Treatment of Acute Respiratory Distress Syndrome With Tenecteplase: A Dose Escalation Pilot Study
Status:
Withdrawn
Trial end date:
2008-12-01
Target enrollment:
Participant gender:
Summary
The pathogenesis of ARDS appears to be from damage to the alveolar-capillary barrier, which
is composed of the microvascular endothelium and the alveolar epithelium. This damage may
occur from direct or indirect lung injury. The mechanism of injury to the alveolar capillary
barrier appears to be through neutrophil-mediated injury, pro-inflammatory cytokines,
ventilator-induced lung injury with alveolar over distention and abnormalities of the
coagulation system. This results in blood clot formation in the microcirculation of the lung.
Thrombolytics can dissolve blood clots and result in increased blood flow to the organs. This
treatment may benefit ARDS patients, thus the purpose of this study.
Hardaway, et al.studied the effects of thrombolytics on ARDS in pigs. The experimental group
showed improved oxygenation and survival as compared to controls. There was no bleeding
complications noted with this therapy. Dr. Hardaway followed this animal study with a phase I
clinical trial involving 20 patients with ARDS. The patients were treated with IV
streptokinase or urokinase. Nineteen of the 20 patients showed an increase in PA02 after
thrombolytic therapy. There were no significant bleeding complications in patients that were
critically ill on ventilators.
We propose an additional phase I pilot study to evaluate the effectiveness and safety of
Tenecteplase for the treatment of ARDS. Unlike the other fibrinolytics studied in this
disease state, Tenecteplase, is more fibrin specific and has increased resistance to
plasminogen activator inhibitor (PAI-I) at greater levels than other available fibrinolytics.
We have chosen an experimental dose escalation trial design of tenecteplase that has
demonstrated initial safety trends in a Phase I acute ischemic stroke trial. The initial dose
is 0.1 mg/kg IV and will increase to 0.2 mg/kg, 0.3 mg/kg, with a final cohort of patients
receiving 0.4 mg/kg. Drug administration will be a single dose bolus in each cohort.
Advancement of dose will occur if safety is not in question in the previous cohort. We hope
this will provide an acceptable benefit risk ratio as the mortality of ARDS is approximately
30 - 60%. All patients will be closely monitored for any change in clotting parameters and
signs of bleeding. Tenecteplase will be administered via a peripheral IV as described in the
package insert.