Ignite Creation Date:
2024-05-05 @ 11:52 AM
Last Modification Date:
2024-10-26 @ 9:15 AM
Study NCT ID:
NCT00159952
Status:
COMPLETED
Last Update Posted:
2013-11-27
First Post:
2005-09-07
Brief Title:
Effect of Hyperglycemia in PAI-1 Activity and the Relationship With Outcome in Severe Sepsis and Septic Shock
Sponsor:
Policlinico Hospital
Organization:
Policlinico Hospital
Study Overview
Official Title:
Effect of Hyperglycemia in PAI-1 Activity and the Relationship With Outcome in Severe Sepsis and Septic Shock
Status:
COMPLETED
Status Verified Date:
2009-02
Last Known Status:
None
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:
None
Brief Summary:
The purpose of this study is to determine the effect of the intensive insulin therapy on coagulation and fibrinolysis in patients affected by severe sepsis and septic shock As a secondary endpoints the investigators will determine the effect of intensive insulin therapy on organ dysfunction and mortality of these patients
Detailed Description:
BACKGROUND
The treatment of the sepsis can be done at three different level
1 Etiologic therapy The eradication of the infectious agent is the primary end-point An appropriate surgical treatment and antibiotic therapy are the key of the etiologic therapy
2 Symptomatic therapy It is the traditional approach in the Intensive Care Unit It involves to correct the symptomatic issues that can lead to the death of the patients buying the time necessary for the action of the etiologic and the pathogenic therapy The key point of the symptomatic therapy are a an adequate expansion of the volemia and the use of cardiovascular-acting drugs for the maintenance of an adequate cardiocirculatory homeostasis Recently it has been demonstrated that an early aggressive haemodynamic therapy direct to maintain a mixed venous Oxygen Saturation above 70 improved the mortality compared with a standard approach 3 b apply a mechanical ventilation adequate for the maintenance of the respiratory homeostasis In fact it has been recently shown an increased survival rate in patients treated with low tidal volume ventilation strategy compared to standard strategy
3 Pathogenic therapy It consists to block the inflammatory andor coagulation pathway at different level In the last 30 years a number of report studied different approach anti-endotoxin antibodies anti-TNF antibodies anti-IL6 antibodies treatment with high doses of corticosteroid etc While all these approaches showed an efficacy in experimental settings when given preventively most of them have no effect in phase 3 clinical trial This discrepancy may be explained considering 1 the system can be considered chaotic with riddance and interdependency of the response 2 in the clinical studies the treatment was applied after the development of the sepsis when the inflammatory and coagulation systems are still largely activated
Three study has recently demonstrated a benefit in survival
1 The treatment with low-dosage corticosteroids in patients non-responders to ACH stimulation test 5 This is a substitutive therapy It is important to note that the treatment with high dosage corticosteroids to block completely the inflammatory response is not effective 6
2 The treatment with recombinant activated Protein C 7 did increased the relative survival rate by 20 Of note the activated Protein C is the only molecule with three main mechanisms of action anticoagulatory antiinflammatory and profibrinolytic
3 In a recent study in post-surgical patients it has been shown a significant improvement in survival in patients treated with a a tight glycemic control within 80 and 110 mgdL compared to those in which the glycemia was corrected only when reaching higher level 215 mgdL 8We still lack a definitive explanation for these findings and the discussion is mainly on the relative roles of glycemia per se versus insulin therapy per se
However looking at the overall scenario some issues are of note
1 We know that a complete block of the inflammatory reaction or a complete block of the coagulation cascade do not improve outcome in septic patients
2 The activated Protein C is the molecule with the highest spectrum of action in particular is the only molecule within the numerous molecules tested with pro-fibrinolytic activity
3 We know that higher glycemia per se does greatly increase the PAI production the molecule which inhibits the fibrinolysis
4 The septic patients primarily die because of multiple organ dysfunction which is in part due to a widespread microthrombosis
A possible unifying hypothesis is that the improved outcome observed with activate Protein C and with the tight glycemic control is due to the maintenance of a physiologic fibrinolysis This hypothesis has never been tested and if proved could open interesting therapeutical approaches in the septic patients exposed to the high mortality risk
OBJECTIVES The primary end-point is the evaluation of the activationdeactivation of the fibrinolytic system in the two-randomization groups
STUDY DESIGN This study is a multicenter randomized Phase 23 study of adult patients with severe sepsis and septic shock We will enroll a total of approximately 80 adult patients
TREATMENTS ADMINISTERED
1 Control glycemia will be controlled with insulin administration when higher than 215 mgdL
2 Treatment glycemia will be controlled with be controlled with insulin administration when higher than 110 mgdL
RANDOMIZATION The patients enrolled will undergo a block-randomization by center in two arms and stratified according to the clinical decision of the caring physician to use or not use the activated Protein C
DATA COLLECTION The clinical variables and the biochemical variables of fibrinolysis coagulation contact phase and pro-inflammatory cytokines will be recorded daily for the first 7 days each second day until the 14 days and the each fifth until the end of the study 28th day or dimissiondeath if before
At BaselineDemographic data
Every 24 hours
1 Simplified Acute Physiology Score II SAPS II 9 The Simplified Acute Physiology Score assesses the severity of illness on the basis of 12 physiological variables age the type of admission urgent or nonurgent and 3 variables related to the underlying disease Scores can range from 0 to 194 higher scores are correlated with a higher risk of death during hospitalization
2 SOFA Sepsis-related Organ Failure Assessment 10 It is an index of multi-organ dysfunction range 0-24
3 Ramsey scale 11 It is an index of level of sedation range 1-6
4 Respiratory circulatory and biochemical of variables for monitoring the organs dysfunction 4
The main biochemical variables collected are
Fibrinolytic system
1 PAI-1 activity
2 PAI- 1 antigen
3 tPA antigen
4 Plasmin-antiplasmin complex PAP
5 D-Dimer fragment
6 Polymorphism 4G5 of the PAI-1 gene
Final phase pf the coagulation pathway
1 Thrombin-antithrombin complex TAT
2 Prothrombin fragment F1 2
Contact system
1 Activated Factor XII FXIIa
2 Metabolism of endogenous bradykinin
3 Polymorphism insertiondeletion of the gene of angiotensin converting enzyme
Inflammation
1 C reactive protein CRP
2 Interleukin-6 IL-6
3 Tumor necrosis factor TNF
4 C3a
5 SC5b-9
SAFETY ASPECTS AND SEVERE ADVERSE EVENTS SAE REPORTING GCP rules will be strictly applied including timely reporting to the study coordination within 48 hours from their occurrence of the SAEs not included in the efficacy end-points Clinical investigators and nurses of each of the participating centers will be instructed to monitor specifically and to document the adverse events more likely to be associated with the study treatment
STATISTICAL ASPECTS we plan to enroll 80 septic patients in the ICU related with the participating research units This size will allow showing an average difference of 30 of fibrinolysis biochemical parameters alfa 005 1-beta 080
ADMINISTRATIVE LEGAL ETHICAL ISSUES This study is designed by our collaborative group which has been active over the last ten years in conducting clinical trials in intensive care The study has been planned and is managed independently and the clinicians who take active part in the study do not receive economic incentives The Ely Lilly Italia Spa will provide a financial support for performing the laboratory tests required in studying the fibrinolysis It is important to emphasize that we are comparing the effects of two different strategies of glycemic control on the fibrinolysis The Ely Lilly interest in the study is only scientific as if we could show the importance of the fibrinolysis in sepsis this could elucidate one of the putative mechanisms of activated Protein C action This study is also partially funded by a grant of the Ministry of University and research COFIN 2004
The data which are produced belong to the study group who ensures their publication and their availability for public authorities
All data related to the patients included in the study are treated in strict compliance with the Italian Laws related to privacy 6751996
The informed consent for the patients will be administered as soon as and every time the clinical conditions of the same patients are compatible with the procedure thus following the provisions set forth by the ICH-GCP guidelines 13 and confirmed by the most recent European Directive 200120CE Decreto Legislativo 211 24062003 It is worth recalling that there is no legal basis for requiring the consent to a relative of the patient
REFERENCES
1 Gattinoni L Vagginelli F Taccone P Carlesso E Bertoja E Sepsis state of the art Minerva Anestesiologica 2003 69 17-28
2 Salvo I de Cian W Musico M Langer M Piadina R Wolfer A et al The Italian SEPSIS study preliminary results on the incidence and evolution of SIRS sepsis severe sepsis and septic shock Intensive Care Medicine 1995 21 Suppl 2S244-249
3 Rivers E Nguyen B Havstad S Ressler J Muzzin A Knoblich B et al Early goal-directed therapy in the treatment of severe sepsis and septic shock The New England Journal of Medicine 2001 345 1368-1377
4 Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome The New England Journal of Medicine 2000 342 1301-1308
5 Annane D Sibille V Charpentier C Bollaert PE Francois B Korach JM et al Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock JAMA 2002 288 862-871
6 Bone RC Fischer CJJ Clemer TP Slotman GJ Metz CA Balk RA A controlled clinical trial of high-dose methyl-prednisolone in the treatment of severe sepsis and septic shock The New England Journal of Medicine 1987 317 653-658
7 Bernard GR Vincent JL Laterre PF La Rosa SP Dhainaut JF Lopez-Rodriguez A et al Efficacy and safety of recombinant human activated protein C for severe sepsis The New England Journal of Medicine 2001 344699-709
8 Van de Berghe G Wouters P Weekers F Verwaest C Brunynckx F Schets M et al Intensive insulin therapy in the critically ill patients New Engl j med 2001 3451359-1367
9 Knaus WA Draper EA Wagner DP Zimmerman JE APACHE II a severity of disease classification system Crit Care Med 1985 13 818-829
10 Vincent JL de Mendonca A Contraine F Moreno R Takala J Suter PM Sprung CL Colardyn F Blecher S Use of the SOFA score to assess the incidence of organ dysfunctionfailure in intensive care units results of a multicenter prospective study Working group on sepsis-related problems of the European Society of Intensive Care Medicine Crit Care Med 1998 261793-800
11 Ramsay MAE Savege TM Simpson BRJ et al Controlled sedation with alphaxalone-alphadolone Br Med J 1974 2 656-659
12 Dhainaut JF Yan SB Cariou A Mira JP Soluble thrombomodulin plasma-derived unactivated protein C and recombinant human activated protein C in sepsis Crit Care Med 2002 May 30 5 Suppl S318-24
13 Guidelines for Good Clinical Practice par 48 ICH Steering Committee meeting 1 May 1996
The treatment of the sepsis can be done at three different level
1 Etiologic therapy The eradication of the infectious agent is the primary end-point An appropriate surgical treatment and antibiotic therapy are the key of the etiologic therapy
2 Symptomatic therapy It is the traditional approach in the Intensive Care Unit It involves to correct the symptomatic issues that can lead to the death of the patients buying the time necessary for the action of the etiologic and the pathogenic therapy The key point of the symptomatic therapy are a an adequate expansion of the volemia and the use of cardiovascular-acting drugs for the maintenance of an adequate cardiocirculatory homeostasis Recently it has been demonstrated that an early aggressive haemodynamic therapy direct to maintain a mixed venous Oxygen Saturation above 70 improved the mortality compared with a standard approach 3 b apply a mechanical ventilation adequate for the maintenance of the respiratory homeostasis In fact it has been recently shown an increased survival rate in patients treated with low tidal volume ventilation strategy compared to standard strategy
3 Pathogenic therapy It consists to block the inflammatory andor coagulation pathway at different level In the last 30 years a number of report studied different approach anti-endotoxin antibodies anti-TNF antibodies anti-IL6 antibodies treatment with high doses of corticosteroid etc While all these approaches showed an efficacy in experimental settings when given preventively most of them have no effect in phase 3 clinical trial This discrepancy may be explained considering 1 the system can be considered chaotic with riddance and interdependency of the response 2 in the clinical studies the treatment was applied after the development of the sepsis when the inflammatory and coagulation systems are still largely activated
Three study has recently demonstrated a benefit in survival
1 The treatment with low-dosage corticosteroids in patients non-responders to ACH stimulation test 5 This is a substitutive therapy It is important to note that the treatment with high dosage corticosteroids to block completely the inflammatory response is not effective 6
2 The treatment with recombinant activated Protein C 7 did increased the relative survival rate by 20 Of note the activated Protein C is the only molecule with three main mechanisms of action anticoagulatory antiinflammatory and profibrinolytic
3 In a recent study in post-surgical patients it has been shown a significant improvement in survival in patients treated with a a tight glycemic control within 80 and 110 mgdL compared to those in which the glycemia was corrected only when reaching higher level 215 mgdL 8We still lack a definitive explanation for these findings and the discussion is mainly on the relative roles of glycemia per se versus insulin therapy per se
However looking at the overall scenario some issues are of note
1 We know that a complete block of the inflammatory reaction or a complete block of the coagulation cascade do not improve outcome in septic patients
2 The activated Protein C is the molecule with the highest spectrum of action in particular is the only molecule within the numerous molecules tested with pro-fibrinolytic activity
3 We know that higher glycemia per se does greatly increase the PAI production the molecule which inhibits the fibrinolysis
4 The septic patients primarily die because of multiple organ dysfunction which is in part due to a widespread microthrombosis
A possible unifying hypothesis is that the improved outcome observed with activate Protein C and with the tight glycemic control is due to the maintenance of a physiologic fibrinolysis This hypothesis has never been tested and if proved could open interesting therapeutical approaches in the septic patients exposed to the high mortality risk
OBJECTIVES The primary end-point is the evaluation of the activationdeactivation of the fibrinolytic system in the two-randomization groups
STUDY DESIGN This study is a multicenter randomized Phase 23 study of adult patients with severe sepsis and septic shock We will enroll a total of approximately 80 adult patients
TREATMENTS ADMINISTERED
1 Control glycemia will be controlled with insulin administration when higher than 215 mgdL
2 Treatment glycemia will be controlled with be controlled with insulin administration when higher than 110 mgdL
RANDOMIZATION The patients enrolled will undergo a block-randomization by center in two arms and stratified according to the clinical decision of the caring physician to use or not use the activated Protein C
DATA COLLECTION The clinical variables and the biochemical variables of fibrinolysis coagulation contact phase and pro-inflammatory cytokines will be recorded daily for the first 7 days each second day until the 14 days and the each fifth until the end of the study 28th day or dimissiondeath if before
At BaselineDemographic data
Every 24 hours
1 Simplified Acute Physiology Score II SAPS II 9 The Simplified Acute Physiology Score assesses the severity of illness on the basis of 12 physiological variables age the type of admission urgent or nonurgent and 3 variables related to the underlying disease Scores can range from 0 to 194 higher scores are correlated with a higher risk of death during hospitalization
2 SOFA Sepsis-related Organ Failure Assessment 10 It is an index of multi-organ dysfunction range 0-24
3 Ramsey scale 11 It is an index of level of sedation range 1-6
4 Respiratory circulatory and biochemical of variables for monitoring the organs dysfunction 4
The main biochemical variables collected are
Fibrinolytic system
1 PAI-1 activity
2 PAI- 1 antigen
3 tPA antigen
4 Plasmin-antiplasmin complex PAP
5 D-Dimer fragment
6 Polymorphism 4G5 of the PAI-1 gene
Final phase pf the coagulation pathway
1 Thrombin-antithrombin complex TAT
2 Prothrombin fragment F1 2
Contact system
1 Activated Factor XII FXIIa
2 Metabolism of endogenous bradykinin
3 Polymorphism insertiondeletion of the gene of angiotensin converting enzyme
Inflammation
1 C reactive protein CRP
2 Interleukin-6 IL-6
3 Tumor necrosis factor TNF
4 C3a
5 SC5b-9
SAFETY ASPECTS AND SEVERE ADVERSE EVENTS SAE REPORTING GCP rules will be strictly applied including timely reporting to the study coordination within 48 hours from their occurrence of the SAEs not included in the efficacy end-points Clinical investigators and nurses of each of the participating centers will be instructed to monitor specifically and to document the adverse events more likely to be associated with the study treatment
STATISTICAL ASPECTS we plan to enroll 80 septic patients in the ICU related with the participating research units This size will allow showing an average difference of 30 of fibrinolysis biochemical parameters alfa 005 1-beta 080
ADMINISTRATIVE LEGAL ETHICAL ISSUES This study is designed by our collaborative group which has been active over the last ten years in conducting clinical trials in intensive care The study has been planned and is managed independently and the clinicians who take active part in the study do not receive economic incentives The Ely Lilly Italia Spa will provide a financial support for performing the laboratory tests required in studying the fibrinolysis It is important to emphasize that we are comparing the effects of two different strategies of glycemic control on the fibrinolysis The Ely Lilly interest in the study is only scientific as if we could show the importance of the fibrinolysis in sepsis this could elucidate one of the putative mechanisms of activated Protein C action This study is also partially funded by a grant of the Ministry of University and research COFIN 2004
The data which are produced belong to the study group who ensures their publication and their availability for public authorities
All data related to the patients included in the study are treated in strict compliance with the Italian Laws related to privacy 6751996
The informed consent for the patients will be administered as soon as and every time the clinical conditions of the same patients are compatible with the procedure thus following the provisions set forth by the ICH-GCP guidelines 13 and confirmed by the most recent European Directive 200120CE Decreto Legislativo 211 24062003 It is worth recalling that there is no legal basis for requiring the consent to a relative of the patient
REFERENCES
1 Gattinoni L Vagginelli F Taccone P Carlesso E Bertoja E Sepsis state of the art Minerva Anestesiologica 2003 69 17-28
2 Salvo I de Cian W Musico M Langer M Piadina R Wolfer A et al The Italian SEPSIS study preliminary results on the incidence and evolution of SIRS sepsis severe sepsis and septic shock Intensive Care Medicine 1995 21 Suppl 2S244-249
3 Rivers E Nguyen B Havstad S Ressler J Muzzin A Knoblich B et al Early goal-directed therapy in the treatment of severe sepsis and septic shock The New England Journal of Medicine 2001 345 1368-1377
4 Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome The New England Journal of Medicine 2000 342 1301-1308
5 Annane D Sibille V Charpentier C Bollaert PE Francois B Korach JM et al Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock JAMA 2002 288 862-871
6 Bone RC Fischer CJJ Clemer TP Slotman GJ Metz CA Balk RA A controlled clinical trial of high-dose methyl-prednisolone in the treatment of severe sepsis and septic shock The New England Journal of Medicine 1987 317 653-658
7 Bernard GR Vincent JL Laterre PF La Rosa SP Dhainaut JF Lopez-Rodriguez A et al Efficacy and safety of recombinant human activated protein C for severe sepsis The New England Journal of Medicine 2001 344699-709
8 Van de Berghe G Wouters P Weekers F Verwaest C Brunynckx F Schets M et al Intensive insulin therapy in the critically ill patients New Engl j med 2001 3451359-1367
9 Knaus WA Draper EA Wagner DP Zimmerman JE APACHE II a severity of disease classification system Crit Care Med 1985 13 818-829
10 Vincent JL de Mendonca A Contraine F Moreno R Takala J Suter PM Sprung CL Colardyn F Blecher S Use of the SOFA score to assess the incidence of organ dysfunctionfailure in intensive care units results of a multicenter prospective study Working group on sepsis-related problems of the European Society of Intensive Care Medicine Crit Care Med 1998 261793-800
11 Ramsay MAE Savege TM Simpson BRJ et al Controlled sedation with alphaxalone-alphadolone Br Med J 1974 2 656-659
12 Dhainaut JF Yan SB Cariou A Mira JP Soluble thrombomodulin plasma-derived unactivated protein C and recombinant human activated protein C in sepsis Crit Care Med 2002 May 30 5 Suppl S318-24
13 Guidelines for Good Clinical Practice par 48 ICH Steering Committee meeting 1 May 1996
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
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| MIUR 2004060419 | None | None | None |
| Lilly F1K0020 | None | None | None |