Acute Respiratory Distress Syndrome Clinical Network (ARDSNet)

This study has been completed.
Sponsor:
Information provided by:
National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier:
NCT00000579
First received: October 27, 1999
Last updated: January 2, 2014
Last verified: August 2006
  Purpose

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.


Condition Intervention Phase
Respiratory Distress Syndrome, Adult
Lung Diseases
Procedure: Low Tidal Volume Ventilation
Procedure: Positive End-Expiratory Pressure
Drug: Lysofylline
Drug: Methylprednisolone
Drug: Ketoconazole
Procedure: Fluid Management
Procedure: Pulmonary Artery Catheter
Phase 3

Study Type: Interventional
Study Design: Intervention Model: Factorial Assignment
Primary Purpose: Treatment
Official Title: Acute Respiratory Distress Syndrome Clinical Network (ARDSNet)

Resource links provided by NLM:


Further study details as provided by National Heart, Lung, and Blood Institute (NHLBI):

Primary Outcome Measures:
  • Vary by protocol

Study Start Date: September 1994
Study Completion Date: July 2004
  Hide Detailed Description

Detailed Description:

BACKGROUND:

ARDS affects approximately 150,000 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 1,000 patients into the first ARDSNet protocol, "Ketoconazole and Respiratory Management in Acute Lung Injury/Acute Respiratory Distress Syndrome" (KARMA) began in the spring of 1996. KARMA assessed the efficacy of 6 ml/kg versus 12 ml/kg 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 ml/kg) and low (6 ml/kg) 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 FDA/NIH 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 1,000 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 II/III 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 2.5 mg if patients exceed defined heart rate limits. Consequently, a Phase III placebo-controlled double-blinded, randomized trial on approximately 1,000 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.

  Eligibility

Ages Eligible for Study:   13 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men and women
  • 13 years of age or older
  • ARDS or risk factors for ARDS (patients will be considered at risk if they are critically ill and have trauma, sepsis, shock, pneumonia, inhalation injury, drug overdose, pancreatitis, or hypertransfusion)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00000579

  Hide Study Locations
Locations
United States, California
University of California
San Francisco, California, United States, 94143
United States, Colorado
University of Colorado Health Sciences Center
Denver, Colorado, United States, 80262
United States, Illinois
University of Chicago
Chicago, Illinois, United States, 60637
United States, Louisiana
Louisiana State University
New Orleans, Louisiana, United States, 70112
United States, Maryland
University of Maryland
Baltimore, Maryland, United States, 21201
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Baystate Medical Center
Springfield, Massachusetts, United States, 01199
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
Mayo Foundation
Rochester, Minnesota, United States, 55905
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27708
Wake Forest University
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15261
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
University of Texas
San Antonio, Texas, United States, 78229-3900
United States, Utah
Latter Day Saints Hospital
Salt Lake City, Utah, United States, 84143
United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22908
United States, Washington
University of Washington
Seattle, Washington, United States, 98105
Canada, British Columbia
University of British Columbia
Vancouver, British Columbia, Canada, V5Z 1M9
Sponsors and Collaborators
Investigators
Principal Investigator: Edward Abraham, MD University of Colorado, Denver
Principal Investigator: Antonio Anzueto, MD University of Texas
Principal Investigator: Roy Brower, MD Johns Hopkins University
Principal Investigator: Alfred F. Connors, MD University of Virginia
Principal Investigator: Bennett P. deBoisblanc, MD Louisiana State University Health Sciences Center in New Orleans
Principal Investigator: Bennett P. deBoisblanc, MD Louisiana State University Health Science Center
Principal Investigator: Michael Donahoe, MD University of Pittsburgh
Principal Investigator: Kalpalatha K. Guntupalli, MD Baylor College of Medicine
Principal Investigator: Robert D. Hite, MD Wake Forest School of Medicine
Principal Investigator: Rolf Hubmayr, MD Mayo Clinic
Principal Investigator: Neil MacIntyre, MD Duke University
Principal Investigator: Michael A. Matthay, MD University of California, San Francisco
Principal Investigator: Alan Morris, MD Latter Day Saints Hospital
Principal Investigator: Michael J. Murray Mayo Foundation
Principal Investigator: James A. Russell, MD University of British Columbia
Principal Investigator: Gregory A. Schmidt, MD, FCCP University of Chicago
Principal Investigator: David A. Schoenfeld, PhD Massachusetts General Hospital
Principal Investigator: Jay S. Steingrub, MD, FCCP Baystate Medical Center
Principal Investigator: Arthur Wheeler, MD Vanderbilt University
Principal Investigator: Herbert Wiedemann, MD Cleveland Clinic Lerner College of Medicine
  More Information

Additional Information:
Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
ClinicalTrials.gov Identifier: NCT00000579     History of Changes
Other Study ID Numbers: 217, N01 HR16146, N01 HR16147, N01 HR16148, N01 HR16149, N01 HR16150, N01 HR16151, N01 HR16152, N01 HR16153, N01 HR16154, N01 HR16155, N01 HR46054, N01 HR46055, N01 HR46056, N01 HR46057, N01 HR46058, N01 HR46059, N01 HR46060, N01 HR46061, N01 HR46062, N01 HR46063, N01 HR46064, N01 HR56165, N01 HR56166, N01 HR56167, N01 HR56168, N01 HR56169, N01 HR56170, N01 HR56171, N01 HR56172, N01 HR56173, N01 HR56174, N01 HR56175, N01 HR56176, N01 HR56179
Study First Received: October 27, 1999
Last Updated: January 2, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Lung Diseases
Syndrome
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Lung Injury
Disease
Pathologic Processes
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Ketoconazole
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids

ClinicalTrials.gov processed this record on September 16, 2014