Ignite Creation Date:
2024-05-05 @ 9:42 AM
Last Modification Date:
2024-10-26 @ 9:01 AM
Study NCT ID:
NCT00000579
Status:
COMPLETED
Last Update Posted:
2016-03-23
First Post:
1999-10-27
Brief Title:
Acute Respiratory Distress Syndrome Clinical Network ARDSNet
Sponsor:
National Heart Lung and Blood Institute NHLBI
Organization:
National Heart Lung and Blood Institute NHLBI
Study Overview
Official Title:
Acute Respiratory Distress Syndrome Clinical Network ARDSNet
Status:
COMPLETED
Status Verified Date:
2006-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purposes of this study are to assess rapidly innovative treatment methods in patients with adult respiratory distress syndrome ARDS as well as those at risk of developing ARDS and to create a network of interactive Critical Care Treatment Groups CCTGs to establish and maintain the required infrastructure to perform multiple therapeutic trials that may involve investigational drugs approved agents not currently used for treatment of ARDS or treatments currently used but whose efficacy has not been well documented
Detailed Description:
BACKGROUND
ARDS affects approximately 150000 people in the United States each year Despite 20 years of research into the mechanisms that cause this syndrome and numerous developments in the technology of mechanical ventilation the mortality has remained greater than 50 percent Many of the patients are young and to the tragic loss of human life can be added the cost to society because these patients spend an average of 2 weeks in intensive care units and require multiple high tech procedures Because of the overwhelming nature of the lung injury once it is established prevention would appear to be the most effective strategy for improving the outlook in this condition
Basic research has identified numerous inflammatory pathways that are associated with the development of ARDS Agents that block these mediators prolong survival in animals with lung injury and a few of them have been tested in patients Because of the large number of putative mediators and the variety of ways that their action can be blocked the possibility for new drug development is almost infinite This is an exciting prospect since it envisions the first effective pharmacologic treatment for ARDS However preliminary clinical studies have shown conflicting results and there is an urgent need for a mechanism to efficiently and effectively test new drugs in ARDS
Treatment studies in patients with ARDS are difficult to perform for three reasons The complicated clinical picture makes it difficult to accumulate a large number of comparable patients in any one center There is no agreement on the optimal supportive care of these critically ill patients Many of the patients meeting study criteria will not be enrolled in study protocols because of the acute nature of the disease process For these reasons therapeutic trials in ARDS require multicenter cooperation
The concept for the initiative was first discussed at a meeting of the Adult Respiratory Distress Syndrome Foundation and staff of the Division of Lung Diseases The results of a working meeting on uniform definitions in ARDS held at the 1992 meeting of the American Thoracic Society reinforced the recommendation from the community for National Heart Lung and Blood Institute participation in drug evaluation in ARDS The concept for the initiative was approved by the September 1992 National Heart Lung and Blood Advisory Council The Requests for Proposals were released in October 1993
DESIGN NARRATIVE
It is anticipated that over the 12-year period several multicenter clinical trials will be developed and implemented A 12-month Phase I period was devoted to planning and developing the infrastructure and committee structure and to protocol development and prioritization In Phase IIa staff are trained in data acquisition procedures and patients are enrolled Additional protocol development may begin for subsequent studies In Phase IIb after the last patients in the first study have completed their follow-up measurements data will be reviewed and the initial study will be closed out Protocol development continues for subsequent trials In Phase III final data analysis and publication preparation will occur
Enrollment of 1000 patients into the first ARDSNet protocol Ketoconazole and Respiratory Management in Acute Lung InjuryAcute Respiratory Distress Syndrome KARMA began in the spring of 1996 KARMA assessed the efficacy of 6 mlkg versus 12 mlkg positive pressure ventilation in reducing mortality and morbidity in patients with acute lung injury and ARDS It also assessed the efficacy of ketoconazole a thromboxane synthetase inhibitor in reducing mortality and morbidity in patients with acute lung injury and ARDS The ketoconazole arm was stopped by the Data Monitoring Safety Board DSMB in January 1997 after the enrollment of 234 patients Ketoconazole did not show any benefit in survival duration of ventilation or any measure of lung function The ventilator arm of the protocol continued until March 10 1999 and compared the efficacy of high 12 mlkg and low 6 mlkg tidal volume ventilation in reducing mortality and morbidity in patients with acute lung injury and ARDS The ventilator portion of the trial was stopped on March 10 1999 on the recommendation of the DSMB when the data from the first 861 patients showed approximately 25 percent fewer deaths among patients receiving small rather than large breaths of air from the mechanical ventilator
A new drug lisofylline was selected to replace ketoconazole in the factorial design ventilation protocol The lisofylline study LARMA began in February 1998 The study tested the efficacy of lisofylline an analog of pentoxifylline that has been shown to protect against tissue injury mediated by oxidants and to suppress production of a number of cytokine mediators that amplify the inflammatory process Patients were randomized to either the high or low tidal volume ventilation treatment group and between lisofylline and placebo The aim of the lisofylline protocol was to determine whether the administration of lisofylline early after the onset of acute lung injury or ARDS would reduce morbidity or mortality The study was cosponsored by Cell Therapeutics Incorporated The trial was stopped by the DSMB on May 27 1999 after results were obtained on 221 patients There was no effect on mortality time on ventilation or organ failure
The Late Steroid Rescue Study LaSRS The Efficacy of Corticosteroids as Rescue Therapy for the Late Phase of Acute Respiratory Distress Syndrome LaSRS is pronounced Lazarus compared the effect of corticosteroids with placebo in the management of late-phase greater than 7 days ARDS The study determined if the administration of the corticosteroid methylprednisolone sodium succinate in severe ARDS that was either stable or worsening after 7 days would reduce mortality and morbidity The primary end point was mortality at 60 days Secondary endpoints included ventilator-free days and organ failure-free days LaSRS was designed to include 400 patients and began recruiting in the spring of 1997 In October 1999 the DSMB reduced the recruitment target number to 200 patients because the eligible patients were fewer than anticipated
In November 1999 the Network began a new trial as a follow-on to the ventilator trial that has been named the Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury ALVEOLI This trial was a prospective randomized controlled multicenter trial that included 549 patients and compared two groups of patients Patients were randomized to receive mechanical ventilation with either lower or higher PEEP which were set according to different tables of predetermined combinations of PEEP and fraction of inspired oxygen The primary end point was mortality at 60 days Secondary endpoints included ventilator-free days and organ failure-free days The trial has ended and results were published in the July 22 2004 issue of the New England Journal of Medicine The results suggest that in patients with acute lung injury and ARDS who receive mechanical ventilation with a tidal-volume goal of 6 ml per kilogram of predicted body weight and an end-inspiratory plateau-pressure limit of 30 centimeters of water clinical outcomes are similar whether lower or higher PEEP levels are used
Network investigators have developed a plan for a new protocol to assess the pulmonary artery catheter PAC as a management tool in ARDS The new study was prompted by recommendations from the FDANIH Pulmonary Artery Catheter Clinical Outcomes workshop convened in August 1997 in response to concerns in the medical community regarding the clinical benefit and safety of PACs The new protocol in the Fluids and Catheters Treatment Trial FACTT is a two-by-two factorial design comparing the patients receiving PAC or a central venous catheter CVC with one of two fluid management strategies conservative versus liberal The randomized multicenter trial is designed to include 1000 patients The primary end point is mortality at 60 days Secondary endpoints include ventilator-free days and organ failure-free days See NCT00281268 for more information on this study
Albuterol versus Placebo in Acute Lung Injury ALTA Study The Phase IIIII study will test the safety and efficacy of aerosolized beta-2 adrenergic agonist therapy albuterol sulfate for reducing mortality in patients with acute lung injury In Phase II the safety of albuterol at the 5-mg dose will be compared to saline in approximately 100 patients The dose will be reduced to 25 mg if patients exceed defined heart rate limits Consequently a Phase III placebo-controlled double-blinded randomized trial on approximately 1000 patients will compare 60-day mortality and ventilator-free days to Day 28 between the safe albuterol dose established in Phase II and placebo saline
New efforts have been initiated to increase sample collection and utilize collected patient materials to investigate mechanisms of ARDS pathogenesis In addition to investigations of hypotheses related to cytokines and inflammatory mediators the Network is preparing to collect samples for future studies of genetic determinants of ARDS The ARDSNet has been extended through September 2012 to continue clinical trials
ARDS affects approximately 150000 people in the United States each year Despite 20 years of research into the mechanisms that cause this syndrome and numerous developments in the technology of mechanical ventilation the mortality has remained greater than 50 percent Many of the patients are young and to the tragic loss of human life can be added the cost to society because these patients spend an average of 2 weeks in intensive care units and require multiple high tech procedures Because of the overwhelming nature of the lung injury once it is established prevention would appear to be the most effective strategy for improving the outlook in this condition
Basic research has identified numerous inflammatory pathways that are associated with the development of ARDS Agents that block these mediators prolong survival in animals with lung injury and a few of them have been tested in patients Because of the large number of putative mediators and the variety of ways that their action can be blocked the possibility for new drug development is almost infinite This is an exciting prospect since it envisions the first effective pharmacologic treatment for ARDS However preliminary clinical studies have shown conflicting results and there is an urgent need for a mechanism to efficiently and effectively test new drugs in ARDS
Treatment studies in patients with ARDS are difficult to perform for three reasons The complicated clinical picture makes it difficult to accumulate a large number of comparable patients in any one center There is no agreement on the optimal supportive care of these critically ill patients Many of the patients meeting study criteria will not be enrolled in study protocols because of the acute nature of the disease process For these reasons therapeutic trials in ARDS require multicenter cooperation
The concept for the initiative was first discussed at a meeting of the Adult Respiratory Distress Syndrome Foundation and staff of the Division of Lung Diseases The results of a working meeting on uniform definitions in ARDS held at the 1992 meeting of the American Thoracic Society reinforced the recommendation from the community for National Heart Lung and Blood Institute participation in drug evaluation in ARDS The concept for the initiative was approved by the September 1992 National Heart Lung and Blood Advisory Council The Requests for Proposals were released in October 1993
DESIGN NARRATIVE
It is anticipated that over the 12-year period several multicenter clinical trials will be developed and implemented A 12-month Phase I period was devoted to planning and developing the infrastructure and committee structure and to protocol development and prioritization In Phase IIa staff are trained in data acquisition procedures and patients are enrolled Additional protocol development may begin for subsequent studies In Phase IIb after the last patients in the first study have completed their follow-up measurements data will be reviewed and the initial study will be closed out Protocol development continues for subsequent trials In Phase III final data analysis and publication preparation will occur
Enrollment of 1000 patients into the first ARDSNet protocol Ketoconazole and Respiratory Management in Acute Lung InjuryAcute Respiratory Distress Syndrome KARMA began in the spring of 1996 KARMA assessed the efficacy of 6 mlkg versus 12 mlkg positive pressure ventilation in reducing mortality and morbidity in patients with acute lung injury and ARDS It also assessed the efficacy of ketoconazole a thromboxane synthetase inhibitor in reducing mortality and morbidity in patients with acute lung injury and ARDS The ketoconazole arm was stopped by the Data Monitoring Safety Board DSMB in January 1997 after the enrollment of 234 patients Ketoconazole did not show any benefit in survival duration of ventilation or any measure of lung function The ventilator arm of the protocol continued until March 10 1999 and compared the efficacy of high 12 mlkg and low 6 mlkg tidal volume ventilation in reducing mortality and morbidity in patients with acute lung injury and ARDS The ventilator portion of the trial was stopped on March 10 1999 on the recommendation of the DSMB when the data from the first 861 patients showed approximately 25 percent fewer deaths among patients receiving small rather than large breaths of air from the mechanical ventilator
A new drug lisofylline was selected to replace ketoconazole in the factorial design ventilation protocol The lisofylline study LARMA began in February 1998 The study tested the efficacy of lisofylline an analog of pentoxifylline that has been shown to protect against tissue injury mediated by oxidants and to suppress production of a number of cytokine mediators that amplify the inflammatory process Patients were randomized to either the high or low tidal volume ventilation treatment group and between lisofylline and placebo The aim of the lisofylline protocol was to determine whether the administration of lisofylline early after the onset of acute lung injury or ARDS would reduce morbidity or mortality The study was cosponsored by Cell Therapeutics Incorporated The trial was stopped by the DSMB on May 27 1999 after results were obtained on 221 patients There was no effect on mortality time on ventilation or organ failure
The Late Steroid Rescue Study LaSRS The Efficacy of Corticosteroids as Rescue Therapy for the Late Phase of Acute Respiratory Distress Syndrome LaSRS is pronounced Lazarus compared the effect of corticosteroids with placebo in the management of late-phase greater than 7 days ARDS The study determined if the administration of the corticosteroid methylprednisolone sodium succinate in severe ARDS that was either stable or worsening after 7 days would reduce mortality and morbidity The primary end point was mortality at 60 days Secondary endpoints included ventilator-free days and organ failure-free days LaSRS was designed to include 400 patients and began recruiting in the spring of 1997 In October 1999 the DSMB reduced the recruitment target number to 200 patients because the eligible patients were fewer than anticipated
In November 1999 the Network began a new trial as a follow-on to the ventilator trial that has been named the Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury ALVEOLI This trial was a prospective randomized controlled multicenter trial that included 549 patients and compared two groups of patients Patients were randomized to receive mechanical ventilation with either lower or higher PEEP which were set according to different tables of predetermined combinations of PEEP and fraction of inspired oxygen The primary end point was mortality at 60 days Secondary endpoints included ventilator-free days and organ failure-free days The trial has ended and results were published in the July 22 2004 issue of the New England Journal of Medicine The results suggest that in patients with acute lung injury and ARDS who receive mechanical ventilation with a tidal-volume goal of 6 ml per kilogram of predicted body weight and an end-inspiratory plateau-pressure limit of 30 centimeters of water clinical outcomes are similar whether lower or higher PEEP levels are used
Network investigators have developed a plan for a new protocol to assess the pulmonary artery catheter PAC as a management tool in ARDS The new study was prompted by recommendations from the FDANIH Pulmonary Artery Catheter Clinical Outcomes workshop convened in August 1997 in response to concerns in the medical community regarding the clinical benefit and safety of PACs The new protocol in the Fluids and Catheters Treatment Trial FACTT is a two-by-two factorial design comparing the patients receiving PAC or a central venous catheter CVC with one of two fluid management strategies conservative versus liberal The randomized multicenter trial is designed to include 1000 patients The primary end point is mortality at 60 days Secondary endpoints include ventilator-free days and organ failure-free days See NCT00281268 for more information on this study
Albuterol versus Placebo in Acute Lung Injury ALTA Study The Phase IIIII study will test the safety and efficacy of aerosolized beta-2 adrenergic agonist therapy albuterol sulfate for reducing mortality in patients with acute lung injury In Phase II the safety of albuterol at the 5-mg dose will be compared to saline in approximately 100 patients The dose will be reduced to 25 mg if patients exceed defined heart rate limits Consequently a Phase III placebo-controlled double-blinded randomized trial on approximately 1000 patients will compare 60-day mortality and ventilator-free days to Day 28 between the safe albuterol dose established in Phase II and placebo saline
New efforts have been initiated to increase sample collection and utilize collected patient materials to investigate mechanisms of ARDS pathogenesis In addition to investigations of hypotheses related to cytokines and inflammatory mediators the Network is preparing to collect samples for future studies of genetic determinants of ARDS The ARDSNet has been extended through September 2012 to continue clinical trials
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| N01 HR56179 | None | None | None |
| N01 HR16146 | None | None | None |
| N01 HR16147 | None | None | None |
| N01 HR16148 | None | None | None |
| N01 HR16149 | None | None | None |
| N01 HR16150 | None | None | None |
| N01 HR16151 | None | None | None |
| N01 HR16152 | None | None | None |
| N01 HR16153 | None | None | None |
| N01 HR16154 | None | None | None |
| N01 HR16155 | None | None | None |
| N01 HR46054 | None | None | None |
| N01 HR46055 | None | None | None |
| N01 HR46057 | None | None | None |
| N01 HR46056 | None | None | None |
| N01 HR46058 | None | None | None |
| N01 HR46059 | None | None | None |
| N01 HR46060 | None | None | None |
| N01 HR46061 | None | None | None |
| N01 HR46062 | None | None | None |
| N01 HR46063 | None | None | None |
| N01 HR46064 | None | None | None |
| N01 HR56165 | None | None | None |
| N01 HR56166 | None | None | None |
| N01 HR56167 | None | None | None |
| N01 HR56168 | None | None | None |
| N01 HR56169 | None | None | None |
| N01 HR56170 | None | None | None |
| N01 HR56171 | None | None | None |
| N01 HR56172 | None | None | None |
| N01 HR56173 | None | None | None |
| N01 HR56174 | None | None | None |
| N01 HR56175 | None | None | None |
| N01 HR56176 | None | None | None |