GM-CSF to Decrease ICU Acquired Infections

Study Overview
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Brief Summary
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The concept of acquired immunodeficiency after a first severe infection in the ICU is widely described in the literature. There is a dual risk: increased mortality and increased secondary infections. Several approaches of immunostimulatory treatments have been proposed in the literature. The treatment proposed by this study consists of the administration of Granulocyte-macrophage colony-stimulating factor (GM-CSF), colony stimulating factor widely used particularly in the USA where it is marketed. A phase 2 clinical trial was conducted in Germany in 2009. The main objective is to measure the incidence of ICU-acquired infections in 2 groups of patients treated by GM-CSF or placebo. ICU patients at risk are defined as surviving at D3 from a severe sepsis or septic shock and presenting a sepsis associated immunodepression. The detection of immunosuppressed patients will be achieved by measuring the HLA-DR (Human Leucocyte Antigen DR)with a threshold of less to 8000 sites. Our hypothesis is that the number of secondary infections (primary endpoint) will be significantly reduced in the treated group.

Official Title
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A Double-Blind, Randomized, Placebo-controlled Multicenter Trial of GRanulocyte-Macrophage Colony-stimulating Factor Administration to Decrease ICU Acquired Infections in Sepsis-induced ImmunoDepression

Conditions
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Septic Shock, Severe Sepsis

Intervention / Treatment
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* Drug: Sargramostim: Leukine (Genzyme USA)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ICU patients presenting a severe sepsis or a septic shock associated with a sepsis-induced immunosuppression. - Severe sepsis OR septic shock defined by the association of: at least 2 criteria of Systemic Inflammation Response Syndrome (SIRS) a clinically or microbiologically defined infection and respectively at least one organ failure (level ≥ 2 in one organ failure of the SOFA score) OR the need of a vasopressor treatment (epinephrine or norepinephrine ≥ 0,25mg/kg/min for at least 6 hrs to maintain a systolic pressure ≥ 90 mmHg or a mean arterial pressure ≥ 65 mmHg). - AND Sepsis-induced immunosuppression: reduced mHLA-DR levels (< 8,000 monoclonal antibodies (mAb) per cell at D3). Exclusion Criteria: - Therapeutic limitation Evolutive hemopathy, neutropenia < 500/mm3, stemcell transplant Solid tumor with on-going chemotherapy or radiotherapy Human immunodeficiency virus (HIV) infection with CD 4 count < 200 cell/mm3 Immunosuppressive treatment (including corticosteroid at immunosuppressive dose : > 10 mg equivalent prednisolone and cumulative dose > 700 mg) Primary immunodeficiency . Extra corporeal circulation within one month Recent cardio-pulmonary resuscitation (within the current clinical episode) Patients admitted in ICU for extensive burns Contraindications to sargramostim Pregnant or lactating women Participation to another interventional study.

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Leukine<br>Sargramostim: Leukine (Genzyme USA), 125µg/m2 , once per day during 5 days, by subcutaneous route | Drug: Sargramostim: Leukine (Genzyme USA)<br>* Leukine: 125 µg/m² daily, subcutaneously, for 5 days.<br>|
| Placebo Comparator: placebo<br>placebo, once per day during 5 days by subcutaneous route | Drug: Placebo<br>* placebo subcutaneously, for 5 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients presenting at least one ICU-acquired infection at D28 or ICU discharge. | ICU-acquired infections will be recorded in accordance with the definitions of the European CDC used in the French network of IAI surveillance Rea Raisin. An independent committee blinded to treatment group will ensure the classification of hospital-acquired infections. | At Day 28 or ICU discharge. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and incidence density of pneumonia, catheter related infections, and urinary tract infections |  | At Day 28 or ICU discharge. | 
| Survival at D28, end of ICU and hospital stay, and at 1 year |  | At Day 28 or ICU discharge. | 
| Organ failure free days |  | At Day 28 or ICU discharge. | 
| Number of serious adverse events and number of patients having presented at least one serious adverse event. |  | At Day 28 or ICU discharge. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Septic shock, Severe sepsis, GM-CSF, Immunosuppression, Hospital-acquired infections, ICU-acquired infections, HLA-DR, Monocytes