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Lessons Learned from ARDSnet (1995-2011)
B. Taylor Thompson MDMassachusetts General Hospital
Harvard Medical SchoolBoston, MA
ARDS Network: History• Concept presented to the NIH Division of
Lung Diseases pulmonary advisory committee and approved Fall, 1992
ARDS Network: History• Concept presented to the NIH Division of
Lung Diseases pulmonary advisory committee and approved Fall, 1992
ARDS Network: History• Concept presented to the NIH Division of
Lung Diseases pulmonary advisory committee and approved Fall, 1992
• 1993 Request for Proposals Released
ARDS Network: History• Concept presented to the NIH Division of
Lung Diseases pulmonary advisory committee and approved Fall, 1992
• 1993 Request for Proposals Released• Two clinical trial ideas required from each
applicant
ARDS Network: History• Concept presented to the NIH Division of
Lung Diseases pulmonary advisory committee and approved Fall, 1992
• 1993 Request for Proposals Released• Two clinical trial ideas required from each
applicant• Demonstrated ability to enroll 30 patients per
year
ARDS Network: History• Concept presented to the NIH Division of
Lung Diseases pulmonary advisory committee and approved Fall, 1992
• 1993 Request for Proposals Released• Two clinical trial ideas required from each
applicant• Demonstrated ability to enroll 30 patients per
year• 7 year contract (1/5/1)
ARDS Network: History• Concept presented to the NIH Division of
Lung Diseases pulmonary advisory committee and approved Fall, 1992
• 1993 Request for Proposals Released• Two clinical trial ideas required from each
applicant• Demonstrated ability to enroll 30 patients per
year• 7 year contract (1/5/1)
• 1994 July, 10 centers selected
ARDS Clinical Research Network
CCC
Steering Com (Chair, Site PIs, NHLBI)
NIH
DMC
PRCClinical Sites
Industry may provides
drug/placebo, bioassays
Results: Ketoconazole vs. Placebo (n=234)
0.6
0.7
0.8
0.9
1.0
0 3 6 91216202428323640444852566064687276808487
Prop
ortio
n Su
rviv
ing
Days after Entry
PlaceboKetoconazole
JAMA 2000
Results: Ketoconazole vs. Placebo (n=234)
0.6
0.7
0.8
0.9
1.0
0 3 6 91216202428323640444852566064687276808487
Prop
ortio
n Su
rviv
ing
Days after Entry
PlaceboKetoconazole
JAMA 2000
• Detectable serum keto levels
• No change in TXA2 or LTB4
Lisofylline - 28 Day Survival (n=235)
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 910 12 14 16 18 20 22 24 26 28
Prop
ortio
n Su
rviv
ing
Days after study entry
Lisofylline
Placebo
Abraham et al. CCM 2002
Lisofylline - 28 Day Survival (n=235)
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 910 12 14 16 18 20 22 24 26 28
Prop
ortio
n Su
rviv
ing
Days after study entry
Lisofylline
Placebo
Abraham et al. CCM 2002
No change biomarkers or oxidized lipids
ARDS Net I Studies
Lower Tidal Volume n=861
Keto n=234
LSF n=236
March 18, 1996 Nov 2005
Late Steroid Rescue Study n=180
2000
30 Years of Failed Drug Trials for ARDS
Failed Trials• Surfactant• Prostaglandin E1• Procysteine• Nitric oxide• Ibuprofen• Soluble neutrophil elastase
inhibitor • sPLA2 inhibitor
30 Years of Failed Drug Trials for ARDS
Failed Trials• Surfactant• Prostaglandin E1• Procysteine• Nitric oxide• Ibuprofen• Soluble neutrophil elastase
inhibitor • sPLA2 inhibitor
ARDS Net Contribution• Corticosteroids?• Ketoconazole• Lisofylline
ARDS Net: Improved Survival with Lower Vt
1.00.90.80.70.60.50.40.30.20.10.0
180160140120100806040200
Prop
ortio
n of
Pat
ient
s
Days after Randomization
Lower tidal volumesSurvivalDischarge
Traditional tidal valuesSurvivalDischarge
ARDS Net N Engl J Med 2000.
Additional Findings
Lower Vt strategy was associated with:– Lower PaO2/FI02 and Crs in 6 ml/kg
– Minimal auto-PEEP and hypercapnia– Less organ failures– Similar sedative requirements, fluid balance– Modulation of IL-6, IL-8, TNFR1, SPD
ARDS Net N Engl J Med 2000; Hough et al CCM 2005, Cheng CCM 2005, Parsons et al CCM 2005, AJP-Lung 2005; Eisner Crit Care 2003
ARDS Network SitesOriginal NetworkCleveland ClinicDukeUCSFUniv. ColoradoUniv. MarylandUniv. MichiganUniv. PennsylvaniaUniv. UtahUniv. WashingtonVanderbilt
New Sites (Oct 31, 2000)BaylorBaystate (Mass)Louisiana StateUniv. British ColumbiaUniv. ChicagoUniv. PittsburghUniv Texas, San AntonioUniv VirginiaWake Forest
Coordinating CenterMassachusetts General Hospital
Fluid And Catheter Treatment Trial (FACTT)
Factorial Design:
• PAC vs CVC guided therapy (n=1000)
• Liberal Versus Conservative Fluid Management for 7 Days (n=1000)
ARDS Network, NEJM 2006: v304, p2213; p2564
Cumulative fluid balance
-2000
0
2000
4000
6000
8000
0 1 2 3 4 5 6 7
ml o
f flu
id
Study Day
LiberalConservativeARMA 6 ml (1996-1999)ALVEOLI all (1999-2002)
Murray lung injury score
1.75
2.00
2.25
2.50
2.75
0 1 2 3 4 7Study Day
LiberalConservative
P < 0.001
ARDS Net I Studies (n=2,630)
Lower Tidal Volume n=861
Keto n=234
LSF n=236
March 18, 1996 Nov 2005
Late Steroid Rescue Study n=180
Higher PEEPn=549
FACTT n=1000PAC vs CVC
Liberal vs Cons Fluids
2000
ARDS Net I Studies (n=2,630)
Lower Tidal Volume n=861
Keto n=234
LSF n=236
March 18, 1996 Nov 2005
Late Steroid Rescue Study n=180
Higher PEEPn=549
FACTT n=1000PAC vs CVC
Liberal vs Cons Fluids
2000
ARDS Net I Studies (n=2,630)
Lower Tidal Volume n=861
Keto n=234
LSF n=236
March 18, 1996 Nov 2005
Late Steroid Rescue Study n=180
Higher PEEPn=549
FACTT n=1000PAC vs CVC
Liberal vs Cons Fluids
Keto: JAMA 2000Lower Vt: NEJM 2000LSF: CCM 2002Higher PEEP: NEJM 2004Late Steroid: NEJM 2006PAC vs CVC; NEJM 2006Fluid Rx; NEJM 2006
2000
• Louisiana• Mayo• Seattle• Utah• Vanderbilt• Wake Forest
• Baystate• California• Chesapeake• Cleveland• Denver • Duke
NIH NHLBI ARDS Network II
Coordinating Center Massachusetts General Hospital
Refunded to 2012 funds for ~3000 pts
ARDS Net II Studies
EDEN n=10002 x 2 Factorial
ALTA n=282
OMEGA n=272
2006 2012
H1N1 Registry
N=633
2009
SAILSn=284
ARDS Net II Studies
EDEN n=10002 x 2 Factorial
ALTA n=282
OMEGA n=272
2006 2012
H1N1 Registry
N=633
2009
SAILSn=284
N~2,500
ARDS Net: keys to success• Insightful, determined, collaborative PIs• Adopted efficient trial methodologies
– Factorial design– Concomitant testing of early and late intervention
strategies• Explicit methodologies = replicable methods• Commitment to mechanistic ancillary studies
– Sample repository– DNA banking
ARDS Net: keys to success• Web based infrastructure
– allowed for nimble handling of factorial designs when one factor stopped early
– Quickly create a registry during a pandemic
• Supported junior investigators with an internal peer review process and analytic support
www.ardsnet.org• Site information and contacts• Complete Protocols• Datasets publically available
– (ARMA, ALVEOLI, FACTT)– https://biolincc.nhlbi.nih.gov/home/
• Clinical tools for mechanical ventilation, fluid management, predicted body weight calculator.
• FAQ’s• Publications
www.ardsnet.org• Site information and contacts• Complete Protocols• Datasets publically available
– (ARMA, ALVEOLI, FACTT)– https://biolincc.nhlbi.nih.gov/home/
• Clinical tools for mechanical ventilation, fluid management, predicted body weight calculator.
• FAQ’s• Publications
https://biolincc.nhlbi.nih.gov/home/
ARDS Net III?
• With falling mortality larger trials will be needed to detect mortality differences. – Should the new Network be configured to
conduct large simple trials? – Should composite endpoints be used?
Spragg et al NHLBI Beyond Mortality Workshop AJRCCM (in press)
ARDS Net III ? • Should the new network conduct more
Phase II trials of novel therapeutic agents, perhaps in parallel, to “screen” for active drugs and accelerate the process of discovery?
• How much of the ARDS Network III should be devoted to the understanding of disease mechanisms and the importance of genetics?
ARDS Net III?
• How can the new Network collaborate with other established groups (ANZIC, SOAP, and the Canadian Clinical Trials group, others) for the conduct of international investigator-initiated trials?
ARDS Net I Studies
Lower Tidal Volume n=861
Keto n=234
LSF n=236
March 18, 1996 Nov 2005
Late Steroid Rescue Study n=180
2000
ARDS Net I Studies
Lower Tidal Volume n=861
Keto n=234
LSF n=236
March 18, 1996 Nov 2005
Late Steroid Rescue Study n=180
Higher PEEPn=549
2000
ARDS Net I Studies
Lower Tidal Volume n=861
Keto n=234
LSF n=236
March 18, 1996 Nov 2005
Late Steroid Rescue Study n=180
Higher PEEPn=549
FACTT n=1000PAC vs CVC
Liberal vs Cons Fluids
2000
“Success in science is defined as moving from failure to failure
with undiminished enthusiasm”
Winston Churchill
ARDS Net I: Initial SitesOriginal NetworkCleveland ClinicDukeUCSFUniv. ColoradoUniv. MarylandUniv. MichiganUniv. PennsylvaniaUniv. UtahUniv. WashingtonVanderbilt
New Sites (Oct 31, 2000)
BaylorBaystate (Mass)Louisiana StateUniv. British ColumbiaUniv. ChicagoUniv. PittsburghUniv Texas, San AntonioUniv VirginiaWake Forest
Coordinating CenterMassachusetts General Hospital
Thomas Jefferson (1743-1826) “Harvey's discovery of the circulation of the
blood was a beautiful addition to our knowledge of the animal economy, but on a review of the practice of medicine before and since that epoch, I do not see any great amelioration which has been derived from that discovery.”
Letter to Edward Jenner, May 14, 1806