ALBumin Italian Outcome Septic Shock-BALANCED Trial (ALBIOSS-BALANCED)

Study Overview
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Brief Summary
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Septic shock is a devastating condition often observed in ICU. It is characterized by pro-inflammatory and immune responses, organ failures, high incidence of AKI and lethality. Fluid resuscitation is pivotal as supportive therapy. At present, there are no effective therapies to improve survival of such clinical condition, often characterized by a mortality as high as 40% during the first 90 days from diagnosis. This project proposes a large 2-by-2 factorial randomized clinical trial testing the efficacy of albumin and the low- chloride balanced crystalloid solutions (either Ringer Lactate, Ringer Acetate, or Crystalsol - BAL) in septic shock. The investigators have recently concluded a multicenter, randomized trial, the ALBIOS trial, in which, in a post-hoc analysis, albumin, in addition to crystalloids, reduced 90-day mortality in patients with septic shock, as compared to crystalloids alone (Caironi P et al, 2014). Crystalloids with supra-physiological chloride content may deteriorate renal perfusion, increasing the risk of acute kidney injury (AKI) and mortality.

Detailed Description
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The project will consist of a 2-by-2 factorial, investigator-initiated, open-label, multicenter, randomized, controlled trial, with PROBE design (Prospective Randomized Open Trial with Blinded Evaluation of Outcomes), in patients with septic shock, as defined according to clinical criteria. Patients will be randomized in a 1:1:1:1 ratio to one of the 4 study groups (Albumin + BAL, Albumin + NS, BAL, NS). Both the primary endpoints will include events evaluated objectively: 90-day mortality and incidence of AKI, as assessed by KDIGO criteria (KDIGO Acute Kidney Injury Work Group, 2012).

Official Title
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Efficacy of Albumin Replacement and Balanced Solution in Patients With Septic Shock (the ALBIOSS-BALANCED Trial): a 2-by-2 Factorial, Investigator-initiated, Open- Label, Multicenter, Randomized, Controlled Trial

Conditions
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Septic Shock

Intervention / Treatment
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* Biological: Albumin
* Other: Balanced


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with septic shock if they meet the two following criteria: Presence of an infection (known or suspected) in at least one site: Lung Abdomen Urinary tract Others (blood, skin and soft tissues, central nervous system, bones and joints, cardiac system, reproductive organs). Presence of a severe and acute, sepsis-related cardiovascular failure (as assessed by the SOFA score - see Annex 1), requiring vasopressor to maintain mean arterial pressure >=65 mmHg, despite adequate volume resuscitation a) Cardiovascular SOFA score > 2 (3 or 4) If the patient is unable to provide informed consent, she/he can be included in the trial provided that the requirements of ongoing laws are fulfilled; details on this approach are provided in the protocol, par 11.1 and related Annex 3. The patient will be informed about having been included in a clinical trial, as soon as she/he will regain consciousness. Exclusion Criteria: Age < 18 years Moribund state Known or suspected adverse reaction to albumin administration Septic shock in patients with traumatic brain injury or a clinically active cerebral lesion (known or suspected) Severe congestive heart failure (NYHA III and IV classes) Clinical situations in which the use of albumin is known or supposed to be clinically beneficial (hepatic cirrhosis with ascites, malabsorption syndrome or protein-losing enteropathy, nephrotic syndrome, burns) More than 24 hours after the onset of septic shock Religious objection to the administration of human blood products Presence of chronic end-stage renal disease Severe hyperkalemia Enrollment in other experimental interventional studies

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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
Interventional Model Description: 2-by-2 factorial design, open-label, multicenter, randomized, controlled trial, in patients with septic shock, as defined according to clinical criteria. Patients will be randomized in a 1:1:1:1 ratio to one of the 4 groups (Albumin + BAL, Albumin + NS, BAL, NS).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Albumin + Balanced<br>Human Albumin In parallel with fluid administration for volume resuscitation, patients will receive 400 ml of 20% albumin solution both at randomization (D0) and at day 1 (D1). Subsequently, from day 2 (D2) until day 90 (D90) or ICU discharge (whichever comes first), 20% albumin will be administered on a daily basis, to maintain serum albumin concentration equal to or greater than 30 g/L, based upon serum albumin determination. Balanced crystalloid solutions According to the preference and the standard use of the participating center: Ringer Lactate Ringer Acetate Crystalsol | Biological: Albumin<br>* Human Albumin In parallel with fluid administration for volume resuscitation, patients will receive 400 ml of 20% albumin solution both at randomization (D0) and at day 1 (D1). Subsequently, from day 2 (D2) until day 90 (D90) or ICU discharge (whichever comes first), 20% albumin will be administered on a daily basis, to maintain serum albumin concentration equal to or greater than 30 g/L, based upon serum albumin determination.<br>Other: Balanced<br>* Balanced crystalloid solutions are traditionally crystalloid solutions containing a relatively low concentration of chloride as compared to 0.9% NaCl containing solutions (Normal Saline).<br>* Other names: Ringer Lactate, Ringer Acetate, Crystalsol;|
| Experimental: Albumin + Saline<br>Human Albumin In parallel with fluid administration for volume resuscitation, patients will receive 400 ml of 20% albumin solution both at randomization (D0) and at day 1 (D1). Subsequently, from day 2 (D2) until day 90 (D90) or ICU discharge (whichever comes first), 20% albumin will be administered on a daily basis, to maintain serum albumin concentration equal to or greater than 30 g/L, based upon serum albumin determination. Normal Saline Na+ 154 mEq/L, Cl- 154 mEq/L (0.9% NaCl). | Biological: Albumin<br>* Human Albumin In parallel with fluid administration for volume resuscitation, patients will receive 400 ml of 20% albumin solution both at randomization (D0) and at day 1 (D1). Subsequently, from day 2 (D2) until day 90 (D90) or ICU discharge (whichever comes first), 20% albumin will be administered on a daily basis, to maintain serum albumin concentration equal to or greater than 30 g/L, based upon serum albumin determination.<br>|
| Experimental: Balanced<br>Balanced crystalloid solutions (Ringer Lactate, Ringer Acetate, Crystalsol) | Other: Balanced<br>* Balanced crystalloid solutions are traditionally crystalloid solutions containing a relatively low concentration of chloride as compared to 0.9% NaCl containing solutions (Normal Saline).<br>* Other names: Ringer Lactate, Ringer Acetate, Crystalsol;|
| No Intervention: Saline<br>Normal Saline Na+ 154 mEq/L, Cl- 154 mEq/L (0.9% NaCl). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause 90-day mortality | All-cause death from randomization to 90 days | Up to 90 days | 
| Combined co-primary endpoint | The composite of all-cause death from randomization to 90 days and new occurrence of acute kidney injury (AKI). | Up to 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ICU mortality | All-cause death occurring in Intensive Care Unit (ICU) | Up to ICU discharge, a median of 9 days | 
| In-hospital mortality | All-cause death occurring during hospital stay | Up to hospital discharge, a median of 20 days | 
| 1-year mortality | All-cause death from randomization to 1 year | Up to 1 year | 
| SOFA score | Severity and incidence of organ failures, as assessed by the Sequential Organ Failure Assessment (SOFA) score. SOFA score is used to determine the extent of organ function in a patient while in the intensive care unit. The score is based on 6 different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. The scale of each score ranges from 0 (no dysfunction) to 4 (maximal dysfunction). The 6 scores are then added up to provide a global score: the highest the value, the worst the condition of the patient. | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first | 
| Incidence of AKI | Assessed by the Kidney Disease Improving Global Outcome (KDIGO) criteria as any of the following: (1) increase in serum creatinine >=0.3 mg/dl (26.5 mmol/l) within 48 hours; or (2) increase in SCr to >=1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or (3) urine volume <0.5 ml/kg/h for 6 hours. | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first | 
| RRT | First use of Renal Replacement Therapy (RRT) during ICU stay | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first | 
| Need for vasopressors | Duration of the need for vasopressors during ICU stay | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first | 
| Mechanical ventilation | Duration of mechanical ventilation during ICU stay | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first | 
| Secondary infections in ICU | Incidence of secondary-acquired infections during ICU stay | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first | 
| Duration of stay in ICU | Duration expressed as number of days spent in ICU | Up to ICU discharge, a median of 9 days | 
| Duration of stay in hospital | Duration expressed as number of days spent in hospital | Up to hospital discharge, a median of 20 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Septic Shock, Albumin, Balanced crystalloids