Extended Steroid in Use in Community Acquired Pneumonia (CAP)(e)
Condition: Community Acquired Respiratory Disease Syndrome
MeSH terms: Pneumonia; Respiratory Tract Diseases; Respiration Disorders
Intervention: Inactive Substance; Methylprednisolone
Intervention description: 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).; 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).
Intervention MeSH terms: Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 584.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: pneumoniae

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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.:

          -  1 Major Criteria

               1. Use of invasive or noninvasive mechanical ventilation

               2. Vasopressors for shock despite adequate fluid resuscitation

               3. Arterial pH < 7.30 -OR >=3 Minor Criteria

               1. New onset of confusion or disorientation

               2. Hypothermia (core temperature <=36 C)

               3. Respiratory rate >=30 breaths/min

               4. Hypotension requiring aggressive fluid resuscitation

               5. Uremia (BUN >=20 mg/dL)

               6. PaO2: FiO2 ratio <=250 or SaO2:FiO2 ratio <=250

               7. Leukopenia (WBC count < 4000 cells/mm3)

               8. Platelet count < 100,000 cells/mm3 or > 400,000 cells/mm3

               9. Multilobar infiltrates

                  Exclusion Criteria:

                  - 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).