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

Albimmune SL

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Conditions

Septic Shock

Interventions

Human albuminDRUG

Human albumin from day 0 to 7 if serum albumin concentrations \<35g/l.

Saline solutionOTHER

Saline solution from day 0 to day 7.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 84 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Male or female ≥ 18 years and \<85 years of age. 2. Community-acquired pneumonia, urinary, skin or biliary infection. 3. Treatment with antibiotics at least one course in the first 6 hours of suspected infection. 4. 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). 5. SOFA score ≥ 5 points. 6. Albumin plasma level \<35g/L. 7. Lymphocytes count \< 1,100 cel/mL. 8. Admitted to ICU or IMU Exclusion Criteria: 1. Septic shock lasting for more than 24h. 2. ECMO or hemoadsortion therapy. 3. Contraindications to receive albumin. 4. Nosocomial or healthcare-associated infections (surgical intervention or hospitalization within 30 days prior to diagnosis of sepsis). 5. Chronic Renal Failure (KIDGO stage 3-5) or dialysis. 6. Liver cirrhosis. 7. A known malignancy that is progressing or has required active treatment within the past 3 months. 8. 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). 9. 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. 10. Known immunocompromised state, including human immunodeficiency virus infection, or medication known to be immunosuppressive. 11. Participation in an interventional investigational study within 30 days prior to diagnosis of sepsis. 12. 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). 13. Albumin administration within the last 14 days. 14. Subjects with severe neurological or severe head trauma disorders. 15. Pregnant and/or breast-feeding woman. 16. 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.

Outcomes

Primary Outcomes

1.1 Evaluate B cell response to albumin treatment

Measured by the Immunology Complex (Discovery Study).

Time frame: at day 0

1.2 Evaluate B cell response to albumin treatment

Measured by the Immunology Complex (Discovery Study).

Time frame: at day 1

1.3 Evaluate B cell response to albumin treatment

Measured by the Immunology Complex (Discovery Study).

Time frame: at day 3

1.4 Evaluate B cell response to albumin treatment

Measured by the Immunology Complex (Discovery Study).

Time frame: at day 7

1.5 Evaluate B cell response to albumin treatment

Measured by the Immunology Complex (Discovery Study).

Time frame: at day 14

1.6 Evaluate other immune cell response to albumin treatment

Measured by the Immunology Complex (Discovery Study).

Time frame: at day 0

1.7 Evaluate other immune cell response to albumin treatment

Measured by the Immunology Complex (Discovery Study).

Time frame: at day 1

1.8 Evaluate other immune cell response to albumin treatment

Measured by the Immunology Complex (Discovery Study).

Time frame: at day 3

1.9 Evaluate other immune cell response to albumin treatment

Data from ClinicalTrials.gov

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Secondary Outcomes

1.1. Identify additional biomarkers of the immune response to albumin treatment.

Measured by the IGCGS score.

Time frame: at day 0, 1, 3, 7 and 14.

1.2.1 Evaluate the functionality of antibody-secreting B cells.

Measurated by B cell function.

Time frame: 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).

Time frame: at day 0, 1, 3, 7 and 14.

1.2.3 Evaluate the functionality of antibody-secreting B cells.

Measurated by glycosylation.

Time frame: at day 0, 1, 3, 7 and 14.

1.2.4 Evaluate the functionality of antibody-secreting B cells.

Measurated by blood immunophenotyping.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: at day 0, 1, 3, 7 and 14.

4.2.1 Evaluate kidney.

Measurated by sCr (mg/dL).

Time frame: at day 0, 1, 3, 7 and 14.

4.2.2 Evaluate kidney.

Measurated by urine output.

Time frame: at day 0, 1, 3, 7 and 14.

4.2.3 Evaluate kidney.

Measurated by balance fluid.

Time frame: at day 0, 1, 3, 7 and 14.

4.2.4 Evaluate kidney.

Measurated by KDIGO stage 2-3.

Time frame: at day 0, 1, 3, 7 and 14.

4.2.5 Evaluate kidney.

Measurated by TIMP-2.

Time frame: at day 0, 1, 3, 7 and 14.

4.2.6 Evaluate kidney.

Measurated by IGFBP 7.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: at day 0, 3, 7 and 14.

5.1 Evaluate the effect of albumin on endothelial and glycocalix function.

Measurated by angiopoeitin 1.

Time frame: at day 0, 1, 3, 7 and 14.

5.2 Evaluate the effect of albumin on endothelial and glycocalix function.

Measurated by angiopoeitin 2.

Time frame: at day 0, 1, 3, 7 and 14.

5.3 Evaluate the effect of albumin on endothelial and glycocalix function.

Measurated by MR-proADM.

Time frame: at day 0, 1, 3, 7 and 14.

5.4 Evaluate the effect of albumin on endothelial and glycocalix function.

Measurated by Selectin.

Time frame: at day 0, 1, 3, 7 and 14.

5.5 Evaluate the effect of albumin on endothelial and glycocalix function.

Measurated by VCAM-1.

Time frame: at day 0, 1, 3, 7 and 14.

5.6 Evaluate the effect of albumin on endothelial and glycocalix function.

Measurated by ICAM-1.

Time frame: at day 0, 1, 3, 7 and 14.

5.7 Evaluate the effect of albumin on endothelial and glycocalix function.

Measurated by endothelin-1.

Time frame: at day 0, 1, 3, 7 and 14.

5.8 Evaluate the effect of albumin on endothelial and glycocalix function.

Measurated by thrombomodulin.

Time frame: 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.

Time frame: 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).

Time frame: at day 0, 1, 3, 7 and 14.

5.11 Evaluate the effect of albumin on endothelial and glycocalix function.

Measurated by heparan sulfate.

Time frame: at day 0, 1, 3, 7 and 14.

5.12 Evaluate the effect of albumin on endothelial and glycocalix function.

Measurated by VEGF.

Time frame: 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).

Time frame: at day 0, 1, 3, 7 and 14.

5.14 Evaluate the effect of albumin on endothelial and glycocalix function.

Measurated by PAI-1.

Time frame: at day 0, 1, 3, 7 and 14.

6.1 Time on vasopressors.

Measurated by time on vasopressors.

Time frame: 14 days

6.2 Time on mechanical ventilation.

Measurated by time on mechanical ventilation.

Time frame: 14 days

6.3 Time on renal replacement.

Measurated by time on renal replacement.

Time frame: 14 days

7. Proportion of patients with secondary infections.

Measurated by the number of patients with secondary infections.

Time frame: 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.

Time frame: 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.

Time frame: 28 days

8.3. Proportion of re-hospitalized patients at 28 days.

Measurated by the number of re-hospitalized patients at 28 days.

Time frame: 28 days

8.4.1 Evaluate the sequential SOFA score.

Measurated by SOFA score.

Time frame: at day 0, 1, 3, 7 and 14.

8.4.2 Evaluate the sequential APACHE II score.

Measurated by APACHE II score.

Time frame: at day 0, 1, 3, 7 and 14.

8.4.3 Evaluate the sequential TISS-28 score.

Measurated by TISS-28 score.

Time frame: at day 0, 1, 3, 7 and 14.

9. Evaluate quality of life (QoL) at day 90.

Measurated by the EQ-5D-5L questionnaire.

Time frame: 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.

Time frame: 90 days