Clot Dissolving Treatment for Blood Clots in the Lungs

Study Overview
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Brief Summary
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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
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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.

Official Title
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Randomized Trial of Tenecteplase to Treat Severe Submassive Pulmonary Embolism

Conditions
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Pulmonary Embolism

Intervention / Treatment
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* Drug: Tenecteplase + Enoxaparin
* Drug: 0.9% Saline + Enoxaparin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 2<br>Saline + Enoxaparin | Drug: 0.9% Saline + Enoxaparin<br>* Enoxaparin: 1 mg/kg within 12 hours before receiving saline.<br>|
| Experimental: 1<br>Tenecteplase + Enoxaparin | Drug: Tenecteplase + Enoxaparin<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Embolism, Tenecteplase, Enoxaparin, Thrombosis, Fibrinolytics