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.

Acute Respiratory Distress Syndrome Clinical Network (ARDSNet)

Respiratory Distress Syndrome, Adult

Lung Diseases

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.

Acute Respiratory Distress Syndrome Clinical Network (ARDSNet)

About this trial

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Placebo

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