Statins for Acutely Injured Lungs From Sepsis (SAILS)

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ClinicalTrials.gov Identifier: NCT00979121

Recruitment Status : Terminated (stopped for futility)

First Posted : September 17, 2009

Results First Posted : October 3, 2014

Last Update Posted : May 16, 2016

Sponsor:

Information provided by (Responsible Party):

National Heart, Lung, and Blood Institute (NHLBI)

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Conditions	Sepsis Acute Lung Injury
Interventions	Drug: Rosuvastatin Drug: Placebo
Enrollment	745

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Rosuvastatin	Placebo
Arm/Group Description	Half of the subjects will receive t...	Half of the patients will be random...
Arm/Group Description	Half of the subjects will receive the active drug, Rosuvastatin. Rosuvastatin: Patients will receive 20 mg of study drug daily by mouth or feeding tube for 28 days or until discharged from the study hospital.	Half of the patients will be randomized to the placebo. Placebo: Patients will receive one placebo by mouth or feeding tube daily for 28 days or until discharged form study hospital.
Period Title: Overall Study
Started	379	366
Completed	379	366
Not Completed	0	0

Baseline Characteristics

Arm/Group Title		Rosuvastatin	Placebo	Total
Arm/Group Description		Half of the subjects will receive t...	Half of the patients will be random...	Total of all reporting groups
Arm/Group Description		Half of the subjects will receive the active drug, Rosuvastatin. Rosuvastatin: Patients will receive 20 mg of study drug daily by mouth or feeding tube for 28 days or until discharged from the study hospital.	Half of the patients will be randomized to the placebo. Placebo: Patients will receive one placebo by mouth or feeding tube daily for 28 days or until discharged form study hospital.	Total of all reporting groups
Overall Number of Baseline Participants		379	366	745
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	379 participants	366 participants	745 participants
	<=18 years	3 0.8%	2 0.5%	5 0.7%
	Between 18 and 65 years	262 69.1%	272 74.3%	534 71.7%
	>=65 years	114 30.1%	92 25.1%	206 27.7%
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	379 participants	366 participants	745 participants
		54.2 (17.1)	54.1 (15.6)	54.1 (16.3)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	379 participants	366 participants	745 participants
	Female	195 51.5%	185 50.5%	380 51.0%
	Male	184 48.5%	181 49.5%	365 49.0%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	379 participants	366 participants	745 participants
	Hispanic or Latino	46 12.1%	40 10.9%	86 11.5%
	Not Hispanic or Latino	333 87.9%	326 89.1%	659 88.5%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB) Measure Type: Number Unit of measure: Participants	Number Analyzed	379 participants	366 participants	745 participants
American Indian or Alaska Native		1	5	6
Asian		9	7	16
Native Hawaiian or Other Pacific Islander		2	3	5
Black or African American		52	53	105
White		289	301	590
More than one race		NA ^[1]	NA ^[1]	NA ^[2]
Unknown or Not Reported		14	10	24
		[1] not captured [2] Total not calculated because data are not available (NA) in one or more arms.
Region of Enrollment Measure Type: Number Unit of measure: Participants
United States	Number Analyzed	379 participants	366 participants	745 participants
United States		379	366	745
APACHE III Score ^[1] Mean (Standard Deviation) Unit of measure: Units on a scale
	Number Analyzed	379 participants	366 participants	745 participants
		92.1 (28.4)	94.8 (27.9)	93.4 (28.2)
		[1] Measure Description: APACHE III Score: Acute, Physiology, Age, Chronic Health Evaluation III Prognostic System is a measure of hospital mortality risk for critically ill adult patients. Our study used a refined version based on the study by Knause and colleagues (Chest, 1991; 100:1619-36). The score is based on results from addition of 3 groups of variables (physiology, range: 0-252; age: 0-23; and chronic health: 0-24). Overall score range: 0-299; higher number indicates higher risk.
Primary cause of lung injury ^[1] Measure Type: Number Unit of measure: Participants	Number Analyzed	379 participants	366 participants	745 participants
Aspiration		26	23	49
Multiple Transfusion		3	1	4
Other		7	4	11
Pneumonia		267	260	527
Sepsis		72	73	145
Trauma		2	4	6
		[1] Measure Description: Based on coding of primary vs. secondary by the site; data entry errors account for total count discrepancy.
Baseline Shock ^[1] Measure Type: Number Unit of measure: Participants
	Number Analyzed	379 participants	366 participants	745 participants
		173	166	339
		[1] Measure Description: The number of participants who were in shock at the time of randomization. Baseline shock was defined as meeting one of the following conditions: a mean arterial pressure less than 60 mm Hg, receiving a vasopressor (norepinephrine, epinephrine, vasopressin or neosynephrine) at any dose, or receiving dopamine at a dose greater than or equal to 6 mcg/kg/min (or mcg/min) .
PaFiO2:FiO2 ratio less than or equal to 200 mm Hg ^[1] Measure Type: Number Unit of measure: Participants
	Number Analyzed	379 participants	366 participants	745 participants
		267	253	520
		[1] Measure Description: The number of participants with a P/F ratio of 200 mm Hg or less at baseline.
Hours from intubation to randomization Measure Type: Number Unit of measure: Participants	Number Analyzed	379 participants	366 participants	745 participants
24 hours or less		124	129	253
between 24 and 48 hours		204	192	396
between 48 and 72 hours		41	31	72
more than 72 hours		10	13	23
Unknown		0	1	1

Outcome Measures

1.Primary Outcome


Title	Hospital Mortality to Day 60.
Description	The percentage of subjects alive at study day 60. Those subjects disch...
Description	The percentage of subjects alive at study day 60. Those subjects discharged home prior to day 60 were counted as alive at day 60.
Time Frame	60 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Rosuvastatin	Placebo
Arm/Group Description:	Half of the subjects were randomize...	Half of the subjects were randomize...
Arm/Group Description:	Half of the subjects were randomized to active drug (Rosuvastatin). Rosuvastatin: Subjects received 20 mg of study drug daily by mouth or feeding tube for 28 days or until discharge from the study hospital.	Half of the subjects were randomized to placebo. Placebo: Subjects received placebo by mouth or feeding tube daily for 28 days or until discharge from study hospital.
Overall Number of Participants Analyzed	379	366
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	28.5 (24.0 to 33.0)	24.9 (20.5 to 29.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rosuvastatin, Placebo
	Comments	Hospital mortality to day 60 was estimated using the Kaplan Meier estimate, with patients discharged home before day 60 considered alive at day 60. The analysis was stratified by co-enrolled treatment assignments for 81 patients also enrolled in a randomized clinical trial of two different nutritional strategies. A maximum of 1000 patients were to be enrolled, providing a 92% probability of rejecting the null hypothesis for the effect on mortality if a true difference in mortality was 9%.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.21
	Comments	The monitoring boundaries were designed to have a low probability of stopping for futility before 750 patients. The maximum sample size was 1000 patients. Efficacy stopping was based on mortality; futility stopping was based on mortality and VFDs.
	Method	Proc lifetest
	Comments	Proc lifetest was used to calculate mortality mean and variance due to one subject lost to follow up who was censored.

Method of Estimation	Estimation Parameter	difference in % of pts alive at 60 days
	Estimated Value	4.0
	Confidence Interval	(2-Sided) 95% -2.3 to 10.2
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Ventilator Free Days at Study Day 28
Description	Ventilator Free Days (VFDs) to day 28 were defined as the number of da...
Description	Ventilator Free Days (VFDs) to day 28 were defined as the number of days from the time of initiating unassisted breathing to day 28 after randomization, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a subject received assisted breathing at day 27 or died prior to day 28, a value of zero VFDs was given.
Time Frame	time of initiating unassisted breathing to day 28 after study randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Rosuvastatin	Placebo
Arm/Group Description:	Half of the subjects were randomize...	Half of the subjects were randomize...
Arm/Group Description:	Half of the subjects were randomized to active drug (Rosuvastatin). Rosuvastatin: Subjects received 20 mg of study drug daily by mouth or feeding tube for 28 days or until discharge from the study hospital.	Half of the subjects were randomized to placebo. Placebo: Subjects received placebo by mouth or feeding tube daily for 28 days or until discharged from study hospital.
Overall Number of Participants Analyzed	379	366
Mean (Standard Deviation) Unit of Measure: days
	15.1 (10.8)	15.1 (11.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rosuvastatin, Placebo
	Comments	Ventilator, ICU free, and organ failure free days were analyzed by analysis of variance, utilizing treatment assignment where applicable.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.96
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	95% -1.6 to 1.5
	Estimation Comments	[Not Specified]

3.Other Pre-specified Outcome


Title	Organ Failure Free Days at Day 14
Description	The number of days from randomization to day 14 without an organ failu...
Description	The number of days from randomization to day 14 without an organ failure. Four main organ systems were measured: cardiovascular, coagulation, hepatic function, and renal function.
Time Frame	14 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Rosuvastatin	Placebo
Arm/Group Description:	Half of the subjects were randomize...	Half of the subjects were randomize...
Arm/Group Description:	Half of the subjects were randomized to active drug (Rosuvastatin). Rosuvastatin: Patients received 20 mg of study drug daily by mouth or feeding tube for 28 days or until discharge from the study hospital.	Half of the subjects were randomized to placebo. Placebo: Subjects received placebo by mouth or feeding tube daily for 28 days or until discharge from study hospital.
Overall Number of Participants Analyzed	379	366
Mean (Standard Deviation) Unit of Measure: days
Cardiovascular	8.5 (4.8)	8.7 (4.9)
Coagulation	10.7 (5.1)	11.1 (4.8)
Hepatic	10.8 (5.0)	11.8 (4.3)
Renal	10.1 (5.3)	11.0 (4.7)

4.Other Pre-specified Outcome


Title	ICU Free Days to Day 28
Description	[Not Specified]
Description	[Not Specified]
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Rosuvastatin	Placebo
Arm/Group Description:	Half of the subjects will receive t...	Half of the patients will be random...
Arm/Group Description:	Half of the subjects will receive the active drug, Rosuvastatin. Rosuvastatin: Patients will receive 20 mg of study drug daily by mouth or feeding tube for 28 days or until discharged from the study hospital.	Half of the patients will be randomized to the placebo. Placebo: Patients will receive one placebo by mouth or feeding tube daily for 28 days or until discharged form study hospital.
Overall Number of Participants Analyzed	379	366
Mean (Standard Deviation) Unit of Measure: days
	14.3 (10.1)	14.4 (10.3)

5.Other Pre-specified Outcome


Title	Other Secondary Out-comes
Description	Percentage of subjects with Arrhythmia's, Bowel Ischemia, Myocardial I...
Description	Percentage of subjects with Arrhythmia's, Bowel Ischemia, Myocardial Infarction, Ischemic Stroke, and Thromboembolism were measured.
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Rosuvastatin	Placebo
Arm/Group Description:	Half of the subjects were randomize...	Half of the subjects were randomize...
Arm/Group Description:	Half of the subjects were randomized to active drug (Rosuvastatin). Rosuvastatin: Subjects received 20 mg of study drug daily by mouth or feeding tube for 28 days or until discharge from the study hospital.	Half of the subjects were randomized to placebo. Placebo: Subjects received placebo by mouth or feeding tube daily for 28 days or until discharge from study hospital.
Overall Number of Participants Analyzed	367	360
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
Arrhythmias	9.0 (6.1 to 11.9)	8.4 (5.5 to 11.3)
Bowel Ischemia	1.4 (0.2 to 2.6)	1.9 (0.5 to 3.3)
Myocardial Infarction	0.5 (-0.3 to 1.3)	0.6 (-0.2 to 1.4)
Ischemic Stroke	0.3 (-.03 to 0.9)	0.3 (-0.3 to 0.9)
Thromboembolism	6.3 (3.8 to 8.9)	6.9 (4.4 to 9.5)

6.Other Pre-specified Outcome


Title	Changes in Plasma Concentrations of C-reactive Protein (CRP) From Baseline to Day 6 and Day 14
Description	CRP levels were collected on subjects at baseline and on-study. The ch...
Description	CRP levels were collected on subjects at baseline and on-study. The change in concentration from baseline levels to levels on study days 6 and 14 was analyzed. Those subjects that were still alive and on study at day 6 and 14 with a measured CRP level were included in the analysis.
Time Frame	6 and 14 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Rosuvastatin	Placebo
Arm/Group Description:	Half of the subjects were randomize...	Half of the subjects were randomize...
Arm/Group Description:	Half of the subjects were randomized to active drug (Rosuvastatin). Rosuvastatin:Subjects received 20 mg of study drug daily by mouth or feeding tube for 28 days or until discharge from the study hospital.	Half of the subjects were randomized to placebo. Placebo: Subjects received placebo by mouth or feeding tube daily for 28 days or until discharge from study hospital.
Overall Number of Participants Analyzed	229	229
Mean (Standard Deviation) Unit of Measure: mg/dL
Day 6	-12.9 (27.79)	-15.1 (23.26)
Day 14	-19.8 (31.23)	-14.8 (26.28)

Adverse Events

Time Frame	Investigators conducted daily assessments for the presence of adverse events (AE) from enrollment through study day 28 or hospital discharge, whichever occurred first.
Adverse Event Reporting Description	AE definition: any clinically important untoward medical occurrence in a patient receiving study drug/procedures which was different than expected in the clinical course of a patient with ALI or an occurrence thought to be associated with the study drug/procedures. CK, ALT/AST at specified levels and CNS bleed were also systematically reported.

Arm/Group Title	Rosuvastatin		Placebo
Arm/Group Description	Half of the subjects were randomize...		Half of the subjects were randomize...
Arm/Group Description	Half of the subjects were randomized to the active drug (Rosuvastatin). Rosuvastatin: Subjects received 20 mg of study drug daily by mouth or feeding tube for 28 days or until discharge from the study hospital.		Half of the subjects were randomized to placebo. Placebo: Subjects received placebo by mouth or feeding tube daily for 28 days or until discharge from study hospital.
All-Cause Mortality
	Rosuvastatin		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events Serious Adverse Events
	Rosuvastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/379 (8.97%)		32/366 (8.74%)
Blood and lymphatic system disorders
Pancytopenia ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
Thrombocytopenia ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
Cardiac disorders
Asystole ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
Cardiac Arrest ^† 1	3/379 (0.79%)	3	4/366 (1.09%)	4
Cardiopulmonary Arrest ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
Hemorrhage (Nos) ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
Thrombosis Venous Arm ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
Venous Thrombosis ^† 1	1/379 (0.26%)	1	1/366 (0.27%)	1
Gastrointestinal disorders
ALT > 8 times upper limit of normal ^† 1	0/379 (0.00%)	0	3/366 (0.82%)	3
Bowel Perforation ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
Gastrointestinal Bleeding ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
Ischemia Bowel ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
Necrosis Bowel ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
Obstruction Small Intestine ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
Peforation Bowel ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
Proctitis ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
General disorders
Hemorrhage Retroperitoneal ^† 1	1/379 (0.26%)	1	1/366 (0.27%)	1
Hyperpyrexia ^† 1	2/379 (0.53%)	2	0/366 (0.00%)	0
Necrosis ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
Neuroleptic Malignant Syndrome ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
Investigations
AST > 8 times upper limit of normal ^† 1	2/379 (0.53%)	2	0/366 (0.00%)	0
Aspartate Aminotransferase Increased ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
Ast Increased ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
Creatinine Serum Increased ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
Musculoskeletal and connective tissue disorders
CK > 10 times upper limit of normal ^† 1	4/379 (1.06%)	4	4/366 (1.09%)	4
Rhabdomyolysis ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
Nervous system disorders
Agitation ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
Brain Disorder (Nos) ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
Cognitive Disturbance ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
Delirium ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
Encephalopathy ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
Intracerebral Hemorrhage ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
Stroke ^† 1	2/379 (0.53%)	2	0/366 (0.00%)	0
Renal and urinary disorders
Failure Kidney Acute ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Pneumothorax ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
Aspiration ^† 1	1/379 (0.26%)	1	1/366 (0.27%)	1
Coughing Blood ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
Embolism Pulmonary ^† 1	2/379 (0.53%)	2	2/366 (0.55%)	2
Hypoxemia ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
Pleural Effusion ^† 1	1/379 (0.26%)	1	0/366 (0.00%)	0
Pneumothorax ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
Skin and subcutaneous tissue disorders
Skin Ulceration ^† 1	0/379 (0.00%)	0	1/366 (0.27%)	1
† Indicates events were collected by systematic assessment 1 Term from vocabulary, COSTART
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Rosuvastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/379 (0.00%)		0/366 (0.00%)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

sponsor can review results communications prior to public release and can embargo communications regarding trial results until presented at the American Thoracic Society international meeting.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	David A. Schoenfeld, PhD ARDSNet CCC PI
Organization:	ARDS Network
Phone:	617-726-6111
EMail:	dschoenfeld@mgh.harvard.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Dinglas VD, Hopkins RO, Wozniak AW, Hough CL, Morris PE, Jackson JC, Mendez-Tellez PA, Bienvenu OJ, Ely EW, Colantuoni E, Needham DM. One-year outcomes of rosuvastatin versus placebo in sepsis-associated acute respiratory distress syndrome: prospective follow-up of SAILS randomised trial. Thorax. 2016 May;71(5):401-10. doi: 10.1136/thoraxjnl-2015-208017. Epub 2016 Mar 2.

Needham DM, Colantuoni E, Dinglas VD, Hough CL, Wozniak AW, Jackson JC, Morris PE, Mendez-Tellez PA, Ely EW, Hopkins RO. Rosuvastatin versus placebo for delirium in intensive care and subsequent cognitive impairment in patients with sepsis-associated acute respiratory distress syndrome: an ancillary study to a randomised controlled trial. Lancet Respir Med. 2016 Mar;4(3):203-12. doi: 10.1016/S2213-2600(16)00005-9. Epub 2016 Jan 29.

National Heart, Lung, and Blood Institute ARDS Clinical Trials Network, Truwit JD, Bernard GR, Steingrub J, Matthay MA, Liu KD, Albertson TE, Brower RG, Shanholtz C, Rock P, Douglas IS, deBoisblanc BP, Hough CL, Hite RD, Thompson BT. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med. 2014 Jun 5;370(23):2191-200. doi: 10.1056/NEJMoa1401520. Epub 2014 May 18.

Layout table for additonal information

Responsible Party:	National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier:	NCT00979121
Other Study ID Numbers:	670 N01HR056179 ( Other Grant/Funding Number: NHLBI )
First Submitted:	September 16, 2009
First Posted:	September 17, 2009
Results First Submitted:	August 22, 2014
Results First Posted:	October 3, 2014
Last Update Posted:	May 16, 2016

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