or a pulse oximetry reading \<95% within previous two hours (\<93% in Denver).
Exclusion criteria
* Systolic blood pressure \< 90 mm Hg at time of informed consent * Do not resuscitate or do not intubate order * Systemic fibrinolytic treatment within previous 7 days * Inability to follow-up at 3 months * Documented gastrointestinal bleeding within previous 30 days * Active hemorrhage in any of the following sites at the time of enrollment: intraperitoneal, retroperitoneal, pulmonary, uterine, bladder, or nose. * Head trauma causing loss of consciousness within previous 7 days * Any history of hemorrhagic stroke * Ischemic stroke within the past year * Prior history of heparin-induced thrombocytopenia * History of intraocular hemorrhage * Intracranial metastasis * Known inherited bleeding disorder, e.g., hemophilia * Platelet count \< 50,000/uL * Prothrombin time with an INR \>1.7 * Chest, abdominal, intracranial or spinal surgery within the previous 14 days * Subacute bacterial endocarditis * Pregnancy (positive pregnancy test) * Prior enrollment in the study * Current treatment with fondiparinux, dalteparin, a direct thrombin inhibitor or administration of a glycoprotein inhibitor within the previous 48 hours. * Known pericarditis * Allergy to heparins,or tenecteplase * Elapsed time that would preclude drug or placebo administration within 24 hours after diagnosis * Evidence of non-end stage kidney injury (creatinine clearance \< 30 ml/min without chronic hemodialysis treatment; chronic hemodialysis-treated patients are eligible) * Preexisting end-stage cardiopulmonary disease (heart failure with left ventricular ejection fraction \<20%, known severe pulmonary hypertension or other lung disease causing permanent dependence upon oxygen) * Any other condition that the investigator believes would pose a significant hazard to the subject
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Patients With Cardiogenic Shock or Respiratory Failure From Pulmonary Embolism and Number of Patietnts With Major Hemorrhage | 1,2,3,4, and 5 days |
| Number With Functional Cardiopulmonary Limitations Assessed With a Composite Measurement (Six Minute Walk Distance, Right Ventricular Function and Quality of Life Score on the SF-36) | 90 days |
| Number With Recurrent Venous Thromboembolism and/or Severe Post-phlebitic Syndrome | 90 days |
Countries
United States
Participant flow
Recruitment details
Patients enrolled from 8 hospitals from August 2008 until October, 2012. Genentech funded the study. Carolinas Medical Center was the prime contractor site and subcontracted 7 other hospitals.
Pre-assignment details
The investigator relocated to a new institution in July 2012, which led to insoluble problems with the subcontracts that forced early study closure.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Tenecteplase + Enoxaparin
Tenecteplase + Enoxaparin : Enoxaparin: 1 mg/kg within 12 hours before receiving tenecteplase.Subsequently, patients will receive 1 mg/kg enoxaparin SQ Q12 hours until discontinuation is clinically indicated.
Tenecteplase:will be administered using a tiered-dosing schedule according to patient weight: \<60Kg=30mg; ≥60Kg to \<70Kg=35mg; ≥70Kg to \<80Kg=40mg; ≥80Kg to \<90Kg=45mg; ≥90Kg=50mg | 43 |
| Tenecteplase Saline + Enoxaparin
0.9% Saline + Enoxaparin : Enoxaparin: 1 mg/kg within 12 hours before receiving saline. | 40 |
| Total | 83 |
Baseline characteristics
| Characteristic | Tenecteplase | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 6 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 34 Participants | 37 Participants | 71 Participants |
| Age, Continuous | 57 years STANDARD_DEVIATION 14 | 54 years STANDARD_DEVIATION 14 | 55 years STANDARD_DEVIATION 14 |
| Region of Enrollment United States | 40 participants | 43 participants | 83 participants |
| Sex: Female, Male Female | 20 Participants | 19 Participants | 39 Participants |
| Sex: Female, Male Male | 20 Participants | 24 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 43 | 0 / 40 |
| serious Total, serious adverse events | 1 / 43 | 1 / 40 |
Outcome results
Primary
Number of Patients With Cardiogenic Shock or Respiratory Failure From Pulmonary Embolism and Number of Patietnts With Major Hemorrhage
Time frame: 1,2,3,4, and 5 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Patients With Cardiogenic Shock or Respiratory Failure From Pulmonary Embolism and Number of Patietnts With Major Hemorrhage | 1 participants |
| Tenecteplase | Number of Patients With Cardiogenic Shock or Respiratory Failure From Pulmonary Embolism and Number of Patietnts With Major Hemorrhage | 1 participants |
Primary
Number With Functional Cardiopulmonary Limitations Assessed With a Composite Measurement (Six Minute Walk Distance, Right Ventricular Function and Quality of Life Score on the SF-36)
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number With Functional Cardiopulmonary Limitations Assessed With a Composite Measurement (Six Minute Walk Distance, Right Ventricular Function and Quality of Life Score on the SF-36) | 8 participants |
| Tenecteplase | Number With Functional Cardiopulmonary Limitations Assessed With a Composite Measurement (Six Minute Walk Distance, Right Ventricular Function and Quality of Life Score on the SF-36) | 4 participants |
Primary
Number With Recurrent Venous Thromboembolism and/or Severe Post-phlebitic Syndrome
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number With Recurrent Venous Thromboembolism and/or Severe Post-phlebitic Syndrome | 4 participants |
| Tenecteplase | Number With Recurrent Venous Thromboembolism and/or Severe Post-phlebitic Syndrome | 1 participants |