6-Methyl-Prednisolone for Multiple Organ Dysfunction Syndrome (NAIF)

The recruitment status of this study is unknown because the information has not been verified recently.
Verified May 2008 by Hospital Universitario Principe de Asturias.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
Pfizer
Information provided by:
Hospital Universitario Principe de Asturias
ClinicalTrials.gov Identifier:
NCT00127985
First received: August 8, 2005
Last updated: May 12, 2008
Last verified: May 2008
  Purpose

Background: Systemic corticosteroids are considered in patients with an adverse clinical course suffering from conditions like the acute respiratory distress syndrome (ARDS) and septic shock. Treated patients not only show improved respiratory function, but also hemodynamic status and overall multiple organ dysfunction score.

Objective: To evaluate the safety and effectiveness of 6-methyl-prednisolone on the clinical course of multiple organ dysfunction syndrome (MODS).

Design: Multi-center, double-blind, randomized, placebo-controlled.

Intervention: Intravenous administration of 6-methyl-prednisolone or placebo (aqueous solution). The duration of the study medication administration protocol is 32 days (1).

Primary Endpoints:

  1. All cause Intensive Care Unit (ICU) and 28-day mortality
  2. Organ dysfunction score on days 4, 7, 14, and 28 of the protocol.

Condition Intervention Phase
Multiple Organ Dysfunction Syndrome
Drug: 6-methyl-prednisolone
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Effect of 6-Methyl-Prednisolone on Organ Dysfunction and Mortality of Patients With Unresolving Multiple Organ Dysfunction Syndrome

Resource links provided by NLM:


Further study details as provided by Hospital Universitario Principe de Asturias:

Primary Outcome Measures:
  • All cause ICU and 28-day mortality [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  • Organ dysfunction score on days 4, 7, 14, and 28 of the protocol [ Time Frame: Days 4, 7, 14, and 28. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Mortality [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  • Morbidity: Duration of mechanical ventilation and endotracheal intubation (also a surrogate for acute steroid myopathy) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Length of ICU-stay [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  • Complications of steroid therapy [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Infections acquired during the protocol [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Other complications (hyperglycemia, GI bleeding, acute myopathy, pneumothorax) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Adrenal reserve as evaluated by adrenocorticotropic hormone (ACTH) test. [ Time Frame: Baseline ] [ Designated as safety issue: No ]

Estimated Enrollment: 240
Study Start Date: August 2005
Estimated Study Completion Date: July 2008
Estimated Primary Completion Date: July 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Active
IV 6-methyl-prednisolone
Drug: 6-methyl-prednisolone
iv, 2 mg/kg/day, qid
Placebo Comparator: Comparator
IV Placebo
Drug: 6-methyl-prednisolone
iv, 2 mg/kg/day, qid

  Hide Detailed Description

Detailed Description:

Background:

Worldwide intensive care physicians consider administering systemic corticosteroids in patients with an adverse clinical course suffering from conditions like the acute respiratory distress syndrome (ARDS) and septic shock. Data from recent small studies performed in patients with unresolving ARDS (1;2) suggest survival benefits associated with rescue therapy with relatively prolonged courses of corticosteroids. Treated patients not only show improved respiratory function, but also hemodynamic status and overall multiple organ dysfunction score. It has been suggested that that the integrity of the hypothalamic-pituitary-adrenal axis may be impaired in this patient subset (3;4)

Objective(s):

To evaluate the safety and effectiveness of a non-selective anti-inflammatory strategy, i.e. 6-methyl-prednisolone, on persistent and unresolving inflammatory states, i.e. multiple organ dysfunction syndrome, on the degree of organ dysfunction and mortality.

Design:

Multi-center, double-blind, randomized, placebo-controlled. Randomization and data entry is internet based (htpp://www.webnaif.com). Patients will be randomized through a computer-generated random-number table and stratified by center in blocs of 6. Sample size, by group 120 patients. The study is powered to detect a 20% reduction in mortality, from 50% to 30% in 100 patients per study group at the 5% significance level with a power of 80%. An additional 20% (n=20) per group have been planned to compensate for losses.

Main Inclusion Criteria:

  • Patients with established, unresolving, refractory MODS, in whom all reversible and treatable causes of persistent MODS have been treated or ruled out.
  • Patients under endotracheal intubation and mechanical ventilation for at least 7 days.
  • Aggregate Multiple Organ Dysfunction Score (5) of greater than 8 over the first seven days of mechanical ventilation and greater than 5 on the day of inclusion.
  • Written informed consent to participate in the trial signed by next of kin or other authorized person.

Additional Inclusion Criteria:

  • Main cause or disease at admission: Adequate "source control" is required and refers to optimal, complete, and definitive surgical and/or medical therapy.
  • Infections:

    1. Infectious causes of persistence of MODS have reasonably been ruled out on clinical or other grounds (infectious endocarditis, undrained abscesses like sinusitis, empyema or abdominal pus). Consider sampling for culture of broncho-alveolar lavage fluid, protected specimen brush or other (empyema fluid, lung tissue) in order to rule out respiratory infection, as well as intra-vascular catheter change and culture.
    2. Present or previous infections, either documented or strongly suspected, have been treated for at least 3 days before inclusion.
  • Supportive Care: Optimal hemodynamic, renal, hematologic, nutritional "supportive care" is provided.

Exclusion Criteria:

  • Decision not to provide full support.
  • Immune status and steroid therapy.

    1. Steroid therapy

      • Currently indicated for chronic or concurrent disease (meningitis, auto-immune disease, asthma, acute exacerbation of COPD, or other). Inhaled steroids are allowed.
      • Administered during current admission (> 20 mg/day of 6-methyl-prednisolone or equivalent for >48 hours).
      • Chronic steroid therapy prior to current admission (> 20 mg of 6-methyl-prednisolone or equivalent/day for > 1 month during previous 3 months).
    2. Other immune-suppressive therapy within the previous 6 months.
    3. Known AIDS.
    4. Neutropenia < 500/mcl.
    5. Preceding organ transplantation.
  • Irreversible and or ultimately fatal clinical conditions like metastatic malignant disease or cardiogenic shock caused by coronary artery disease.
  • Presence of invasive fungal infection
  • Other significant pre-existing underlying chronic diseases:

    1. Severe parenchymal liver disease (Child-Pugh grade C)
    2. Severe and irreversible acute or chronic central nervous system disease.
    3. Severe end-stage chronic obstructive pulmonary disease (home oxygen or more than 1 exacerbation in previous year)
    4. End-stage renal disease (Chronic dialysis).
  • Age less than 18 years.
  • Pregnancy.
  • Morbid obesity: body mass index above 40.
  • Recent (last 3 months) upper GI hemorrhage.
  • Extensive burns (>30% BSA)
  • Known allergy to steroids.
  • Written informed consent not available.

Intervention:

Intravenous administration of 6-methyl-prednisolone or placebo(aqueous solution). The duration of the study medication administration protocol is 32 days (1):

  • Initial iv loading dose of 160 mg.
  • An iv bolus injection of 6-methyl-prednisolone is administered every 6 hours:

    1. 40 mg on days 1 to 14,
    2. 20 mg on days 15 to 21,
    3. 10 mg on days 22 to 28,
    4. 5 mg on days 29 and 30, and
    5. 2.5 mg on days 31 and 32.

Informed consent form and information sheet have been reviewed and approved by the regional Ethics Committee of Madrid (10 centres), the local review boards of the other participating centres, and the Agencia Española del Medicamento (Spanish Ministry of Health).

Ethical Approval:

The study protocol has been approved by the regional Ethics Committee of Madrid (10 centres), the local review boards of the other participating centres, and the Agencia Española del Medicamento (Spanish Ministry of Health).

Stopping Rules:

The independent Data Monitoring Committee (DMC) will have real-time access to the main variable "28-day mortality" (and allocation to study group "A" or "B") and will propose premature interruption of the trial based on sequential analysis if significant differences become apparent. The DMC will perform 5 interim analysis, one every 48 included patients and the criterium used will be a statistically significant difference at the level of p < 0,01 (S.J. Pocock. Clinical Trials. A practical Approach. John Wiley & Sons. New York. 1994).

Primary Endpoints:

  1. All cause ICU and 28-day mortality
  2. Organ dysfunction score on days 4, 7, 14, and 28 of the protocol.

Planned Subgroup Analysis:

No subgroup analysis are planned.

Side-effects Quantification:

The investigators will use the NIH Toxicity Form with a scale from 1 to 5. Severe adverse events in this severely ill population are precisely defined and require immediate (less than 24 hours) communication to the study website. The DMC will have access to the variables that define and describe the SAEs.

Analysis Plan:

Main comparisons are 28-day and ICU mortality between study groups (chi square test for percentages and log-rank test Kaplan-Meier survival curves. Multiple organ dysfunction score and Sequential Organ Failure Assessment score will be compared at baseline and on days 4, 7, 14 and 28 (Student's t test and/or non-parametric tests). Independent risk factors for mortality will be studied by multivariate analysis (Cox regression) of significant comparisons of the univariate analysis. Analysis sample according to the principle of intention to treat.

Finishing Date:

The finishing date is 18 months after the first inclusion at each centre. Scheduled beginning of the trial is August 2005

Reporting Date:

First trimester 2007.

A large study like the present trial is required to obtain definitive data about safety and effectiveness of 6-methyl-prednisolone administered as rescue therapy in patients with the multiple organ dysfunction syndrome.

Reference List

  1. Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA 1998;280(2):159-65.
  2. Biffl WL, Moore FA, Moore EE, Haenel JB, McIntyre RC, Jr., Burch JM. Are corticosteroids salvage therapy for refractory acute respiratory distress syndrome? Am.J.Surg. 1995;170(6):591-5.
  3. Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med. 2003;31(1):141-5.
  4. Loisa P, Rinne T, Kaukinen S. Adrenocortical function and multiple organ failure in severe sepsis. Acta Anaesthesiol.Scand. 2002;46(2):145-51.
  5. Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med. 1995;23(10):1638-52.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Main Inclusion Criteria:

Patients with established, unresolving, refractory MODS, in whom all reversible and treatable causes of persistent MODS have been treated or ruled out:

  • Patients under endotracheal intubation and mechanical ventilation for at least 7 days.
  • Aggregate Multiple Organ Dysfunction Score (5) of greater than 8 over the first seven days of mechanical ventilation and greater than 5 on the day of inclusion.
  • Written informed consent to participate in the trial signed by next of kin or other authorized person.

Additional Inclusion Criteria:

  • Main cause or disease at admission: Adequate "source control" is required and refers to optimal, complete, and definitive surgical and/or medical therapy.
  • Infections:

    1. Infectious causes of persistence of MODS have reasonably been ruled out on clinical or other grounds (infectious endocarditis, undrained abscesses like sinusitis, empyema or abdominal pus). Consider sampling for culture of broncho-alveolar lavage fluid, protected specimen brush or other (empyema fluid, lung tissue) in order to rule out respiratory infection, as well as intra-vascular catheter change and culture.
    2. Present or previous infections, either documented or strongly suspected, have been treated for at least 3 days before inclusion.
  • Supportive Care: Optimal hemodynamic, renal, hematologic, nutritional "supportive care" is provided.

Exclusion Criteria:

  • Decision not to provide full support.
  • Immune status and steroid therapy.

    1. Steroid therapy

      • Currently indicated for chronic or concurrent disease (meningitis, auto-immune disease, asthma, acute exacerbation of chronic obstructive pulmonary disease [COPD], or other). Inhaled steroids are allowed.
      • Administered during current admission (> 20 mg/day of 6-methyl-prednisolone or equivalent for >48 hours).
      • Chronic steroid therapy prior to current admission (> 20 mg of 6-methyl-prednisolone or equivalent/day for > 1 month during previous 3 months).
    2. Other immune-suppressive therapy within the previous 6 months.
    3. Known AIDS.
    4. Neutropenia < 500/mcl.
    5. Preceding organ transplantation.
  • Irreversible and or ultimately fatal clinical conditions like metastatic malignant disease or cardiogenic shock caused by coronary artery disease.
  • Presence of invasive fungal infection
  • Other significant pre-existing underlying chronic diseases:

    1. Severe parenchymal liver disease (Child-Pugh grade C)
    2. Severe and irreversible acute or chronic central nervous system disease.
    3. Severe end-stage chronic obstructive pulmonary disease (home oxygen or more than 1 exacerbation in previous year)
    4. End-stage renal disease (Chronic dialysis).
  • Age less than 18 years.
  • Pregnancy.
  • Morbid obesity: body mass index above 40.
  • Recent (last 3 months) upper gastrointestinal [GI] hemorrhage.
  • Extensive burns (>30% body surface area [BSA])
  • Known allergy to steroids.
  • Written informed consent not available.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00127985

Contacts
Contact: Miguel Sanchez, MD, PhD 34-91-887-8100 ext 2205 miguelsanchez.areachip@wanadoo.es

Locations
Spain
Hospital Principe de Asturias Recruiting
Alcala de Henares, Madrid, Spain, 28805
Contact: Raul De Pablo    34-91-8871-8100 ext 2205    rdepablosanchez@yahoo.es   
Principal Investigator: Raul De Pablo, MD         
Hospital Clinic Recruiting
Barcelona, Spain
Contact: Antoni Torres, MD, PhD         
Principal Investigator: Antoni Torres, MD, PhD.         
Sub-Investigator: Juan Ramón Badía, MD, PhD         
Hospital Universitario de la Princesa Recruiting
Madrid, Spain, 28006
Contact: Antonio Reyes, MD., PhD.    34-91-520-2200    Areyes.hlpr@salud.madrid.org   
Contact: Fernando Lopez, MD., PhD.    34-91-520-2200    fld@inicia.es   
Principal Investigator: Antonio Reyes, MD., PhD.         
Sub-Investigator: Fernando - Lopez, MD, PhD         
Francisco Ortuño Anderiz Recruiting
Madrid, Spain, 28040
Contact: Francisco - Ortuño Anderiz, MD    34-91-330-3223    portunoa@yahoo.es   
Sub-Investigator: Fernando - Martinez Sagasti, MD, PhD         
Clinica Moncloa Recruiting
Madrid, Spain
Contact: Manuel Alvarez, MD, PhD.         
Contact: Juan Jose Oñoro, MD         
Principal Investigator: Manuel Alvarez, MD, PhD         
María Mar Cruz Acuaroni Recruiting
Toledo, Spain, 45004
Contact: Maria Mar - Cruz Acuaroni, MD    34-925-26-9237    mdelca@sescam.jccm.es   
Contact: Maria José - Pérez Pedrero, MD    34-925-26-9237      
Principal Investigator: Maria Mar - Cruz Acuaroni, MD         
Sub-Investigator: Maria Jose - Perez Pedrero, MD         
Sponsors and Collaborators
Hospital Universitario Principe de Asturias
Pfizer
Investigators
Study Chair: Miguel Sanchez, MD, PhD Hosp. Univ. Principe de Asturias
  More Information

Publications:
Responsible Party: Miguel Sanchez Garcia, MD, PhD, Hospital Principe de Asturias
ClinicalTrials.gov Identifier: NCT00127985     History of Changes
Other Study ID Numbers: NAIF6MPMODS088UNK9071296
Study First Received: August 8, 2005
Last Updated: May 12, 2008
Health Authority: Spain: Ministry of Health

Keywords provided by Hospital Universitario Principe de Asturias:
multiple organ dysfunction syndrome
corticosteroids
mortality

Additional relevant MeSH terms:
Syndrome
Multiple Organ Failure
Disease
Pathologic Processes
Shock
Methylprednisolone acetate
Prednisolone acetate
Prednisolone
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Gastrointestinal Agents
Neuroprotective Agents
Protective Agents

ClinicalTrials.gov processed this record on October 19, 2014