Statins for Acutely Injured Lungs From Sepsis

NCT ID: NCT00979121

Last Updated: 2016-05-16

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 745 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-01-31
• Study Completion Date: 2013-11-30

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.

Conditions

Sepsis; Acute Lung Injury

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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

Group Type: ACTIVE_COMPARATOR

Rosuvastatin

Intervention Type: DRUG

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

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Interventions

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.

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

Other Intervention Names

Crestor

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:

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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.

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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jonathon Truwit, MD

Role: STUDY_CHAIR

University of Virginia, Medical Center

Locations

University of San Francisco-Fresno Medical Center

Fresno, California, United States

University of California, Davis Medical Center

Sacramento, California, United States

UCSF-Moffitt Hospital

San Francisco, California, United States

University of California, San Francisco (UCSF)-Moffitt Hospital

San Francisco, California, 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

Washington Hospital Center

Washington D.C., District of Columbia, 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

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

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

Baystate Medical Center

Springfield, Massachusetts, United States

Rochester Methodist Hospital

Rochester, Minnesota, United States

St. Mary's Hospital, Mayo Clinic

Rochester, Minnesota, United States

Duke University Medical Center

Durham, North Carolina, United States

Durham Regional Medical Center

Durham, North Carolina, United States

Moses Cone Health System

Greensboro, North Carolina, United States

Wesley Long Community Hospital

Greensboro, North Carolina, United States

Wake Forest University Baptist Medical Center

Winston-Salem, North Carolina, United States

Cleveland Clinic Foundation

Cleveland, Ohio, United States

MetroHealth Medical Center

Cleveland, Ohio, United States

University Hospitals of Cleveland

Cleveland, Ohio, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Baylor College of Medicine

Houston, Texas, United States

Intermountain Medical Center

Murray, Utah, United States

McKay-Dee Hospital

Ogden, Utah, United States

Utah Valley Regional Medical Center

Provo, Utah, United States

LDS Hospital

Salt Lake City, Utah, United States

University of Virginia Medical Center

Charlottesville, Virginia, United States

Providence Hospital

Everett, Washington, United States

Harborview Medical Center

Seattle, Washington, United States

University of Washington

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 36119770 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26936876 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26832963 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24835849 (View on PubMed)

Study Documents

Document Type: Individual Participant Data Set

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.

View Document

Document Type: Study Protocol

View Document

Document Type: Study Forms

View Document

Related Links

http://www.ardsnet.org

ARDS Network Website

Other Identifiers

N01HR056179

Identifier Type: NIH

Identifier Source: secondary_id

View Link

670

Identifier Type: -

Identifier Source: org_study_id