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Activated Protein C to Treat Acute Lung Injuries

Information source: University of California, San Francisco
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Respiratory Distress Syndrome, Adult

Intervention: Xigris (Drug)

Phase: Phase 2

Status: Terminated

Sponsored by: University of California, San Francisco

Official(s) and/or principal investigator(s):
Michael Matthay, Study Chair, Affiliation: University of California, San Francisco

Summary

The purpose of this study is to test the efficacy of activated Protein C (Xigris) for improving clinical outcomes in individuals with acute lung injury (ALI).

Clinical Details

Official title: Prospective, Randomized Phase II Clinical Trial of Activated Protein C (Xigris) Versus Placebo for the Treatment of Acute Lung Injury

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Primary outcome: Number of ventilator-free days (measured at Day 28)

Detailed description: BACKGROUND: The hypothesis that procoagulant and inflammatory mechanisms may have a dual role in tissue injury was tested in the phase III clinical trial of recombinant Xigris for severe sepsis (Bernard, 2001). There was a significant reduction in mortality from 30% to 24% in patients treated with Xigris. However, there is no information on the effect of Xigris on patients with sepsis and co-existing ALI. Because Xigris is known to have both anti-coagulant and anti-inflammatory properties, it is plausible that it may be effective at treating patients with ALI from pulmonary and non-pulmonary infectious causes. There is also a good rationale for the hypothesis that Xigris may be effective at treating ALI from non-infectious causes. In experimental lung injury, from a non-infectious cause, such as hyperoxia or a like acid-lung injury, pro-coagulant mechanisms play a role in the pathogenesis of the ALI (Eitzman, 1996; Barazzone, 1996). Furthermore, research has shown that plasma-protein C deficiency occurs in almost all patients with ALI, and reduced Protein C levels are associated with a higher mortality and more non-pulmonary organ system dysfunction, even in patients with non-septic causes of ALI (Ware, 2003). Elevated levels of thrombomodulin, a product of endothelial injury, were measured in the plasma of all patients with ALI regardless of the clinical disorder associated with lung injury. The elevations of thrombomodulin were much higher in edema fluid than in plasma, suggesting that local activation and release of thrombomodulin had occurred, probably from both epithelial and endothelial sources from the lung, again supporting the hypothesis that a common pathway to lung injury may occur in both septic and non-septic causes of ALI. In addition, there is considerable evidence that the normal fibrinolytic mechanisms are impaired in the alveolar compartment in patients with ALI. Elevated levels of plasminogen-activator-inhbitor-1 (PAI-1) in the plasma of pulmonary edema fluid have a predictive value for identifying patients with ALI who are more likely to die than survive, regardless of the clinical risk factors that predisposes the development of ALI (Prabhakaran, 2003). Thus, this supports the rationale for testing Xigris as a treatment for patients with ALI, regardless of the clinical disorder associated with the cause of the lung injury. Since Xigris has both anti-coagulant and anti-inflammatory properties (Esmon, 2000; Grey, 1994), this treatment could reverse both the intravascular and the extravascular lung injuries and allow the lung epithelial and endothelial barriers to recover from a functional breakdown of both barriers. This study will evaluate the effects of the treatment of biochemical markers on alveolar epithelial injury. DESIGN NARRATIVE: Participants will be randomly assigned to receive either Xigris or saline placebo, to be administered continuously for 96 hours. Participants will be followed for 28 days, regardless of whether the drug is stopped for an adverse event, if the participant or physician decides to stop the drug, if the participant is discharged from the hospital with unassisted breathing, or until death.

Eligibility

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

Criteria:

Inclusion Criteria:

- PaO2/FiO2 levels less than or equal to 300

- Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph

- Positive pressure ventilation through an endotracheal tube or tracheostomy

- No clinical evidence of left atrial hypertension that would explain the pulmonary

infiltrates; if measured, pulmonary arterial wedge pressure less than or equal to 18 mm Hg Exclusion Criteria:

- Family / patient refuses

- Patient / surrogate unavailable

- Attending refuses

- Age younger than 18 years

- Severe sepsis and Acute Physiology and Chronic Health Evaluation (APACHE) II scores

greater than 25 within 48 hours of onset of severe sepsis

- Greater than 72 hours since all inclusion criteria are met

- Neuromuscular disease that impairs ability to ventilate without assistance, such as

C5 or higher spinal cord injury, amyotrophic lateral sclerosis, Guillain-Barré syndrome, myasthenia gravis, or kyphoscoliosis

- Pregnant

- Severe chronic respiratory disease

- Weighs more than 160 kg

- Burns to more than 70% of total body surface area

- Cancer or other irreversible disease or condition for which 6-month mortality is

estimated to be greater than 50%

- Bone marrow transplant in the 5 years prior to study entry

- Not committed to full support

- Severe chronic liver disease, as determined by a Child-Pugh Score of 11 to 15

- Diffuse alveolar hemorrhage from vasculitis

- Participation in another experimental medication study within 30 days of study entry

- Patients who have already received APC therapy

- Active internal bleeding

- Hemorrhagic or ischemic stroke within 3 months of study entry

- Intracranial or intraspinal surgery or severe head trauma within 2 months of study

entry

- Trauma with an increased risk of life-threatening bleeding

- Presence of an epidural catheter

- Intracranial neoplasm mass lesion or evidence of cerebral herniation

- High risk of intracranial hemorrhage, as determined by 1 of the following: 1)

intracranial or spinal pathology which places individuals at risk for intracranial hemorrhage (e. g., arterio-venous malformation or previous intracranial bleeding events, not including meningitis); 2) acute change in neurological status with focal neurological findings; 3) documented intracranial hypertension by lumbar puncture or imaging; or 4) seizures in which there is a clinical suspicion of intracranial hemorrhage

- Known bleeding diathesis

- Concurrent therapeutic heparin (greater than 14 units/kg/hr)

- Platelet count less than 30,000 x 106/L, even if the platelet count is increased

after transfusions

- Prothrombin time greater than 3. 0 INR

- Gastrointestinal bleeding within 6 weeks of study entry

- Concurrent need for systemic anticoagulation with therapeutic unfractionated heparin

or low molecular weight heparin during the study drug infusion

- Concurrent administration of an anticoagulant (other than subcutaneous heparin for

prophylaxis)

- Concurrent need for platelet glycoprotein Iib/IIIa antagonists or any other

antiplatelet agents (patients taking aspirin or other antiplatelet agents at study entry are eligible if medication can be discontinued during study drug infusion)

- Surgery within 30 days of study entry and single organ failure

Locations and Contacts

University of California San Francisco at Fresno, Fresno, California 93702, United States

University of Southern California, Los Angeles, California 97239-3098, United States

San Francisco General Hospital, San Francisco, California 94110, United States

University of California San Francisco, San Francisco, California 94143-0130, United States

Stanford University, Department of Pulmonary and Critical Care, Stanford, California 94305, United States

Yale School of Medicine, Section of Pulmonary & Critical Care Medicine, New Haven, Connecticut 06520-8057, United States

Joseph M. Still Burn Center, Augusta, Georgia 97239-3098, United States

Bay State Medical Center, Springfield, Massachusetts 01199, United States

Oregon Health Sciences University, Portland, Oregon 97239-3098, United States

Additional Information

Related publications:

Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1334-49. Review.

Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001 Mar 8;344(10):699-709.

Nuckton TJ, Alonso JA, Kallet RH, Daniel BM, Pittet JF, Eisner MD, Matthay MA. Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med. 2002 Apr 25;346(17):1281-6.

Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000 May 4;342(18):1301-8.

Starting date: January 2005
Last updated: March 11, 2014

Page last updated: August 23, 2015

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