Clot Dissolving Treatment for Blood Clots in the Lungs

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