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

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT01283009
• Collaborator: (none)
• Enrollment: 584
• Locations: 30
• Arms: 2
• Actual Duration (Months): 55.7
• Patients Per Site: 19.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Community Acquired Respiratory Disease Syndrome	Drug: Inactive Substance; Drug: Methylprednisolone	Phase 3

Detailed Description

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 Intensive Care Unit (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 (CSP) 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. The investigators 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, the investigators estimate the all cause 60-day mortality in severe CAP patients admitted to ICU is 28%. The investigators 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 Veterans Affairs Medical Center (VAMC), the investigators 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 584 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: CSP #574 - Evaluate the Safety and Efficacy of Methylprednisolone in Hospitalized Veterans With Severe Community-Acquired Pneumonia
• Actual Study Start Date: Jan 9, 2012
• Actual Primary Completion Date: Jul 31, 2016
• Actual Study Completion Date: Aug 31, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Arm 1: Inactive substance Inactive substance	Drug: Inactive Substance; 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).
Active Comparator: Arm 2: Methylprednisolone Methylprednisolone	Drug: Methylprednisolone; 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).; Other Names: Medrol

Outcome Measures

Primary Outcome Measures

1. 60-day Mortality [60-day]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

4. New onset of confusion or disorientation

5. Hypothermia (core temperature <=36 C)

6. Respiratory rate >=30 breaths/min

7. Hypotension requiring aggressive fluid resuscitation

8. Uremia (BUN >=20 mg/dL)

9. PaO2: FiO2 ratio <=250 or SaO2:FiO2 ratio <=250

10. Leukopenia (WBC count < 4000 cells/mm3)

11. Platelet count < 100,000 cells/mm3 or > 400,000 cells/mm3

12. 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix VA Health Care System Carl T. Hayden VA Medical Center, Phoenix, AZ	Phoenix	Arizona	United States	85012
2	VA Loma Linda Healthcare System, Loma Linda, CA	Loma Linda	California	United States	92357
3	VA Long Beach Healthcare System, Long Beach, CA	Long Beach	California	United States	90822
4	VA Palo Alto Health Care System, Palo Alto, CA	Palo Alto	California	United States	94304-1290
5	VA San Diego Healthcare System, San Diego, CA	San Diego	California	United States	92161
6	VA Greater Los Angeles Healthcare System, West Los Angeles, CA	West Los Angeles	California	United States	90073
7	Bay Pines VA Healthcare System, Pay Pines, FL	Bay Pines	Florida	United States	33744
8	North Florida/South Georgia Veterans Health System, Gainesville, FL	Gainesville	Florida	United States	32608
9	Miami VA Healthcare System, Miami, FL	Miami	Florida	United States	33125
10	Atlanta VA Medical and Rehab Center, Decatur	Decatur	Georgia	United States	30033
11	Richard L. Roudebush VA Medical Center, Indianapolis, IN	Indianapolis	Indiana	United States	46202-2884
12	Robley Rex VA Medical Center, Louisville, KY	Louisville	Kentucky	United States	40206
13	Minneapolis VA Health Care System, Minneapolis, MN	Minneapolis	Minnesota	United States	55417
14	Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE	Omaha	Nebraska	United States	68105-1873
15	VA Sierra Nevada Health Care System, Reno, NV	Reno	Nevada	United States	89502
16	VA Western New York Healthcare System, Buffalo, NY	Buffalo	New York	United States	14215
17	Syracuse VA Medical Center, Syracuse, NY	Syracuse	New York	United States	13210
18	Asheville VA Medical Center, Asheville, NC	Asheville	North Carolina	United States	28805
19	Cincinnati VA Medical Center, Cincinnati, OH	Cincinnati	Ohio	United States	45220
20	Louis Stokes VA Medical Center, Cleveland, OH	Cleveland	Ohio	United States	44106
21	Oklahoma City VA Medical Center, Oklahoma City, OK	Oklahoma City	Oklahoma	United States	73104
22	VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA	Pittsburgh	Pennsylvania	United States	15240
23	Wm. Jennings Bryan Dorn VA Medical Center, Columbia SC	Columbia	South Carolina	United States	29209
24	Memphis VA Medical Center, Memphis, TN	Memphis	Tennessee	United States	38104
25	Michael E. DeBakey VA Medical Center, Houston, TX	Houston	Texas	United States	77030
26	South Texas Health Care System, San Antonio, TX	San Antonio	Texas	United States	78229
27	VA Salt Lake City Health Care System, Salt Lake City, UT	Salt Lake City	Utah	United States	84148
28	Salem VA Medical Center, Salem, VA	Salem	Virginia	United States	24153
29	Clement J. Zablocki VA Medical Center, Milwaukee, WI	Milwaukee	Wisconsin	United States	53295-1000
30	VA Caribbean Healthcare System, San Juan, PR	San Juan		Puerto Rico	00921

Sponsors and Collaborators

• VA Office of Research and Development

Investigators

• Study Chair: Gianfranco U Meduri, MD, Memphis VA Medical Center, Memphis, TN

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT01283009
• Other Study ID Numbers: 574
• First Posted: Jan 25, 2011
• Last Update Posted: Oct 8, 2020
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by VA Office of Research and Development: pneumoniae
• Additional relevant MeSH terms: Pneumonia; Respiration Disorders; Respiratory Tract Diseases; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate

Study Results

Participant Flow

Arm/Group Title	Arm 1: Inactive Substance	Arm 2: Methylprednisolone
Arm/Group Description	Inactive substance Inactive Substance: 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 Methylprednisolone: 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).
Period Title: Overall Study
STARTED	287	297
COMPLETED	169	180
NOT COMPLETED	118	117

Baseline Characteristics

Arm/Group Title	Arm 1: Inactive Substance	Arm 2: Methylprednisolone	Total
Arm/Group Description	Inactive substance 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 Methylprednisolone: 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).	Total of all reporting groups
Overall Participants	287	297	584
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68.6 (11.1)	69.0 (10.8)	68.8 (11.0)
Sex: Female, Male (Count of Participants)
Female	13 4.5%	8 2.7%	21 3.6%
Male	273 95.1%	289 97.3%	562 96.2%
Race/Ethnicity, Customized (Count of Participants)
Not Spanish, Hispanic or Latino	251 87.5%	255 85.9%	506 86.6%
Mexican, Mexican American, or Chicano	12 4.2%	16 5.4%	28 4.8%
Puerto Rican	8 2.8%	5 1.7%	13 2.2%
Cuban	1 0.3%	0 0%	1 0.2%
Other Spanish, Hispanic, or Latino	8 2.8%	10 3.4%	18 3.1%
Race/Ethnicity, Customized (Count of Participants)
White	227 79.1%	245 82.5%	472 80.8%
Black/African American	48 16.7%	36 12.1%	84 14.4%
Other	10 3.5%	15 5.1%	25 4.3%
BMI >=30 (Count of Participants)
Yes	70 24.4%	62 20.9%	132 22.6%
No	215 74.9%	235 79.1%	450 77.1%
Mechanical Ventilation at Study Entry (Count of Participants)
Yes	96 33.4%	97 32.7%	193 33%
No	191 66.6%	200 67.3%	391 67%
SOFA Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.29 (2.85)	6.68 (3.0)	6.49 (2.93)
Vasopressor Dependent Shock at or Prior to Study Entry (Count of Participants)
Yes	32 11.1%	44 14.8%	76 13%
No	253 88.2%	252 84.8%	505 86.5%
Any Major Co-Morbidities (Count of Participants)
Yes	275 95.8%	290 97.6%	565 96.7%
No	10 3.5%	7 2.4%	17 2.9%
Number of Major Co-Morbidities (Comorbidities) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Comorbidities]	3.9 (1.9)	4.0 (1.8)	4.0 (1.8)
Charlson Comorbidity Index (comorbidity score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [comorbidity score]	5.65 (2.24)	5.77 (2.39)	5.71 (2.32)
ACE 27 Overall Comorbidity Score (Count of Participants)
0 (None)	8 2.8%	6 2%	14 2.4%
1 (Mild)	33 11.5%	38 12.8%	71 12.2%
2 (Moderate)	59 20.6%	51 17.2%	110 18.8%
3 (Severe)	185 64.5%	202 68%	387 66.3%
ACE 27 total score (units on a scale) [Mean (Full Range) ]
Mean (Full Range) [units on a scale]	2.48	2.51	2.50
Karnofsky Performance Score (units on a scale) [Mean (Full Range) ]
Mean (Full Range) [units on a scale]	72.9	72.4	72.6
Health Care Associated Pneumonia (Count of Participants)
Pts. w/No HCAP (%)	198 69%	185 62.3%	383 65.6%
Pts. with HCAP (%)	89 31%	112 37.7%	201 34.4%
Admission from the Ward (Count of Participants)
Pts. Admitted from Ward (%)	57 19.9%	66 22.2%	123 21.1%
Pts. not Admitted from Ward (%)	230 80.1%	231 77.8%	461 78.9%
Pneumonia Severity Index (PSI) Score (Severity Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Severity Score]	122.3 (34.4)	125.6 (37.2)	124.0 (35.8)
Pneumonia Severity Index (PSI) Class (Count of Participants)
I	4 1.4%	3 1%	7 1.2%
II	13 4.5%	13 4.4%	26 4.5%
III	29 10.1%	41 13.8%	70 12%
IV	126 43.9%	121 40.7%	247 42.3%
V	113 39.4%	119 40.1%	232 39.7%
Chest Radiographic Score (units on a scale) [Mean (Full Range) ]
Mean (Full Range) [units on a scale]	1.94	2.09	2.02
Chest Radiograph Class (Count of Participants)
No Alveolar Consolidation	15 5.2%	13 4.4%	28 4.8%
Alveolar Consolidation, 1 quadrant	93 32.4%	68 22.9%	161 27.6%
Alveolar Consolidation, 2 quadrants	103 35.9%	127 42.8%	230 39.4%
Alveolar Consolidation, 3 quadrants	36 12.5%	52 17.5%	88 15.1%
Alveolar Consolidation, 4 quadrants	35 12.2%	34 11.4%	69 11.8%
Bilateral Involvement (Count of Participants)
Bilateral Involvement	163 56.8%	189 63.6%	352 60.3%
No Bilateral Involvement	113 39.4%	99 33.3%	212 36.3%
PaO2:FiO2 (If PaOD is available) (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	188 (90)	181 (85)	184 (87)
SpO2:FiO2 (if PaO2 is not available) (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	286 (98)	283 (101)	284 (99)
ALI/ARDS at randomization (Count of Participants)
Yes	39 13.6%	26 8.8%	65 11.1%
No	246 85.7%	271 91.2%	517 88.5%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Numbers provided are overall and by stratum.

Arm/Group Title	Arm 1: Inactive Substance	Arm 2: Methylprednisolone
Arm/Group Description	Inactive substance 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 Methylprednisolone: 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).
Measure Participants	287	297
Yes	50 17.4%	47 15.8%
No	227 79.1%	239 80.5%
Unknown	10 3.5%	11 3.7%
Yes	24 8.4%	22 7.4%
No	70 24.4%	72 24.2%
Unknown	2 0.7%	3 1%
Yes	26 9.1%	25 8.4%
No	157 54.7%	167 56.2%
Unknown	8 2.8%	8 2.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Inactive Substance, Arm 2: Methylprednisolone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.635
	Comments
	Method	Mantel Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.58 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	All SAEs were reported from Randomization to day 180.
Adverse Event Reporting Description	We did not collect data on non-serious adverse events.
Arm/Group Title	Arm 1: Inactive Substance		Arm 2: Methylprednisolone
Arm/Group Description	Inactive substance Methylprednisolone: 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).		Methylprednisolone Methylprednisolone: 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).
All Cause Mortality
	Arm 1: Inactive Substance		Arm 2: Methylprednisolone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	84/287 (29.3%)		79/297 (26.6%)
Serious Adverse Events
	Arm 1: Inactive Substance		Arm 2: Methylprednisolone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	162/287 (56.4%)		167/297 (56.2%)
Blood and lymphatic system disorders
Anaemia	5/287 (1.7%)		4/297 (1.3%)
Blood disorder	0/287 (0%)		1/297 (0.3%)
Haemorrhagic disorder	1/287 (0.3%)		2/297 (0.7%)
Immune thrombocytopenic purpura	0/287 (0%)		1/297 (0.3%)
Leukocytosis	0/287 (0%)		1/297 (0.3%)
Cardiac disorders
Acute myocardial infarction	6/287 (2.1%)		2/297 (0.7%)
Angina pectoris	0/287 (0%)		1/297 (0.3%)
Angina unstable	1/287 (0.3%)		0/297 (0%)
Aortic valve stenosis	1/287 (0.3%)		0/297 (0%)
Atrial fibrillation	5/287 (1.7%)		4/297 (1.3%)
Atrial flutter	1/287 (0.3%)		1/297 (0.3%)
Atrioventricular block complete	0/287 (0%)		1/297 (0.3%)
Bradycardia	1/287 (0.3%)		0/297 (0%)
Cardiac arrest	2/287 (0.7%)		0/297 (0%)
Cardiac failure	5/287 (1.7%)		1/297 (0.3%)
Cardiac failure congestive	18/287 (6.3%)		25/297 (8.4%)
Cardiac tamponade	1/287 (0.3%)		0/297 (0%)
Cardiomyopathy	1/287 (0.3%)		0/297 (0%)
Cardio-respiratory arrest	1/287 (0.3%)		1/297 (0.3%)
Chordae tendinae rupture	0/287 (0%)		1/297 (0.3%)
Conduction disorder	1/287 (0.3%)		0/297 (0%)
Coronary artery disease	2/287 (0.7%)		0/297 (0%)
Coronary artery occlusion	1/287 (0.3%)		0/297 (0%)
Coronary artery stenosis	2/287 (0.7%)		0/297 (0%)
Ischaemic cardiomyopathy	1/287 (0.3%)		0/297 (0%)
Palpitations	0/287 (0%)		1/297 (0.3%)
Pulseless electrical activity	0/287 (0%)		1/297 (0.3%)
Supraventricular tachycardia	0/287 (0%)		1/297 (0.3%)
Tachyarrhythmia	0/287 (0%)		1/297 (0.3%)
Tachycardia	0/287 (0%)		1/297 (0.3%)
Ventricular fibrillation	1/287 (0.3%)		0/297 (0%)
Ventricular tachycardia	1/287 (0.3%)		0/297 (0%)
Congenital, familial and genetic disorders
Haemorrhagic arteriovenous malformation	1/287 (0.3%)		0/297 (0%)
Endocrine disorders
Diabetes insipidus	0/287 (0%)		1/297 (0.3%)
Gastrointestinal disorders
Alcoholic pancreatitis	0/287 (0%)		1/297 (0.3%)
Colitis	1/287 (0.3%)		0/297 (0%)
Diarrhoea	0/287 (0%)		1/297 (0.3%)
Diverticulum intestinal	0/287 (0%)		1/297 (0.3%)
Diverticulum intestinal haemorrhagic	1/287 (0.3%)		0/297 (0%)
Dysphagia	0/287 (0%)		1/297 (0.3%)
Gastric ulcer	1/287 (0.3%)		0/297 (0%)
Gastritis	0/287 (0%)		1/297 (0.3%)
Gastrointestinal haemorrhage	1/287 (0.3%)		3/297 (1%)
Gastrointestinal polyp haemorrhage	0/287 (0%)		1/297 (0.3%)
Gastrointestinal ulcer haemorrhage	0/287 (0%)		1/297 (0.3%)
Haematemesis	0/287 (0%)		1/297 (0.3%)
Hiatus hernia	1/287 (0.3%)		0/297 (0%)
Ileus paralytic	1/287 (0.3%)		0/297 (0%)
Mallory-Weiss syndrome	1/287 (0.3%)		0/297 (0%)
Oesophageal fistula	0/287 (0%)		1/297 (0.3%)
Oesophageal varices haemorrhage	1/287 (0.3%)		0/297 (0%)
Pancreatitis acute	2/287 (0.7%)		1/297 (0.3%)
Pancreatitis necrotising	1/287 (0.3%)		0/297 (0%)
Rectal ulcer	0/287 (0%)		1/297 (0.3%)
Salivary hypersecretion	0/287 (0%)		1/297 (0.3%)
Small intestinal obstruction	0/287 (0%)		1/297 (0.3%)
Upper gastrointestinal haemorrhage	1/287 (0.3%)		0/297 (0%)
Volvulus	0/287 (0%)		1/297 (0.3%)
General disorders
Adverse drug reaction	1/287 (0.3%)		3/297 (1%)
Complication associated with device	0/287 (0%)		1/297 (0.3%)
Death	1/287 (0.3%)		2/297 (0.7%)
Impaired healing	0/287 (0%)		1/297 (0.3%)
Multiple organ dysfunction syndrome	5/287 (1.7%)		9/297 (3%)
Non-cardiac chest pain	1/287 (0.3%)		1/297 (0.3%)
Sudden cardiac death	2/287 (0.7%)		0/297 (0%)
Vascular stent restenosis	1/287 (0.3%)		0/297 (0%)
Hepatobiliary disorders
Bile duct obstruction	1/287 (0.3%)		0/297 (0%)
Cholecystitis acute	1/287 (0.3%)		0/297 (0%)
Hepatic cirrhosis	1/287 (0.3%)		1/297 (0.3%)
Hepatitis chronic active	1/287 (0.3%)		0/297 (0%)
Liver disorder	0/287 (0%)		1/297 (0.3%)
Immune system disorders
Anaphylactic reaction	0/287 (0%)		1/297 (0.3%)
Infections and infestations
Arthritis bacterial	0/287 (0%)		1/297 (0.3%)
Bacteraemia	1/287 (0.3%)		0/297 (0%)
Bronchitis	0/287 (0%)		2/297 (0.7%)
Bronchopulmonary aspergillosis	0/287 (0%)		1/297 (0.3%)
Cellulitis	0/287 (0%)		3/297 (1%)
Clostridium difficile colitis	3/287 (1%)		4/297 (1.3%)
Clostridium difficile infection	0/287 (0%)		2/297 (0.7%)
Clostridium difficile sepsis	1/287 (0.3%)		0/297 (0%)
Empyema	1/287 (0.3%)		1/297 (0.3%)
Gangrene	1/287 (0.3%)		0/297 (0%)
Implant site infection	0/287 (0%)		1/297 (0.3%)
Infectious pleural effusion	1/287 (0.3%)		1/297 (0.3%)
Influenza	1/287 (0.3%)		0/297 (0%)
Lower respiratory tract infection	0/287 (0%)		1/297 (0.3%)
Lung abscess	0/287 (0%)		1/297 (0.3%)
Meningitis listeria	0/287 (0%)		1/297 (0.3%)
Osteomyelitis	1/287 (0.3%)		1/297 (0.3%)
Pancreatic abscess	1/287 (0.3%)		0/297 (0%)
Pneumonia	38/287 (13.2%)		27/297 (9.1%)
Pneumonia bacterial	1/287 (0.3%)		1/297 (0.3%)
Pneumonia cryptococcal	1/287 (0.3%)		0/297 (0%)
Pneumonia haemophilus	0/287 (0%)		2/297 (0.7%)
Pneumonia necrotising	1/287 (0.3%)		0/297 (0%)
Pneumonia pneumococcal	0/287 (0%)		1/297 (0.3%)
Pneumonia pseudomonal	1/287 (0.3%)		1/297 (0.3%)
Pneumonia staphylococcal	1/287 (0.3%)		0/297 (0%)
Pneumonia streptococcal	0/287 (0%)		2/297 (0.7%)
Post procedural infection	0/287 (0%)		1/297 (0.3%)
Sepsis	3/287 (1%)		4/297 (1.3%)
Septic shock	0/287 (0%)		3/297 (1%)
Staphylococcal bacteraemia	1/287 (0.3%)		0/297 (0%)
Tracheobronchitis	1/287 (0.3%)		0/297 (0%)
Urinary tract infection	5/287 (1.7%)		6/297 (2%)
Urosepsis	0/287 (0%)		1/297 (0.3%)
Vaccine breakthrough infection	1/287 (0.3%)		0/297 (0%)
Injury, poisoning and procedural complications
Accidental overdose	1/287 (0.3%)		0/297 (0%)
Arterial injury	0/287 (0%)		1/297 (0.3%)
Endotracheal intubation complication	0/287 (0%)		1/297 (0.3%)
Fall	1/287 (0.3%)		1/297 (0.3%)
Feeding tube complication	1/287 (0.3%)		1/297 (0.3%)
Heat stroke	0/287 (0%)		1/297 (0.3%)
Iatrogenic injury	1/287 (0.3%)		0/297 (0%)
Intentional overdose	1/287 (0.3%)		0/297 (0%)
Joint injury	1/287 (0.3%)		0/297 (0%)
Overdose	0/287 (0%)		1/297 (0.3%)
Procedural complication	0/287 (0%)		2/297 (0.7%)
Procedural hypotension	0/287 (0%)		1/297 (0.3%)
Procedural pneumothorax	0/287 (0%)		1/297 (0.3%)
Pubis fracture	0/287 (0%)		1/297 (0.3%)
Rib fracture	1/287 (0.3%)		0/297 (0%)
Toxicity to various agents	1/287 (0.3%)		1/297 (0.3%)
Tracheostomy malfunction	0/287 (0%)		1/297 (0.3%)
Wound complication	0/287 (0%)		1/297 (0.3%)
Investigations
Blood creatinine increased	0/287 (0%)		1/297 (0.3%)
Laboratory test abnormal	1/287 (0.3%)		0/297 (0%)
Transaminases increased	0/287 (0%)		1/297 (0.3%)
Metabolism and nutrition disorders
Decreased appetite	0/287 (0%)		1/297 (0.3%)
Dehydration	0/287 (0%)		3/297 (1%)
Diabetic complication	1/287 (0.3%)		0/297 (0%)
Diabetic ketoacidosis	1/287 (0.3%)		1/297 (0.3%)
Failure to thrive	0/287 (0%)		1/297 (0.3%)
Fluid overload	1/287 (0.3%)		0/297 (0%)
Hyperglycaemia	1/287 (0.3%)		2/297 (0.7%)
Hyperkalaemia	1/287 (0.3%)		1/297 (0.3%)
Hyperosmolar hyperglycaemic state	1/287 (0.3%)		0/297 (0%)
Hypoglycaemia	3/287 (1%)		2/297 (0.7%)
Musculoskeletal and connective tissue disorders
Arthritis	1/287 (0.3%)		0/297 (0%)
Lumbar spinal stenosis	1/287 (0.3%)		0/297 (0%)
Muscular weakness	1/287 (0.3%)		1/297 (0.3%)
Musculoskeletal chest pain	0/287 (0%)		1/297 (0.3%)
Osteoarthritis	1/287 (0.3%)		0/297 (0%)
Osteonecrosis	1/287 (0.3%)		0/297 (0%)
Rhabdomyolysis	1/287 (0.3%)		1/297 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric	0/287 (0%)		1/297 (0.3%)
Bladder neoplasm	1/287 (0.3%)		0/297 (0%)
Bronchial carcinoma	0/287 (0%)		1/297 (0.3%)
Chronic lymphocytic leukaemia	0/287 (0%)		1/297 (0.3%)
Lung adenocarcinoma	1/287 (0.3%)		1/297 (0.3%)
Lung neoplasm malignant	0/287 (0%)		1/297 (0.3%)
Myelodysplastic syndrome	0/287 (0%)		1/297 (0.3%)
Oesophageal carcinoma	1/287 (0.3%)		0/297 (0%)
Plasma cell myeloma	0/287 (0%)		1/297 (0.3%)
Prostate cancer metastatic	1/287 (0.3%)		0/297 (0%)
Squamous cell carcinoma of lung	1/287 (0.3%)		0/297 (0%)
Tonsil cancer	1/287 (0.3%)		0/297 (0%)
Nervous system disorders
Amyotrophic lateral sclerosis	1/287 (0.3%)		0/297 (0%)
Basal ganglia stroke	1/287 (0.3%)		0/297 (0%)
Carotid artery aneurysm	1/287 (0.3%)		0/297 (0%)
Carotid artery stenosis	0/287 (0%)		1/297 (0.3%)
Cerebral ischaemia	1/287 (0.3%)		0/297 (0%)
Cerebrovascular accident	3/287 (1%)		6/297 (2%)
Hypoxic-ischaemic encephalopathy	0/287 (0%)		2/297 (0.7%)
Myoclonic epilepsy	0/287 (0%)		1/297 (0.3%)
Myxoedema coma	0/287 (0%)		1/297 (0.3%)
Parkinson's disease	0/287 (0%)		2/297 (0.7%)
Seizure	2/287 (0.7%)		0/297 (0%)
Status epilepticus	1/287 (0.3%)		0/297 (0%)
Syncope	0/287 (0%)		2/297 (0.7%)
Vascular dementia	1/287 (0.3%)		0/297 (0%)
Product Issues
Unintentional medical device removal	1/287 (0.3%)		0/297 (0%)
Psychiatric disorders
Alcohol abuse	1/287 (0.3%)		0/297 (0%)
Alcohol withdrawal syndrome	1/287 (0.3%)		0/297 (0%)
Delirium	3/287 (1%)		4/297 (1.3%)
Delirium tremens	1/287 (0.3%)		1/297 (0.3%)
Drug abuse	0/287 (0%)		1/297 (0.3%)
Drug dependence	1/287 (0.3%)		0/297 (0%)
Mental status changes	4/287 (1.4%)		1/297 (0.3%)
Substance-induced psychotic disorder	0/287 (0%)		1/297 (0.3%)
Suicidal ideation	2/287 (0.7%)		2/297 (0.7%)
Renal and urinary disorders
Acute kidney injury	6/287 (2.1%)		11/297 (3.7%)
Chronic kidney disease	0/287 (0%)		1/297 (0.3%)
End stage renal disease	0/287 (0%)		3/297 (1%)
Glomerulonephritis rapidly progressive	0/287 (0%)		1/297 (0.3%)
Nephrolithiasis	1/287 (0.3%)		0/297 (0%)
Pulmonary renal syndrome	0/287 (0%)		1/297 (0.3%)
Renal failure	1/287 (0.3%)		1/297 (0.3%)
Urinary retention	1/287 (0.3%)		1/297 (0.3%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/287 (0.3%)		0/297 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	3/287 (1%)		4/297 (1.3%)
Acute respiratory failure	0/287 (0%)		3/297 (1%)
Alveolitis allergic	0/287 (0%)		1/297 (0.3%)
Aspiration	1/287 (0.3%)		0/297 (0%)
Bronchial secretion retention	1/287 (0.3%)		0/297 (0%)
Bronchospasm	1/287 (0.3%)		0/297 (0%)
Chronic obstructive pulmonary disease	16/287 (5.6%)		11/297 (3.7%)
Dyspnoea	0/287 (0%)		2/297 (0.7%)
Haemoptysis	1/287 (0.3%)		1/297 (0.3%)
Haemothorax	0/287 (0%)		1/297 (0.3%)
Hypoventilation	0/287 (0%)		1/297 (0.3%)
Hypoxia	1/287 (0.3%)		1/297 (0.3%)
Increased bronchial secretion	1/287 (0.3%)		0/297 (0%)
Interstitial lung disease	2/287 (0.7%)		3/297 (1%)
Lung infiltration	1/287 (0.3%)		0/297 (0%)
Organising pneumonia	1/287 (0.3%)		2/297 (0.7%)
Pickwickian syndrome	0/287 (0%)		1/297 (0.3%)
Pleural effusion	4/287 (1.4%)		2/297 (0.7%)
Pleuritic pain	1/287 (0.3%)		0/297 (0%)
Pneumonia aspiration	8/287 (2.8%)		5/297 (1.7%)
Pneumonitis	0/287 (0%)		1/297 (0.3%)
Pneumothorax	2/287 (0.7%)		3/297 (1%)
Pulmonary embolism	6/287 (2.1%)		5/297 (1.7%)
Pulmonary fibrosis	1/287 (0.3%)		0/297 (0%)
Pulmonary hypertension	0/287 (0%)		1/297 (0.3%)
Pulmonary oedema	1/287 (0.3%)		2/297 (0.7%)
Respiratory arrest	0/287 (0%)		2/297 (0.7%)
Respiratory failure	8/287 (2.8%)		9/297 (3%)
Sleep apnoea syndrome	1/287 (0.3%)		0/297 (0%)
Skin and subcutaneous tissue disorders
Diabetic foot	0/287 (0%)		1/297 (0.3%)
Surgical and medical procedures
Medical device battery replacement	1/287 (0.3%)		0/297 (0%)
Rehabilitation therapy	0/287 (0%)		2/297 (0.7%)
Withdrawal of life support	0/287 (0%)		1/297 (0.3%)
Vascular disorders
Aortic aneurysm	0/287 (0%)		1/297 (0.3%)
Aortic stenosis	0/287 (0%)		1/297 (0.3%)
Arterial thrombosis	1/287 (0.3%)		0/297 (0%)
Arteriosclerosis	1/287 (0.3%)		0/297 (0%)
Deep vein thrombosis	2/287 (0.7%)		1/297 (0.3%)
Dry gangrene	1/287 (0.3%)		0/297 (0%)
Haematoma	1/287 (0.3%)		0/297 (0%)
Hypertension	1/287 (0.3%)		0/297 (0%)
Hypertensive crisis	0/287 (0%)		1/297 (0.3%)
Hypertensive emergency	1/287 (0.3%)		0/297 (0%)
Hypotension	1/287 (0.3%)		1/297 (0.3%)
Orthostatic hypotension	0/287 (0%)		3/297 (1%)
Shock	2/287 (0.7%)		0/297 (0%)
Other (Not Including Serious) Adverse Events
	Arm 1: Inactive Substance		Arm 2: Methylprednisolone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.