Placebo Controlled Trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis

Study Overview
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Brief Summary
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Severe sepsis and septic shock are diseases of infectious origin with a high risk of death. The purpose of this study is to determine whether the intravenous application of selenium (given as sodium-selenite) can reduce mortality in patients with severe sepsis or septic shock. Additionally, it is investigated, whether the measurement of procalcitonin - a marker of infection - can be used to guide anti-infectious measures in this disease.

Detailed Description
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This is a multicenter trial of the German Network Sepsis (SepNet) on patients with severe sepsis or septic shock. This study is supported by unrestricted grants. The release of reactive oxygen species is an important factor in the development of sepsis induced multiorgan dysfunction syndrome. Common protection mechanisms are impaired in this syndrome. Serum levels of selenium, a cofactor of the glutathionperoxidase, are reduced. Several studies suggest a benefit of selenium application in patients with severe sepsis but data from large clinical trials are not available. After inclusion into the study, patients are randomly allocated to a placebo or selenium group. Treating physicians and patients are blinded regarding the allocation. The selenium group receives sodium selenite intravenously - 1000 µg as a bolus followed by a continuous infusion of 1000 µg per day until the end of ICU treatment but not longer than 21 days. Procalcitonin (PCT) is a biomarker which is elevated in the blood of patients with severe sepsis/septic shock. Data from patients with community acquired pneumonia demonstrated that this biomarker can be used to decide on the duration of antimicrobial therapy. Studies with small sample size seem to confirm this in ICU patients with severe sepsis. However, this needs to be confirmed in a larger cohort. All patients are randomly allocated to a PCT guided algorithm or a control group. In the PCT-guided group, PCT is measured at randomization, day 4, 7, 10, and 14. Depending on the PCT course, the protocol recommends to change, alter, or stop anti-infectious measures. In the control group, anti-infectious therapy is left to the discretion of the treating physician.

Official Title
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Prospective, Randomized Multicenter Trial of Adjunctive Intravenous Therapy With Sodium-selenite(Selenase®, Double-blinded) and a Procalcitonin Guided Causal Therapy (Open) of Severe Sepsis or Septic Shock.

Conditions
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Severe Sepsis, Septic Shock

Intervention / Treatment
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* Drug: sodium-selenite
* Drug: Placebo
* Procedure: Procalcitonin guided therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Severe sepsis or septic shock according to ACCP/SCCM criteria Onset of severe sepsis or septic shock <24 h Age >= 18 years Informed consent Exclusion Criteria: Pregnant or breast-feeding women Fertile female women without effective contraception Participation in interventional clinical trial within the last 30 days Current participation in any study Former participation in this trial Selenium intoxication No commitment to full patient support (i.e. DNR order) Patient's death is considered imminent due to coexisting disease Relationship of the patient to study team member (i.e. colleague, relative) Infection where guidelines recommend a longer duration of antimicrobial therapy (i.e. endocarditis, tuberculosis, malaria etc) Immunocompromised patients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: SelPCT<br>Patient receives sodium-selenite; causal therapy is guided by a PCT based algorithm. | Drug: sodium-selenite<br>* An intravenous bolus of 1000 µg followed by a continuous intravenous infusion of 1000 µg/day until patient is discharged from the ICU but not more than 21 applications à 24 hours.<br>* Other names: selenase T;Procedure: Procalcitonin guided therapy<br>* Causal therapy of sepsis is guided by applying the following algorithm: Day 4: PCT drop from baseline >=50%: no change in causal therapy; PCT drop from baseline <50%: change or optimize antimicrobial therapy, new intervention (i.e. surgery, diagnostics) recommended for source control. Day 7, 10, 14: PCT <=1.0 ng/ml: finish antimicrobial therapy; PCT >1.0 ng/ml and PCT drop from last PCT measurement >=50%: finish antimicrobial therapy; PCT >1.0 ng/ml and PCT drop from last PCT measurement <50%: change or optimize antimicrobial therapy, new intervention (i.e. surgery, diagnostics) recommended for source control.<br>|
| Active Comparator: SelKon<br>Patient receives sodium-selenite; causal therapy is not guided by a PCT based algorithm. | Drug: sodium-selenite<br>* An intravenous bolus of 1000 µg followed by a continuous intravenous infusion of 1000 µg/day until patient is discharged from the ICU but not more than 21 applications à 24 hours.<br>* Other names: selenase T;|
| Placebo Comparator: PlacPCT<br>Patient receives placebo; causal therapy is guided by a PCT based algorithm. | Drug: Placebo<br>* An intravenous bolus of placebo followed by a continuous intravenous infusion with placebo until patient is discharged from the ICU but not more than 21 applications à 24 hours.<br>* Other names: 0.9 % sodium chlorid;Procedure: Procalcitonin guided therapy<br>* Causal therapy of sepsis is guided by applying the following algorithm: Day 4: PCT drop from baseline >=50%: no change in causal therapy; PCT drop from baseline <50%: change or optimize antimicrobial therapy, new intervention (i.e. surgery, diagnostics) recommended for source control. Day 7, 10, 14: PCT <=1.0 ng/ml: finish antimicrobial therapy; PCT >1.0 ng/ml and PCT drop from last PCT measurement >=50%: finish antimicrobial therapy; PCT >1.0 ng/ml and PCT drop from last PCT measurement <50%: change or optimize antimicrobial therapy, new intervention (i.e. surgery, diagnostics) recommended for source control.<br>|
| Placebo Comparator: PlacKon<br>Patient receives placebo; causal therapy is not guided by a PCT based algorithm. | Drug: Placebo<br>* An intravenous bolus of placebo followed by a continuous intravenous infusion with placebo until patient is discharged from the ICU but not more than 21 applications à 24 hours.<br>* Other names: 0.9 % sodium chlorid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All cause mortality |  | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean total SOFA and SOFA subscores |  | study duration | 
| All cause mortality |  | 90 days | 
| Frequency and duration of mechanical ventilation |  | 90 days | 
| Frequency and duration of vasopressor support |  | 90 days | 
| Frequency of adverse events and severe adverse events |  | study duration | 
| Clinical cure and microbiological cure |  | days 4, 7, 10, 14 | 
| Duration of antimicrobial therapy |  | study duration | 
| Costs of antimicrobial therapy |  | study duration | 
| Time to change of antibiotic therapy |  | duration of study | 
| Days alive without antimicrobial therapy |  | study duration | 
| Frequency of resistancies against antibiotics (VRE, MRSA, ESBL) |  | study duration | 
| ICU length of stay |  | 90 days | 
| Hospital length of stay |  | 90 days | 
| Rate of surgical procedures for focus control |  | study duration | 
| Rate of procedures to diagnose infections |  | study duration | 
| Frequency of new infections |  | study duration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, adjunctive therapy, sodium-selenite, procalcitonin