Human Albumin Treatment in Adult Septic Shock. A Study Evaluating Immune Response and Organ Failure.

Study Overview
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Brief Summary
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The goal of this phase 2, multicenter, randomized, controlled study is to evaluate the effect of albumin treatment on B cell and other immune cell gene exptression in adults with septic shock.

Official Title
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Human Albumin Treatment in Adult Septic Shock. A Study Evaluating Immune Response and Organ Failure.

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: Human albumin
* Other: Saline solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥ 18 years and <85 years of age. Community-acquired pneumonia, urinary, skin or biliary infection. Treatment with antibiotics at least one course in the first 6 hours of suspected infection. Meets Septic Shock criteria defined by the presence of sepsis with persistent hypotension despite initial adequate volume resuscitation requiring vasopressors for more than 4h to maintain MAP>65 mmHg and having a serum lactate level > 2mmol/L (18mg/L). SOFA score ≥ 5 points. Albumin plasma level <35g/L. Lymphocytes count < 1,100 cel/mL. Admitted to ICU or IMU Exclusion Criteria: Septic shock lasting for more than 24h. ECMO or hemoadsortion therapy. Contraindications to receive albumin. Nosocomial or healthcare-associated infections (surgical intervention or hospitalization within 30 days prior to diagnosis of sepsis). Chronic Renal Failure (KIDGO stage 3-5) or dialysis. Liver cirrhosis. A known malignancy that is progressing or has required active treatment within the past 3 months. Patient with end-stage disease (unrelated to sepsis) defined as patients who prior to the current hospitalization are expected to live < 6 months (as assessed by the study physician). Known New York Heart Association (NYHA) class II to IV heart failure or unstable angina, acute coronary disease or myocardial infarction within 6 months prior to diagnosis of sepsis. Known immunocompromised state, including human immunodeficiency virus infection, or medication known to be immunosuppressive. Participation in an interventional investigational study within 30 days prior to diagnosis of sepsis. Likely to be non-compliant or uncooperative during the study (e.g. substance abuse, uncontrolled psychiatric disorder or any chronic condition that may interfere with the study). Albumin administration within the last 14 days. Subjects with severe neurological or severe head trauma disorders. Pregnant and/or breast-feeding woman. Patients who cannot provide prior informed consent and when there is documented evidence that the patient has no legal surrogate decision marker and it appears unlikely that the patient will regain consciousness or sufficient ability to provide delayed informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 84 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Human Albumim (20%, 300mL, 60gr) in 180 min IV<br>Further doses of albumin (60g/l) will be administered daily from day 0 to day 7 in patients with serum albumin concentrations <35 g/L. | Drug: Human albumin<br>* Human albumin from day 0 to 7 if serum albumin concentrations <35g/l.<br>|
| Placebo Comparator: Saline solution 0,9% (500mL) in 180 min IV<br>Saline solution will be given from day 0 to day 7. | Other: Saline solution<br>* Saline solution from day 0 to day 7.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1.1 Evaluate B cell response to albumin treatment | Measured by the Immunology Complex (Discovery Study). | at day 0 | 
| 1.2 Evaluate B cell response to albumin treatment | Measured by the Immunology Complex (Discovery Study). | at day 1 | 
| 1.3 Evaluate B cell response to albumin treatment | Measured by the Immunology Complex (Discovery Study). | at day 3 | 
| 1.4 Evaluate B cell response to albumin treatment | Measured by the Immunology Complex (Discovery Study). | at day 7 | 
| 1.5 Evaluate B cell response to albumin treatment | Measured by the Immunology Complex (Discovery Study). | at day 14 | 
| 1.6 Evaluate other immune cell response to albumin treatment | Measured by the Immunology Complex (Discovery Study). | at day 0 | 
| 1.7 Evaluate other immune cell response to albumin treatment | Measured by the Immunology Complex (Discovery Study). | at day 1 | 
| 1.8 Evaluate other immune cell response to albumin treatment | Measured by the Immunology Complex (Discovery Study). | at day 3 | 
| 1.9 Evaluate other immune cell response to albumin treatment | Measured by the Immunology Complex (Discovery Study). | at day 7 | 
| 1.10 Evaluate other immune cell response to albumin treatment | Measured by the Immunology Complex (Discovery Study). | at day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1.1. Identify additional biomarkers of the immune response to albumin treatment. | Measured by the IGCGS score. | at day 0, 1, 3, 7 and 14. | 
| 1.2.1 Evaluate the functionality of antibody-secreting B cells. | Measurated by B cell function. | at day 0, 1, 3, 7 and 14. | 
| 1.2.2 Evaluate the functionality of antibody-secreting B cells. | Measurated by serum immunoglobilin levels (g/L). | at day 0, 1, 3, 7 and 14. | 
| 1.2.3 Evaluate the functionality of antibody-secreting B cells. | Measurated by glycosylation. | at day 0, 1, 3, 7 and 14. | 
| 1.2.4 Evaluate the functionality of antibody-secreting B cells. | Measurated by blood immunophenotyping. | at day 0, 1, 3, 7 and 14. | 
| 2.1To further investigate the mechanisms of albumin treatment on the immune system. | Measurated by assessment of whole blood RNA sequencing. | at day 0, 1, 3, 7 and 14. | 
| 2.2 To further investigate the mechanisms of albumin treatment on the immune system. | Measurated by assessment of single-cell RNA sequencing. | at day 0, 1, 3, 7 and 14. | 
| 2.3 To further investigate the mechanisms of albumin treatment on the immune system. | Measurated by assessment of CITE-seq. | at day 0, 1, 3, 7 and 14. | 
| 2.4 To further investigate the mechanisms of albumin treatment on the immune system. | Measurated by assessment of immunophenotyping of B cells by high-dimensional spectral flow cytometry. | at day 0, 1, 3, 7 and 14. | 
| 3. Evaluate whether albumin activates B cells at the mucosal interface. | Measurated by assessment of circulating levels of immunoglobulins and glycosylated immunoglobulins. | at day 0, 3, 7 and 14. | 
| 4.1. Evaluate the effect of albumin treatment on systemic inflammation. | Measurated by plasma cytokines: IL-1β, IL-1ra, IL-6, IL-7, IL-8, IL-10, IL-17, TNF-α, TNFr1, IFN-γ, MCP-1, MCP-3, RAGE. | at day 0, 1, 3, 7 and 14. | 
| 4.2.1 Evaluate kidney. | Measurated by sCr (mg/dL). | at day 0, 1, 3, 7 and 14. | 
| 4.2.2 Evaluate kidney. | Measurated by urine output. | at day 0, 1, 3, 7 and 14. | 
| 4.2.3 Evaluate kidney. | Measurated by balance fluid. | at day 0, 1, 3, 7 and 14. | 
| 4.2.4 Evaluate kidney. | Measurated by KDIGO stage 2-3. | at day 0, 1, 3, 7 and 14. | 
| 4.2.5 Evaluate kidney. | Measurated by TIMP-2. | at day 0, 1, 3, 7 and 14. | 
| 4.2.6 Evaluate kidney. | Measurated by IGFBP 7. | at day 0, 1, 3, 7 and 14. | 
| 4.3.1 To explore the effect of albumin on gut mucosa immunoglobulins. | Measurated by composition of bacterial communities bound to IgA. | at day 0, 3, 7 and 14. | 
| 4.3.2 To explore the effect of albumin on gut mucosa immunoglobulins. | Measurated by composition of whole fecal bacteria. | at day 0, 3, 7 and 14. | 
| 4.3.3 To explore the effect of albumin on gut mucosa immunoglobulins. | Measurated by antibody-binding profile of microbes. | at day 0, 3, 7 and 14. | 
| 4.3.4 To explore the effect of albumin on gut mucosa immunoglobulins. | Measurated by bacterial reactivity of peripheral blood antibodies. | at day 0, 3, 7 and 14. | 
| 5.1 Evaluate the effect of albumin on endothelial and glycocalix function. | Measurated by angiopoeitin 1. | at day 0, 1, 3, 7 and 14. | 
| 5.2 Evaluate the effect of albumin on endothelial and glycocalix function. | Measurated by angiopoeitin 2. | at day 0, 1, 3, 7 and 14. | 
| 5.3 Evaluate the effect of albumin on endothelial and glycocalix function. | Measurated by MR-proADM. | at day 0, 1, 3, 7 and 14. | 
| 5.4 Evaluate the effect of albumin on endothelial and glycocalix function. | Measurated by Selectin. | at day 0, 1, 3, 7 and 14. | 
| 5.5 Evaluate the effect of albumin on endothelial and glycocalix function. | Measurated by VCAM-1. | at day 0, 1, 3, 7 and 14. | 
| 5.6 Evaluate the effect of albumin on endothelial and glycocalix function. | Measurated by ICAM-1. | at day 0, 1, 3, 7 and 14. | 
| 5.7 Evaluate the effect of albumin on endothelial and glycocalix function. | Measurated by endothelin-1. | at day 0, 1, 3, 7 and 14. | 
| 5.8 Evaluate the effect of albumin on endothelial and glycocalix function. | Measurated by thrombomodulin. | at day 0, 1, 3, 7 and 14. | 
| 5.9 Evaluate the effect of albumin on endothelial and glycocalix function. | Measurated by syndecan 1-4. | at day 0, 1, 3, 7 and 14. | 
| 5.10 Evaluate the effect of albumin on endothelial and glycocalix function. | Measurated by prot C (mg/L). | at day 0, 1, 3, 7 and 14. | 
| 5.11 Evaluate the effect of albumin on endothelial and glycocalix function. | Measurated by heparan sulfate. | at day 0, 1, 3, 7 and 14. | 
| 5.12 Evaluate the effect of albumin on endothelial and glycocalix function. | Measurated by VEGF. | at day 0, 1, 3, 7 and 14. | 
| 5.13 Evaluate the effect of albumin on endothelial and glycocalix function. | Measurated by sphingosine-1-phosphate (S1P). | at day 0, 1, 3, 7 and 14. | 
| 5.14 Evaluate the effect of albumin on endothelial and glycocalix function. | Measurated by PAI-1. | at day 0, 1, 3, 7 and 14. | 
| 6.1 Time on vasopressors. | Measurated by time on vasopressors. | 14 days | 
| 6.2 Time on mechanical ventilation. | Measurated by time on mechanical ventilation. | 14 days | 
| 6.3 Time on renal replacement. | Measurated by time on renal replacement. | 14 days | 
| 7. Proportion of patients with secondary infections. | Measurated by the number of patients with secondary infections. | 90 days | 
| 8.1. Proportion of patients dead at 28 and 90 days. | Measurated by the number of patients dead at 28 and 90 days. | 90 days | 
| 8.2. Proportion of patients re-admitted to ICU at 28 days. | Measurated by the number of re-admitted to UCI at 28 days. | 28 days | 
| 8.3. Proportion of re-hospitalized patients at 28 days. | Measurated by the number of re-hospitalized patients at 28 days. | 28 days | 
| 8.4.1 Evaluate the sequential SOFA score. | Measurated by SOFA score. | at day 0, 1, 3, 7 and 14. | 
| 8.4.2 Evaluate the sequential APACHE II score. | Measurated by APACHE II score. | at day 0, 1, 3, 7 and 14. | 
| 8.4.3 Evaluate the sequential TISS-28 score. | Measurated by TISS-28 score. | at day 0, 1, 3, 7 and 14. | 
| 9. Evaluate quality of life (QoL) at day 90. | Measurated by the EQ-5D-5L questionnaire. | At day 0 and 90 | 
| 10. Proportion of participants with any AEs related to albumin treatment, SAEs and SUSARs. | Measured by the number of AE, SAEs and SUSARS presented by the participants. | 90 days |