Extended Steroid in Use in Community Acquired Pneumonia (CAP)(e)

NCT01283009 | Completed Phase 3 Results DMC

• 1 other identifier: 574
• Study Type: interventional
• Target: 584
• Locations: 2 countries
• Sites: 30

Brief Summary

The goal of the study is to determine whether providing early treatment with a glucocorticoid drug, called methylprednisolone, will improve survival in critically ill patients with severe community-acquired pneumonia (CAP). Pneumonia develops when bacteria and other agents invade the lungs. The body's immune system creates a response to produce inflammation to kill the bacteria. A moderate amount of inflammation is beneficial. But, in patients sick enough to be admitted to the ICU, inflammation is frequently out of control. When the body cannot regulate inflammation vital organs (brain, heart, lung, kidney, liver) may be damaged, contributing to death or residual organ damage for those who survive. Glucocorticoids help reduce inflammation. Recent studies have shown that when the body is unable to produce sufficient amounts of glucocorticoids, inflammation can get out of control. Under these circumstances, glucocorticoids given in small doses may help aid the body's ability to reduce inflammation and improve recovery. In a small preliminary trial, glucocorticoid treatment, in addition to standard antibiotic treatment, sped up recovery from pneumonia. It also decreased the length of hospital stay, and increased survival. This Cooperative Studies Program (CSP) study will be the first large-scale, prospective, randomized clinical trial evaluating whether or not this treatment improves recovery. In this study, at each site, patients with severe CAP will be assigned to one of two treatment groups. One group will receive methylprednisolone and the other will receive a placebo (an inert substance that will look like the drug). The investigators have chosen a total duration of treatment of 20 days (7 days full dose followed by slow reduction over 13 days) to prevent relapse of inflammation and allow the body to recover its own ability to produce glucocorticoid. All patients will also receive standardized management of CAP in accordance with current practice guidelines. The study will take into consideration when assigning the treatment each participating site, and whether or not the patient requires mechanical ventilation at the time of assignment. Patients will be followed clinically for 180 days. The primary outcome is all cause 60-day mortality. Secondary outcomes are (1) in-hospital morbidity-mortality, including ventilator-free days, multiorgan dysfunction syndrome (MODS)-free days, duration of ICU and hospital stay, and hospital discharge; and (2) posthospital discharge morbidity-mortality, including cardiovascular complications, functional and general health status in the first 180 days, rehospitalization, and mortality at 1 year. Serial blood samples will also be collected and stored for future translational research relating longitudinal inflammation markers to clinical outcomes. This study will advance knowledge on the relationship between inflammation and long-term outcome in severe CAP.

Conditions

Community Acquired Respiratory Disease Syndrome

Keywords

pneumoniae

Outcome Measures

Primary Outcomes (1)

• 60-day Mortality

  The primary outcome is all-cause mortality at 60 days, defined by whether the patient has died by the end of study day 60.

  60-day

Study Arms (2)

Arm 1: Inactive substance

PLACEBO COMPARATOR

Inactive substance

Drug: Inactive Substance

Arm 2: Methylprednisolone

ACTIVE COMPARATOR

Methylprednisolone

Drug: Methylprednisolone

Interventions

Inactive Substance DRUG

Inactive Substance will be given in a double-blind fashion for 20 full days. The treatment course includes a bolus dose on the day of randomization, 7 days of full dose (40 mg/day), 7 days of half dose (20 mg/day), and 6 days of tapering doses (12 mg/day and 4 mg/day).

Arm 1: Inactive substance

Methylprednisolone DRUG

Methylprednisolone will be given in a double-blind fashion for 20 full days. The treatment course includes a bolus dose on the day of randomization, 7 days of full dose (40 mg/day), 7 days of half dose (20 mg/day), and 6 days of tapering doses (12 mg/day and 4 mg/day).

Also known as: Medrol

Arm 2: Methylprednisolone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient's origin. Patients are classified as having Community Acquired Pneumonia (CAP) if they are admitted directly from outside the hospital, including private residence, nursing home, rehabilitation center, other long-term care facility (health care-associated pneumonia (HCAP)).
• Clinical diagnosis of CAP.
• Have radiographically confirmed pneumonia (new or progressive pulmonary infiltrate(s) on chest radiograph or chest computed tomography scan consistent with bacterial pneumonia) AND have acute illness ( \<=7 days' duration) with at least three of the following clinical signs or symptoms consistent with a lower respiratory tract infection:
• New or increased cough Purulent sputum or change in sputum character Auscultatory findings consistent with pneumonia (e.g., rales, egophony, findings of consolidation) Dyspnea, tachypnea, or hypoxemia (O2 saturation \<90% on room air or PaO2 \<60 mmHg) Fever \>= 38 C oral (\>=38.5 C rectally or tympanically) or hypothermia (\<=36 C) White blood cell count greater than 10,000 cells/mm3 or less than 4,000 cells/mm3 Greater than 15% immature neutrophils (bands) irrespective of WBC count
• Diagnosis of severe CAP. Pneumonia of sufficient severity to require admission to the ICU (including intermediate care unit) and meeting \>=1 major or \>= 3 minor modified Infectious Diseases Society of America (IDSA)/American
• Thoracic Society (ATS) criteria.:
• Major Criteria
• Use of invasive or noninvasive mechanical ventilation
• Vasopressors for shock despite adequate fluid resuscitation
• Arterial pH \< 7.30 -OR \>=3 Minor Criteria
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• New onset of confusion or disorientation
• Hypothermia (core temperature \<=36 C)
• Respiratory rate \>=30 breaths/min
• Hypotension requiring aggressive fluid resuscitation

You may not qualify if:

• \- Patient's age 17 years or younger.
• \- Vasopressor-dependent shock requiring moderate-to-high dose vasopressor (i.e., norepinephrine \>=0.3 mcg/Kg/min) treatment for greater than 2 hours in patient that is adequately fluid-resuscitated (at least 4 liters of crystalloids) WITH central venous pressure (CVP) equal to or greater than 8 mm Hg for nonventilated patients and equal to or greater than 12 mm Hg for ventilated patients. (See explanation below)\*
• \- Major gastrointestinal bleeding requiring transfusion of 5 units or more of packed red blood cells within 3 months of current hospitalization.
• \- Any condition requiring 20 mg of prednisone equivalent/day for greater than 14 days, over the last 3 months.
• \- Chronic obstructive pulmonary disease (COPD) with acute exacerbation requiring glucocorticoid treatment at hospital admission. Patients with short-term glucocorticoid use (e.g., methylprednisolone up to 300 mg within 5 days of randomization) will not be excluded.
• \- Patients enrolled in another experimental (interventional) protocol.
• \- Pregnancy, confirmed by urine or serum test.
• \- Presence of postobstructive pneumonia or cystic fibrosis.
• \- Clinical history consistent with aspiration of gastric content (i.e., loss of consciousness or seizure).
• \- Active tuberculosis or fungal infection.
• \- Moribund patient (i.e., not expected to live more than 24 h) or with recent (within 7 days) cardiopulmonary arrest, or with (known or suspected) irreversible cessation of all brain function, or comfort measure status.
• \- Presence of preexisting medical condition that is irreversible and expected to be fatal within 3 months.
• Patients with severe immunosuppression (i.e., HIV with CD4 \<200), neutropenia (less than 1000 neutrophils) not related to pneumonia, acute burn injury, or receiving immunosuppressive or cytotoxic therapy for any reason.
• Chronic severe cognitive impairment caused by dementia or central nervous system pathologies (tumor, cerebro-vascular accident, infections, or head injuries) as defined by the site investigator by obtaining medical history and reviewing medical record.
• The physician doesn't feel the patient is a viable candidate for the study (e.g., presence of hypersensitivity or previous severe adverse reaction to cosyntropin or any glucocorticoid, history of adrenal insufficiency or chronic systemic steroid use placing the patient at risk for relative adrenal insufficiency).

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (30)

Phoenix VA Health Care System Carl T. Hayden VA Medical Center, Phoenix, AZ

Phoenix, Arizona, 85012, United States

Location

VA Loma Linda Healthcare System, Loma Linda, CA

Loma Linda, California, 92357, United States

Location

VA Long Beach Healthcare System, Long Beach, CA

Long Beach, California, 90822, United States

Location

VA Palo Alto Health Care System, Palo Alto, CA

Palo Alto, California, 94304-1290, United States

Location

VA San Diego Healthcare System, San Diego, CA

San Diego, California, 92161, United States

Location

VA Greater Los Angeles Healthcare System, West Los Angeles, CA

West Los Angeles, California, 90073, United States

Location

Bay Pines VA Healthcare System, Pay Pines, FL

Bay Pines, Florida, 33744, United States

Location

North Florida/South Georgia Veterans Health System, Gainesville, FL

Gainesville, Florida, 32608, United States

Location

Miami VA Healthcare System, Miami, FL

Miami, Florida, 33125, United States

Location

Atlanta VA Medical and Rehab Center, Decatur

Decatur, Georgia, 30033, United States

Location

Richard L. Roudebush VA Medical Center, Indianapolis, IN

Indianapolis, Indiana, 46202-2884, United States

Location

Robley Rex VA Medical Center, Louisville, KY

Louisville, Kentucky, 40206, United States

Location

Minneapolis VA Health Care System, Minneapolis, MN

Minneapolis, Minnesota, 55417, United States

Location

Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE

Omaha, Nebraska, 68105-1873, United States

Location

VA Sierra Nevada Health Care System, Reno, NV

Reno, Nevada, 89502, United States

Location

VA Western New York Healthcare System, Buffalo, NY

Buffalo, New York, 14215, United States

Location

Syracuse VA Medical Center, Syracuse, NY

Syracuse, New York, 13210, United States

Location

Asheville VA Medical Center, Asheville, NC

Asheville, North Carolina, 28805, United States

Location

Cincinnati VA Medical Center, Cincinnati, OH

Cincinnati, Ohio, 45220, United States

Location

Louis Stokes VA Medical Center, Cleveland, OH

Cleveland, Ohio, 44106, United States

Location

Oklahoma City VA Medical Center, Oklahoma City, OK

Oklahoma City, Oklahoma, 73104, United States

Location

VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

Pittsburgh, Pennsylvania, 15240, United States

Location

Wm. Jennings Bryan Dorn VA Medical Center, Columbia SC

Columbia, South Carolina, 29209, United States

Location

Memphis VA Medical Center, Memphis, TN

Memphis, Tennessee, 38104, United States

Location

Michael E. DeBakey VA Medical Center, Houston, TX

Houston, Texas, 77030, United States

Location

South Texas Health Care System, San Antonio, TX

San Antonio, Texas, 78229, United States

Location

VA Salt Lake City Health Care System, Salt Lake City, UT

Salt Lake City, Utah, 84148, United States

Location

Salem VA Medical Center, Salem, VA

Salem, Virginia, 24153, United States

Location

Clement J. Zablocki VA Medical Center, Milwaukee, WI

Milwaukee, Wisconsin, 53295-1000, United States

Location

VA Caribbean Healthcare System, San Juan, PR

San Juan, 00921, Puerto Rico

Location

Related Publications (1)

• Meduri GU, Shih MC, Bridges L, Martin TJ, El-Solh A, Seam N, Davis-Karim A, Umberger R, Anzueto A, Sriram P, Lan C, Restrepo MI, Guardiola JJ, Buck T, Johnson DP, Suffredini A, Bell WA, Lin J, Zhao L, Uyeda L, Nielsen L, Huang GD; ESCAPe Study Group. Low-dose methylprednisolone treatment in critically ill patients with severe community-acquired pneumonia. Intensive Care Med. 2022 Aug;48(8):1009-1023. doi: 10.1007/s00134-022-06684-3. Epub 2022 May 13.

  PMID: 35723686 DERIVED

MeSH Terms

Interventions

Methylprednisolone

Intervention Hierarchy (Ancestors)

Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Dr. Gianfranco U. Meduri
• Organization: Memphis VA Medical Center

Gianfranco.Meduri@va.gov

(901) 577-7520

Study Officials

• Gianfranco U Meduri, MD

  Memphis VA Medical Center, Memphis, TN

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 21, 2011
• First Posted: January 25, 2011
• Study Start: January 9, 2012
• Primary Completion: July 31, 2016
• Study Completion: August 31, 2016
• Last Updated: October 8, 2020
• Results First Posted: October 8, 2020

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will not share

Locations

PR (1); US (29)