Statins for Acutely Injured Lungs From Sepsis (SAILS)

• ClinicalTrials.gov Identifier: NCT00979121
• Recruitment Status: Terminated
• First Posted: September 17, 2009
• Results First Posted: October 3, 2014
• Last Update Posted: May 16, 2016
• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): National Heart, Lung, and Blood Institute (NHLBI)

Tracking Information

• First Submitted Date: September 16, 2009
• First Posted Date: September 17, 2009
• Results First Submitted Date: August 22, 2014
• Results First Posted Date: October 3, 2014
• Last Update Posted Date: May 16, 2016
• Study Start Date: January 2010
• Actual Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 2, 2014)

Hospital Mortality to Day 60. [ Time Frame: 60 days after randomization ]

The percentage of subjects alive at study day 60. Those subjects discharged home prior to day 60 were counted as alive at day 60.

• Original Primary Outcome Measures (submitted: September 16, 2009): The Primary efficacy measure is hospital mortality to day 60. [ Time Frame: 60 days after randomization ]

Current Secondary Outcome Measures (submitted: October 2, 2014)

Ventilator Free Days at Study Day 28 [ Time Frame: time of initiating unassisted breathing to day 28 after study randomization ]

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.

• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: October 2, 2014)

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

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Statins for Acutely Injured Lungs From Sepsis
• Official Title: Randomized Trial of Rosuvastatin for Acutely Injured Lungs From Sepsis

Brief Summary

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.

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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment

Condition

• Sepsis
• Acute Lung Injury

Intervention

• 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 Name: Crestor
• Drug: Placebo
  Subjects received placebo by mouth or feeding tube daily for 28 days or until discharged from study hospital.

Study Arms

• 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:

  1. 28 days after randomization or 3 days after ICU discharge (whichever comes first),
  2. Discharge from study hospital,
  3. Death
  Intervention: Drug: Rosuvastatin
• 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.

  Intervention: Drug: Placebo

Publications *

• 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: October 18, 2013): 745
• Original Estimated Enrollment (submitted: September 16, 2009): 1000
• Actual Study Completion Date: November 2013
• Actual Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00979121
• Other Study ID Numbers: 670; N01HR056179 ( Other Grant/Funding Number: NHLBI )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
• Study Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: Not Provided

Investigators

• Study Chair: Jonathon Truwit, MD; University of Virginia, Medical Center

• PRS Account: National Heart, Lung, and Blood Institute (NHLBI)
• Verification Date: August 2014