Statins for Acutely Injured Lungs From Sepsis

Sepsis Clinical Trial

— SAILS  

Official title:

Randomized Trial of Rosuvastatin for Acutely Injured Lungs From Sepsis

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00979121
• Other study ID #: 670
• Secondary ID: N01HR56179
• Status: Terminated
• Phase: Phase 3
• First received: September 16, 2009
• Last updated: October 2, 2014
• Start date: January 2010
• Est. completion date: November 2013

Study information

• Verified date: August 2014
• Source: National Heart, Lung, and Blood Institute (NHLBI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 745
• Est. completion date: November 2013
• Est. primary completion date: November 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Lung Injury
• Lung Injury
• Respiratory Distress Syndrome, Adult
• Sepsis
• Toxemia

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

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	No
Other	ICU Free Days to Day 28		28 days after randomization	No
Other	Other Secondary Out-comes	Percentage of subjects with Arrhythmia's, Bowel Ischemia, Myocardial Infarction, Ischemic Stroke, and Thromboembolism were measured.	28 days after randomization	No
Other	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	No
Primary	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	No
Secondary	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	No

External Links

•   ARDS Network Website