Acute Respiratory Distress Syndrome Clinical Network (ARDSNet)

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.

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)