Lessons Learned from ARDSnet (1995-2011)

B. Taylor Thompson MDMassachusetts General Hospital

Harvard Medical SchoolBoston, MA

ARDS Network: History

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

ARDS Net I Studies

Lower Tidal Volume n=861

Keto n=234

March 18, 1996 Nov 20052000

ARDS Net I Studies

Lower Tidal Volume n=861

Keto n=234

LSF n=236

March 18, 1996 Nov 20052000

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 20052000

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

60d Mortality (95%CI)P 28.6% (19.8-38.4)MP 29.2% (20.2-39.3)

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

Probab

Probab

Conservative 25.5%Liberal 28.4% p=0.3

Probab

Conservative 25.5%Liberal 28.4% p=0.3

Probab

Conservative 25.5%Liberal 28.4% p=0.3

Probab

Conservative 25.5%Liberal 28.4% p=0.3

Probab3.2 fewer days on vent in survivors (p<0.001)

Conservative 25.5%Liberal 28.4% p=0.3

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

ARDS Net: keys to success• Insightful, determined, collaborative PIs

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

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?

Thank you

ARDSnet Acknowledgements

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