| Conditions: |
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Community Acquired Respiratory Disease Syndrome |
| Purpose: |
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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 and 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 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). We 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.
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| Study Summary: |
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VA Cooperative Study #574 is designed to prospectively evaluate the efficacy of prolonged
glucocorticoid (methylprednisolone) treatment on short- (in hospital) and long-term (after
hospital discharge), morbidity and mortality in veteran patients admitted to the ICU
(including intermediate care unit) with severe community-acquired pneumonia (CAP).
CAP is the sixth most common cause of death (acute mortality) in the United States and the
leading cause of community-acquired infection requiring intensive care unit (ICU) admission.
Despite significant advancements in medical care, there has been little change in crude
mortality from respiratory tract infection for more than 5 decades (1950-2000). In the
United States alone, over 1.3 million people were admitted to the hospital in 2002 with
severe CAP (262 per 10,000 population) with an estimated inpatient cost of approximately
$4.4 billion. In addition, severe CAP patients surviving hospitalization experience a
significant increase in long-term morbidity (cardiovascular complications, impaired
functional status, and recurrent hospitalizations) and a sizable mortality up to 1 year (up
to 25%) that is independent of patient's chronic health condition.
Dysregulated systemic inflammation, characterized by persistent elevation in circulating
inflammatory cytokine levels over time, is the central pathogenetic process contributing to
short- and long-term morbidity and mortality in patients with severe CAP. Even when patients
survive ICU and hospital admission, elevation in inflammatory cytokine lasts for greater
than 3 weeks, and interleukin (IL)-6 levels at hospital discharge predict subsequent
mortality. Endogenous and exogenous glucocorticoids are the most important physiologic
inhibitors of inflammation. In a meta-analysis of four, small, published studies that
included a total of 198 patients with severe CAP, prolonged glucocorticoid treatment was
associated with a significant reduction in short-term mortality (RR = 0.40, 95%CI 0.18-0.89;
p = 0.03; I2 12%). This Cooperative Studies Program study will be the first large-scale,
prospective, randomized clinical trial evaluating the efficacy of prolonged
methylprednisolone in the treatment of severe CAP.
In this study, at each site, patients with severe CAP will be randomized in a 1:1 ratio to
receive methylprednisolone or placebo in a double-blind fashion. We have chosen a total
duration of treatment of 20 days (7 days full dose followed by slow reduction over 13 days)
to forestall relapse of systemic inflammation and allow recovery of the suppressed
hypothalamic-pituitary-adrenal (HPA) axis. All patients will also receive standardized
management of CAP in accordance with current practice guidelines. Randomization will be
stratified separately within each participating site by whether or not the patient requires
mechanical ventilation at the time of randomization. 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.
Based on published studies and VA Decision Support System, we estimate the all cause 60-day
mortality in severe CAP patients admitted to ICU is 28%. We hypothesize that prolonged
methylprednisolone treatment will reduce the 60-day mortality from 28% to 21% (a 25%
relative reduction). A total of 1406 patients (703 per group) will be required to give 85%
power to detect this hypothesized improvement, using a two-sided 5% significance level test.
Adjusting for 1% attrition, the target sample size is 1420. Assuming 5 years of accrual and
an intake rate of 8 patients per year per VAMC, we will need 36 participating VAMCs.
Treatment of severe CAP is of particular importance to the VA health care system because of
the large patient population and because a single episode of severe CAP is associated with
significant short- and long-term morbidity and mortality. In fiscal year 2006, 17,890
patients were admitted to the VA hospital system with a diagnosis of CAP. Of these, 3727
(21%) required ICU admission during their hospital stay. For ICU-admitted patients,
mortality rates in the hospital at 60, 90, 180, and 365 days were 26%, 34%, 37%, 44%, and
51%, respectively. They had on average a hospital stay of 17.7 days with hospital costs of
$49,936, and 48% of them were readmitted within 12 months of hospital discharge. This study
will investigate the effects of an off-patent, inexpensive treatment that, based on strong
experimental and translational evidence and the encouraging findings of preliminary trials,
has the potential of significantly decreasing mortality and morbidity. Equally important,
this study will advance knowledge on the relationship between inflammation and long-term
outcome in severe CAP. Given that methylprednisolone is off-patent, there is little
incentive for the pharmaceutical industry to fund this study. The VA system with its
Cooperative Studies Program is uniquely suited to conduct the study.
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| Criteria: |
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Inclusion Criteria:
- Patient's origin. Patients are classified as having 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 greater than 38 C oral (>38.5 C rectally or tympanically) or hypothermia
(<35 C)
- White blood cell count greater than 10,000 cells/mm3 or less than 4,500
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) by meeting at least three of five CURB-65
criteria or need for mechanical ventilation:
- CURB-65 criteria1.Respiratory rate >30 breaths/min
- Confusion/disorientation
- Uremia (BUN >20 mg/dL)
- Hypotension: SBP <90 or DBP <60
- Age >65 years
- OR Need for invasive or noninvasive mechanical ventilation -- Legend: BUN = blood
urea nitrogen; SBP = systolic blood pressure (mmHg); DBP = diastolic blood pressure
(mmHg).
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.
- COPD with acute exacerbation requiring glucocorticoid treatment at hospital
admission. Patients with short-term glucocorticoid use (e.g., methylprednisolone up
to 60 mg/day for 5 days) 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.
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| NCT ID: |
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NCT01283009 |
| Primary Contact: |
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Study Chair
Gianfranco Umberto Meduri, MD
VA Medical Center, Memphis
Lisa Bridges, MSN
Phone: (901) 523-8990 ext. 6608
Email: lisa.bridges2@va.gov
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| Backup Contact: |
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N/A |
| Location Contact: |
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Buffalo, New York 14215
United States
Ali El Sohl, MD
Phone: 716-862-7366
Email: sohl@buffalo.edu
Site Status: Not yet recruiting |