Clot Dissolving Treatment for Blood Clots in the Lungs

Condition(s) targeted: Pulmonary Embolism

Intervention: Tenecteplase + Enoxaparin (Drug); 0.9% Saline + Enoxaparin (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Carolinas Healthcare System

Official(s) and/or principal investigator(s):
Jeffrey A Kline, MD, Principal Investigator, Affiliation: Carolinas Medical Center

Overall contact:
Jeffrey A Kline, MD, Phone: 704-355-7092, Email: jkline@carolinas.org

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.

Official title: Randomized Trial of Tenecteplase to Treat Severe Submassive Pulmonary Embolism

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome:

Evidence of PE-related and Hemorrhage-related serious adverse outcomes

Evidence of functional cardiopulmonary limitations and death

Secondary outcome: Evidence of recurrent venous thromboembolism and/or severe post-phlebitic syndrome

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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

Jeffrey A Kline, MD, Phone: 704-355-7092, Email: jkline@carolinas.org

University of California, Davis Medical Center, Sacramento, California 95817, United States; Recruiting
Deborah Diercks, MD, Phone: 916-734-4052, Email: dbdiercks@ucdavis.edu
Deborah Diercks, MD, Principal Investigator

University of Colorado Hospital, Aurora, Colorado 80045, United States; Recruiting
Kristen E Nordenholz, MD, Phone: 720-848-6777, Email: Kristen.Nordenholz@ucdenver.edu
Kristen E Nordenholz, MD, Principal Investigator

Northwestern Memorial Hospital, Chicago, Illinois 60611, United States; Recruiting
Daniel M Courtney, MD, Phone: 312-694-7000
Daniel M Courtney, MD, Principal Investigator

Massachusetts General Hospital, Boston, Massachusetts 02114, United States; Recruiting
Christopher Kabrhel, MD, Phone: 617-726-5824, Email: ckabrhel@partners.org
Christopher Kabrhel, MD, Principal Investigator

Carolinas Medical Center, Charlotte, North Carolina 28203, United States; Recruiting
Jefrrey A Kline, MD, Phone: 704-355-7092, Email: jeffrey.kline@carolinashealthcare.org
Jackeline Hernandez, Phone: 704-3552612, Email: jackeline.hernandez@carolinashealthcare.org
Jeffrey A Kline, MD, Principal Investigator

Rhode Island Hospital, Providence, Rhode Island 02903, United States; Recruiting
Amy J Palmisciano, RN, Phone: 401-444-4961, Email: apalmisciano@lifespan.org
James R Klinger, MD, Principal Investigator

University of Utah Hospital, Salt Lake City, Utah 84132, United States; Recruiting
Matthew T Rondina, MD, Phone: 801-581-7818, Email: matthew.rondina@hsc.utah.edu
Matthew T Rondina, MD, Principal Investigator

Starting date: May 2008
Last updated: March 14, 2011