Statins for Acutely Injured Lungs From Sepsis (SAILS)

Randomized Trial of Rosuvastatin for Acutely Injured Lungs From Sepsis

Objective: assess the efficacy and safety of oral rosuvastatin in patients with sepsis-induced Acute Lung Injury (ALI).

Hypothesis: Rosuvastatin therapy will improve mortality in patients with sepsis-induced ALI.

Study Overview

• Status: Terminated
• Conditions: Sepsis; Acute Lung Injury
• Intervention / Treatment: Drug: Rosuvastatin; Drug: Placebo

Detailed Description

Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) involves extensive inflammation in the lungs that can lead to rapid respiratory failure. These conditions are most commonly caused by pneumonia, generalized infection, or severe trauma to the lungs, but can also be less commonly caused by smoke or salt water inhalation, drug overdose, or shock.

For some people, ALI/ARDS resolves without treatment, but many severe cases result in hospitalization in the intensive care unit (ICU), where 30% to 40% of cases end in mortality. Current treatments for ALI/ARDS include assisted breathing with a ventilator, supportive care, and management of the underlying causes.

Upon admission to the ICU, Rosuvastatin or placebo was administered through an enteral feeding tube or administered orally following extubation when patients were able to safely take oral medications. The type and placement of the enteral feeding tube (nasogastric, nasoenteric, PEG, orogastric, oroenteric, etc.) and the ability to safely take oral medications was determined by the patient's primary team. Study drug was blinded with an identical appearing placebo. The first study drug dose (rosuvastatin or placebo) was administered within 4 hours of randomization as a loading dose of 40 mg.

Blood pressure, heart rate, ventilation settings, and various blood factors were measured during treatment. Phone-based follow-up assessments occurred at months 6 and 12 after ICU discharge and included measurements of health-related quality of life; psychological, neurocognitive, and physical activity outcomes; healthcare utilization; and mortality.

• Study Type: Interventional
• Enrollment (Actual): 745
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Fresno, California, United States
      • University of San Francisco-Fresno Medical Center
    • Sacramento, California, United States
      • University of California, Davis Medical Center
    • San Francisco, California, United States
      • UCSF-Moffitt Hospital
    • San Francisco, California, United States
      • University of California, San Francisco (UCSF)-Moffitt Hospital
  • Colorado
    • Denver, Colorado, United States
      • University of Colorado Health Sciences Center
    • Denver, Colorado, United States
      • Centura St. Anthony Central Hospital
    • Denver, Colorado, United States
      • Denver Health Medical Center
    • Denver, Colorado, United States
      • Rose Medical Center
  • District of Columbia
    • Washington DC, District of Columbia, United States
      • Washington Hospital Center
  • Louisiana
    • Baton Rouge, Louisiana, United States
      • Baton Rouge General Hospital-Blue Bonnet
    • Baton Rouge, Louisiana, United States
      • Baton Rouge General Hospital-Midcity
    • Baton Rouge, Louisiana, United States
      • Earl K. Long Medical Center
    • Baton Rouge, Louisiana, United States
      • Our Lady of the Lake Regional Medical Center
    • New Orleans, Louisiana, United States
      • Ochsner Clinic Foundation
    • New Orleans, Louisiana, United States
      • Medical Center of Louisiana
    • New Orleans, Louisiana, United States
      • Tulane University Health Sciences Center
  • Maryland
    • Baltimore, Maryland, United States
      • Johns Hopkins Bayview Medical Center
    • Baltimore, Maryland, United States
      • Johns Hopkins Hospital
    • Baltimore, Maryland, United States
      • University of Maryland Shock Trauma Center
  • Massachusetts
    • Springfield, Massachusetts, United States
      • Baystate Medical Center
  • Minnesota
    • Rochester, Minnesota, United States
      • Rochester Methodist Hospital
    • Rochester, Minnesota, United States
      • St. Mary's Hospital, Mayo Clinic
  • North Carolina
    • Durham, North Carolina, United States
      • Duke University Medical Center
    • Durham, North Carolina, United States
      • Durham Regional Medical Center
    • Greensboro, North Carolina, United States
      • Moses Cone Health System
    • Greensboro, North Carolina, United States
      • Wesley Long Community Hospital
    • Winston Salem, North Carolina, United States
      • Wake Forest University Baptist Medical Center
  • Ohio
    • Cleveland, Ohio, United States
      • University Hospitals Of Cleveland
    • Cleveland, Ohio, United States
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States
      • MetroHealth Medical Center
  • Tennessee
    • Nashville, Tennessee, United States
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States
      • Baylor College of Medicine
  • Utah
    • Murray, Utah, United States
      • Intermountain Medical Center
    • Ogden, Utah, United States
      • McKay-Dee Hospital
    • Provo, Utah, United States
      • Utah Valley Regional Medical Center
    • Salt Lake City, Utah, United States
      • LDS Hospital
  • Virginia
    • Charlottesville, Virginia, United States
      • University of Virginia Medical Center
  • Washington
    • Everett, Washington, United States, 98201
      • Providence Hospital
    • Seattle, Washington, United States
      • University of Washington
    • Seattle, Washington, United States
      • Harborview Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1. Systemic inflammatory response syndrome (SIRS) defined as meeting at least criteria (a) or (b)for a systemic inflammatory response:

  1. White blood cell count >12,000 or <4,000 or >10% band forms
  2. Body temperature >38 degrees Celsius (C) (any route) or <36 degrees C (accepting core temperatures only; indwelling catheter, esophageal, rectal)

  3. Heart rate (> 90 beats/min) or receiving medications that slow heart rate or paced rhythm 2. Suspected or proven infection: Sites of infection include thorax, urinary tract, abdomen, skin, sinuses, central venous catheters, and bacterial meningitis (Appendix A).

     3. ALI as defined by acute onset of:

  1. PaO2 / FiO2 ≤ 300 (intubated). If altitude > 1000m, then PaO2 / FiO2 ≤ 300 x (PB/760), and
  2. Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph, and
  3. Requirement for positive pressure ventilation via an endotracheal tube, and
  4. No clinical evidence of left atrial hypertension, or if measured, a Pulmonary Arterial Wedge Pressure (PAOP) less than or equal to 18 mm Hg. If a patient has a PAOP > 18 mmHg, then the other criteria must persist for more than 12 hours after the PAOP has declined to ≤ 18 mmHg, and still be within the 48-hour enrollment window.

"Acute onset" is defined as follows: the duration of the hypoxemia criterion (#1) and the chest radiograph criterion (#2) must be ≤ 28 days at the time of randomization. Opacities considered "consistent with pulmonary edema" include any patchy or diffuse opacities not fully explained by mass, atelectasis, or effusion or opacities known to be chronic (> 28 days). The findings of vascular redistribution, indistinct vessels, and indistinct cardiac borders are not considered "consistent with pulmonary edema".

All ALI criteria (3a-d above) must occur within the same 24 hour period. The onset of ALI is when the last ALI criterion is met. Patients must be enrolled within 48 hours of ALI onset and no more than 7 days from the initiation of mechanical ventilation. SIRS criteria must occur within the 72 hours before or the 24 hours after ALI onset. Information for determining when these time window criteria were met may come from either the Network hospital or a referring hospital reports.

Exclusion Criteria:

1. No consent/inability to obtain consent
2. Age less than 18 years
3. More than 7 days since initiation of mechanical ventilation
4. More than 48 hours since meeting ALI inclusion criteria
5. Patient, surrogate, or physician not committed to full support ).
6. Unable to receive or unlikely to absorb enteral study drug

7. Rosuvastatin specific exclusions

   • Receiving a statin medication within 48 hours of randomization
   • Allergy or intolerance to statins
   • Physician insistence for the use or avoidance of statins during the current hospitalization
   • Creatine Kinase (CK) , alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 times the upper limit of normal
   • Diagnosis of hypothyroidism and not on thyroid replacement therapy
   • Pregnancy or breast feeding
   • Receiving niacin, fenofibrate or cyclosporine, gemfibrozil, atazanavir, lopinavir, ritonavir, daptomycin
8. Severe chronic liver disease
9. Moribund patient not expected to survive 24 hours
10. Chronic respiratory failure defined as PaCO2 > 60 mm Hg in the outpatient setting
11. Home mechanical ventilation (noninvasive ventilation or via tracheotomy) except for CPAP/BIPAP (Continuous Positive Airway Pressure/BiLevel Positive Airway Pressure) used solely for sleep-disordered breathing
12. Diffuse alveolar hemorrhage from vasculitis
13. Burns > 40% total body surface
14. Interstitial lung disease of severity sufficient to require continuous home oxygen therapy
15. Unwillingness or inability to utilize the ARDS network 6 ml/kg Predicted Body Weight (PBW) ventilation protocol
16. Cardiac disease classified as NYHA (New York Heart Association) class IV
17. Myocardial infarction within past 6 months
18. Intraparenchymal Central Nervous System (CNS) bleed within a month of randomization.
19. Temperature >40.3 C in the 6 hours before randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Rosuvastatin; Half of the subjects were randomized to the active drug (Rosuvastatin). Dosage, Form, and Frequency: drug was provided as 10mg tablets and administered through an enteral feeding tube or orally (following extubation when patients were able to safely take oral medications). An initial 40mg loading dose was administered followed by a daily 20 mg maintenance dose. Maintenance dosing was adjusted for renal failure not compensated by renal replacement therapy. Duration: drug was administered daily until: 28 days after randomization or 3 days after ICU discharge (whichever comes first),; Discharge from study hospital,; Death	Drug: Rosuvastatin; Subjects received an initial 40mg loading dose followed by 20 mg of study drug daily by mouth or feeding tube for 28 days or until discharged from the study hospital.; Other Names: Crestor
Placebo Comparator: Placebo; Half of the subjects were randomized to placebo. 10mg tablets identical to active drug were administered through an enteral feeding tube or orally (following extubation when patients were able to safely take oral medications). Dosage, frequency, and duration was provided in the same manner as the active drug.	Drug: Placebo; Subjects received placebo by mouth or feeding tube daily for 28 days or until discharged from study hospital.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventilator Free Days at Study Day 28	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 of initiating unassisted breathing to day 28 after study randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Organ Failure Free Days at Day 14	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.	14 days after randomization
ICU Free Days to Day 28		28 days after randomization
Other Secondary Out-comes	Percentage of subjects with Arrhythmia's, Bowel Ischemia, Myocardial Infarction, Ischemic Stroke, and Thromboembolism were measured.	28 days after randomization
Changes in Plasma Concentrations of C-reactive Protein (CRP) From Baseline to Day 6 and Day 14	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.	6 and 14 days after randomization

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Study Chair: Jonathon Truwit, MD, University of Virginia, Medical Center

Publications and helpful links

General Publications

• Yu SY, Ge ZZ, Xiang J, Gao YX, Lu X, Walline JH, Qin MB, Zhu HD, Li Y. Is rosuvastatin protective against sepsis-associated encephalopathy? A secondary analysis of the SAILS trial. World J Emerg Med. 2022;13(5):367-372. doi: 10.5847/wjem.j.1920-8642.2022.072.
• 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.

Helpful Links

• ARDS Network Website

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: September 16, 2009
• First Submitted That Met QC Criteria: September 16, 2009
• First Posted (Estimate): September 17, 2009

Study Record Updates

• Last Update Posted (Estimate): May 16, 2016
• Last Update Submitted That Met QC Criteria: April 12, 2016
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: Sepsis; statin; ALI
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Diseases; Lung Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Wounds and Injuries; Thoracic Injuries; Sepsis; Toxemia; Acute Lung Injury; Lung Injury; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rosuvastatin Calcium
• Other Study ID Numbers: 670; N01HR056179 (Other Grant/Funding Number: NIH Contract Number)

Plan for Individual participant data (IPD)

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: ARDSNet-SAILS
   Information comments: NHLBI provides controlled access to IPD through BioLINCC. Access requires registration, evidence of local IRB approval or certification of exemption from IRB review, and completion of a data use agreement.
2. Study Protocol
3. Study Forms