PI changed institution and impossible to solve problem with contract's sites

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.

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.

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

see manuscript