Respiratory Distress Syndrome, AdultPhase 2NCT00112164
Activated Protein C to Treat Acute Lung Injuries
A Phase 2 study testing Xigris in people with Respiratory Distress Syndrome, Adult, run by University of California, San Francisco at 9 sites in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Respiratory Distress Syndrome, Adult
- What is being tested?
- Xigris
- How many people
- 90 participants
- Where
- 9 sitesUnited States
- Study dates
- Jan 2005to Feb 2007
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 34Show fewer
- 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
Trial locations and contacts
9 sites in 1 country.
9 sites in 1 country
United States9 sites
Joseph M. Still Burn Center
Augusta, Georgia, 97239-3098
University of California San Francisco at Fresno
Fresno, California, 93702
University of Southern California
Los Angeles, California, 97239-3098
Yale School of Medicine, Section of Pulmonary & Critical Care Medicine
New Haven, Connecticut, 06520-8057
Oregon Health Sciences University
Portland, Oregon, 97239-3098
San Francisco General Hospital
San Francisco, California, 94110
University of California San Francisco
San Francisco, California, 94143-0130
Bay State Medical Center
Springfield, Massachusetts, 01199
Stanford University, Department of Pulmonary and Critical Care
Stanford, California, 94305
About this study
Official title: Prospective, Randomized Phase II Clinical Trial of Activated Protein C (Xigris) Versus Placebo for the Treatment of Acute Lung Injury
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).
Read the 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.
- Conditions
- Respiratory Distress Syndrome, Adult
- Being tested
- Xigris
- Keywords
- Acute Respiratory Distress Syndrome
- Medical subject headings
- Respiratory Distress Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
XigrisDrug
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of ventilator-free days (measured at Day 28)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 May 2005 (estimated)
- Study startJan 2005
- Study completionFeb 2007
Why it stopped: Per recommendation of the NHLBI DSMB
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Respiratory Distress Syndrome, AdultStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Enrolment
- 90 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Investigators
- Michael Matthay, Study chair, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00112164
- Sponsor's protocol ID
- 175
- Other IDs
- P50HL074005
- Status last verified
- Mar 2014
- First submitted
- 27 May 2005
- Last updated
- 13 Mar 2014
- Results posted
- No
Publications
Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1334-49. doi: 10.1056/NEJM200005043421806. No abstract available.
PubMed 10793167Bernard 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. doi: 10.1056/NEJM200103083441001.
PubMed 11236773Nuckton 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. doi: 10.1056/NEJMoa012835.
PubMed 11973365Acute Respiratory Distress Syndrome Network; Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1301-8. doi: 10.1056/NEJM200005043421801.
PubMed 10793162Liu KD, Levitt J, Zhuo H, Kallet RH, Brady S, Steingrub J, Tidswell M, Siegel MD, Soto G, Peterson MW, Chesnutt MS, Phillips C, Weinacker A, Thompson BT, Eisner MD, Matthay MA. Randomized clinical trial of activated protein C for the treatment of acute lung injury. Am J Respir Crit Care Med. 2008 Sep 15;178(6):618-23. doi: 10.1164/rccm.200803-419OC. Epub 2008 Jun 19.
PubMed 18565951
Study at a glance
From the registry record, last updated by the sponsor on 13 Mar 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prospective, Randomized Phase II Clinical Trial of Activated Protein C (Xigris) Versus Placebo for the Treatment of Acute Lung Injury
- ClinicalTrials.gov ID
- NCT00112164
- Acronym / sponsor ID
- 175
- Conditions
- Respiratory Distress Syndrome, Adult
- Keywords
- Acute Respiratory Distress Syndrome
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Per recommendation of the NHLBI DSMB
- Enrolment
- 90 participants (estimated)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- Jan 2005
- Study completion
- Feb 2007 (actual)
- First posted
- 30 May 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (34 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Xigris | Drug | – |
Primary outcome
Number of ventilator-free days (measured at Day 28)
Results and safety
The study was stopped early (reason given: Per recommendation of the NHLBI DSMB). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Mar 2014.
- Background: PubMed 10793167Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1334-49. doi: 10.1056/NEJM200005043421806. No abstract available.
- Background: PubMed 11236773Bernard 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. doi: 10.1056/NEJM200103083441001.
- Background: PubMed 11973365Nuckton 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. doi: 10.1056/NEJMoa012835.
- Background: PubMed 10793162Acute Respiratory Distress Syndrome Network; Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1301-8. doi: 10.1056/NEJM200005043421801.
- Derived from this study: PubMed 18565951Liu KD, Levitt J, Zhuo H, Kallet RH, Brady S, Steingrub J, Tidswell M, Siegel MD, Soto G, Peterson MW, Chesnutt MS, Phillips C, Weinacker A, Thompson BT, Eisner MD, Matthay MA. Randomized clinical trial of activated protein C for the treatment of acute lung injury. Am J Respir Crit Care Med. 2008 Sep 15;178(6):618-23. doi: 10.1164/rccm.200803-419OC. Epub 2008 Jun 19.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michael Matthay study chair
University of California, San Francisco
9 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Xigris in people with Respiratory Distress Syndrome, Adult, run by University of California, San Francisco at 9 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 34 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 13 Mar 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Per recommendation of the NHLBI DSMB). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of ventilator-free days (measured at Day 28). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00112164, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Mar 2014.