Ignite Creation Date:
2024-05-05 @ 11:46 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00127985
Status:
UNKNOWN
Last Update Posted:
2008-05-13
First Post:
2005-08-08
Brief Title:
6-Methyl-Prednisolone for Multiple Organ Dysfunction Syndrome
Sponsor:
Hospital Universitario Principe de Asturias
Organization:
Hospital Universitario Principe de Asturias
Study Overview
Official Title:
The Effect of 6-Methyl-Prednisolone on Organ Dysfunction and Mortality of Patients With Unresolving Multiple Organ Dysfunction Syndrome
Status:
UNKNOWN
Status Verified Date:
2008-05
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
NAIF
Brief Summary:
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
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
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 12 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 34
Objectives
To evaluate the safety and effectiveness of a non-selective anti-inflammatory strategy ie 6-methyl-prednisolone on persistent and unresolving inflammatory states ie 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 htppwwwwebnaifcom 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 n20 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 andor 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 mgday of 6-methyl-prednisolone or equivalent for 48 hours
Chronic steroid therapy prior to current admission 20 mg of 6-methyl-prednisolone or equivalentday for 1 month during previous 3 months
2 Other immune-suppressive therapy within the previous 6 months
3 Known AIDS
4 Neutropenia 500mcl
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 placeboaqueous 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 25 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 001 SJ 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 Students t test andor 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 19982802159-65
2 Biffl WL Moore FA Moore EE Haenel JB McIntyre RC Jr Burch JM Are corticosteroids salvage therapy for refractory acute respiratory distress syndrome AmJSurg 19951706591-5
3 Marik PE Zaloga GP Adrenal insufficiency during septic shock Crit Care Med 2003311141-5
4 Loisa P Rinne T Kaukinen S Adrenocortical function and multiple organ failure in severe sepsis Acta AnaesthesiolScand 2002462145-51
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 199523101638-52
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 12 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 34
Objectives
To evaluate the safety and effectiveness of a non-selective anti-inflammatory strategy ie 6-methyl-prednisolone on persistent and unresolving inflammatory states ie 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 htppwwwwebnaifcom 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 n20 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 andor 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 mgday of 6-methyl-prednisolone or equivalent for 48 hours
Chronic steroid therapy prior to current admission 20 mg of 6-methyl-prednisolone or equivalentday for 1 month during previous 3 months
2 Other immune-suppressive therapy within the previous 6 months
3 Known AIDS
4 Neutropenia 500mcl
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 placeboaqueous 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 25 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 001 SJ 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 Students t test andor 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 19982802159-65
2 Biffl WL Moore FA Moore EE Haenel JB McIntyre RC Jr Burch JM Are corticosteroids salvage therapy for refractory acute respiratory distress syndrome AmJSurg 19951706591-5
3 Marik PE Zaloga GP Adrenal insufficiency during septic shock Crit Care Med 2003311141-5
4 Loisa P Rinne T Kaukinen S Adrenocortical function and multiple organ failure in severe sepsis Acta AnaesthesiolScand 2002462145-51
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 199523101638-52
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None