Steroids in Patients With Early ARDS

NCT00562835 | Unknown Phase 2

• 1 other identifier: Prot.cm.P662(A.1552)/C.E./2007
• Study Type: interventional
• Target: 400
• Locations: 1 country
• Sites: 1

Brief Summary

Scientific background. Dysregulated systemic inflammation is a key pathogenetic mechanism for morbidity and mortality in ALI/ARDS, and is associated with tissue insensitivity and/or resistance to inappropriately elevated endogenous glucocorticoids. In one study, prolonged methylprednisolone treatment of ARDS patients resulted in rapid and sustained reduction in circulating and pulmonary levels of pro-inflammatory cytokines, chemokines, and procollagen. Preliminary work. Five randomized trials (N = 518) investigating prolonged glucocorticoid treatment in acute lung injury/ARDS reported a significant physiological improvement and a sizable reduction in duration of mechanical ventilation and ICU length of stay. Insufficient data is available on the effects of low dose prolonged methylprednisolone treatment initiated in early ALI/ARDS on mortality. Hypothesis. We hypothesized that the anti-inflammatory activity associated with prolonged methylprednisolone administration improves pulmonary and extra-pulmonary organ dysfunction in early ALI/ARDS and reduces mortality. Objective. To investigate the effects of prolonged low-dose methylprednisolone infusion on mortality and morbidity in early ALI/ARDS. Study design. Multicenter, prospective randomized, placebo-controlled, double-blind clinical trial. Entry criteria. Patients with ALI/ARDS of less than 72 hours duration. Stratification. Patients are prospectively stratified prior to randomization as (1) intubated versus NPPV treated, and (2) ARDS versus severe ARDS. The purpose of stratification is to distribute equally in both arms intubated versus NPPV treated, and ARDS versus severe ARDS. End-points. The primary end-point of trial is 28 days all cause mortality; the secondary end-points are (a) ventilator-free days at 28 days following study entry, (b) organ failure-free days at 28 days following study entry, and (c) duration of ICU stay.

Conditions

Acute Lung Injury; ARDS, Human

Keywords

ARDS; Adult; Methylprednisolone

Outcome Measures

Primary Outcomes (1)

• The primary aim is to determine if low-dose methylprednisolone infusion, compared to placebo, will reduce all cause 28-day mortality, defined as the proportion of patients alive in each group on study day 28 at midnight.

  one year

Secondary Outcomes (1)

• The secondary aims are the effects of treatment on: a. Systemic inflammation b. Duration of mechanical ventilation c. Multiple organ dysfunction syndrome d. Duration of ICU and hospital stay e. Cardiovascular morbidity-mortality f. Complications

  one year

Study Arms (2)

1

ACTIVE COMPARATOR

Methylprednisolone

Drug: Methylprednisolone

2

PLACEBO COMPARATOR

Other: Normal saline intravenously and vitamin B1 per os

Interventions

Methylprednisolone DRUG

Drug: Methylprednisolone Day 0 Loading dose 1 mg/kg IV bolus (30 min) followed by continuous infusion; Days 0 to 14\*† ‡ 1 mg/kg/day mixed in 240cc Normal saline (NS) and infused at 10 cc/hr; Days 15 to 21\*‡ 0.5 mg/kg/day mixed in 240cc NS and infused at 10 cc/hr; Days 22 to 25\*‡ 0.25 mg/kg/day; Days 26 to 28\*‡ 0.125 mg/kg/day \*Five days after the patient is able to ingest medications, methylprednisolone is given per os in one single daily equivalent dose. †If between days 1 to 14 the patient is extubated, he is advanced to day 15 of drug therapy and tapered according to schedule. ‡ When leaving ICU, if the patient is still not tolerating p.o. intake for at least five days, he should receive the specified dosage as IV push every 6 hours until tolerating oral ingestion

1

Normal saline intravenously and vitamin B1 per os OTHER

Patients in this group will receive sterile normal saline in an amount that would equal the total diluted dose of study drug (ie. if initial loading dose equals a total of 25 cc \[prednisolone + diluting fluid\], then the patient will receive 25 cc of sterile normal saline). Tapering doses will be equivalent to that of the study arm. Five days after the patient is able to ingest medications, placebo is administered per os in one single daily equivalent dose. The placebo will be a Vitamin B1 (thiamine) 50-mg tablet. We will now designate each placebo tab as a 16-mg equivalent to each tablet of active drug. These tablets are scored and half tabs can be given if needed. Therefore if a patient is receiving 40 mg of study drug: 40/16 = 2.5 tabs x 50 mg = 125 mg actual dose of thiamine.

Also known as: Thiamine

2

Eligibility Criteria

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

You may qualify if:

• Age. Patients age 18 years or older admitted to the intensive care unit.
• ALI/ARDS criteria. The diagnosis of ALI/ARDS requires all of the following criteria:
• Respiratory failure requiring mechanical ventilation - via endotracheal intubation or noninvasive positive pressure ventilation
• Acute onset of bilateral pulmonary densities on chest radiograph in the contest of appropriate predisposing injury or illness with no evidence of left ventricular failure,
• Static pulmonary compliance \< 50 cm H2O
• Ratio of partial pressure of arterial oxygen to partial pressure of alveolar oxygen (PaO2:FiO2 ) equal or less than 300 (criteria for ALI) or 200 (criteria for ARDS) with FiO2 1.0.
• Severe ARDS. PaO2:FiO2 equal or less than 200 after 30 minutes of standardized ventilatory management on PEEP of 10 cm H2O with FiO2 1.0.

You may not qualify if:

• Failure to obtain written informed consent from the patient or a next of kin.
• Trauma-induced ARDS.
• Major gastrointestinal bleeding requiring transfusion of 5 units or more of packed red blood cells (PRBC) within 3 months current hospitalization
• Condition requiring \> 0.5mg/Kg/day of prednisone equivalent (i.e., acute asthma or chronic obstructive pulmonary disease \[COPD\])
• Patients enrolled in another experimental (interventional) protocol within the past 30 days, which might adversely impact on the results of this study as determined by the investigators
• Pregnancy confirmed by urine or serum test
• Weight is \> 200% of ideal body weight
• Non-ambulatory resident of long-term care facility
• Primary care physician not committed to full, aggressive support of the patient at the time of randomization
• Moribund patient (i.e., not expected to live more than 24 hr) or with recent (within 7 days or anytime during present hospitalization) cardiopulmonary arrest
• Known or suspected irreversible cessation of all brain function
• Presence of preexisting medical condition which is irreversible and expected to be fatal within 3 months
• Immunosuppression including HIV+ status, history of bone marrow or solid organ transplantation, current malignancy, neutropenia, receiving cytotoxic therapy for any reason, and acute burn injury
• Severe chronic liver disease (Child-Pugh Class C score \> 10 points)

Sponsors & Collaborators

• Catholic University of the Sacred Heart: lead

Study Sites (1)

UCSC, Policlinico Universitario A. Gemelli, ICU

Rome, Rome, 00168, Italy

Location

Related Publications (6)

• Meduri GU, Tolley EA, Chrousos GP, Stentz F. Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids. Am J Respir Crit Care Med. 2002 Apr 1;165(7):983-91. doi: 10.1164/ajrccm.165.7.2106014.

  PMID: 11934726 BACKGROUND

• Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T, Tolley EA. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1998 Jul 8;280(2):159-65. doi: 10.1001/jama.280.2.159.

  PMID: 9669790 BACKGROUND

• Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, Thompson BT, Ancukiewicz M; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006 Apr 20;354(16):1671-84. doi: 10.1056/NEJMoa051693.

  PMID: 16625008 BACKGROUND

• Annane D, Sebille V, Bellissant E; Ger-Inf-05 Study Group. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Crit Care Med. 2006 Jan;34(1):22-30. doi: 10.1097/01.ccm.0000194723.78632.62.

  PMID: 16374152 BACKGROUND

• Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, Della Porta R, Giorgio C, Blasi F, Umberger R, Meduri GU. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med. 2005 Feb 1;171(3):242-8. doi: 10.1164/rccm.200406-808OC. Epub 2004 Nov 19.

  PMID: 15557131 BACKGROUND

• Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, Gibson M, Umberger R. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest. 2007 Apr;131(4):954-63. doi: 10.1378/chest.06-2100.

  PMID: 17426195 RESULT

MeSH Terms

Conditions

Acute Lung Injury; Respiratory Distress Syndrome

Interventions

Methylprednisolone; Thiamine

Condition Hierarchy (Ancestors)

Lung Injury; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders

Intervention Hierarchy (Ancestors)

Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Study Officials

• Massimo Antonelli, MD

  Catholic University of Sacred Heart, Rome

  PRINCIPAL INVESTIGATOR

• Umberto Meduri, MD

  University of Tennessee Health Science Center Memphis, TN, USA

  STUDY DIRECTOR

Central Study Contacts

Massimo Antonelli, MD

CONTACT

0039 06 30151; m.antonelli@rm.unicatt.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: November 21, 2007
• First Posted: November 22, 2007
• Study Start: February 1, 2008
• Study Completion: February 1, 2009
• Last Updated: November 22, 2007

Record last verified: 2007-11

Locations

IT (1)