Personalized Immunotherapy in Sepsis (ImmunoSep)

March 17, 2025 updated by: Hellenic Institute for the Study of Sepsis

Personalized Immunotherapy in Sepsis: a Multicentre and Multinational, Double-blind, Double-dummy Randomized Clinical Trial

Αim of ImmunoSep is to assess whether personalized adjunctive immunotherapy directed against a state of either fulminant hyper-inflammation or immunoparalysis is able to change sepsis outcomes. Patients will be selected by a panel of biomarkers and laboratory findings and will be allocated to placebo or immunotherapy treatment according to their needs.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Sepsis is a life-threatening organ dysfunction that results from the dysregulated host response to an infection. Accumulating knowledge suggests that there is a spectrum of dysregulation in this response. On the one end of this spectrum there are patients whose immune response is characterized by fulminant hyper-inflammation. On the other end of this spectrum there are patients whose immune response is characterized by immunoparalysis. The majority of patients are situated between these two extremes. The primary hypothesis of the ImmunoSep trial is to recognize both ends of this spectrum and to administer adjunctive therapy aiming to modulate the sepsis-associated hyper-inflammation or immunoparalysis. It is anticipated that with this strategy patients' organ dysfunctions be improved.

During the last years the Hellenic Sepsis Study Group (HSSG) managed to develop ferritin as the diagnostic tool for the recognition of patients with fulminant sepsis-associated hyper-inflammation. This was done by analysis of 5,121 patients split into a test and a validation cohort and by also studying a confirmation cohort coming from Sweden. Patients were classified according to the criteria for the macrophage activation syndrome developed by the American College of Rheumatology; approximately 4% of patients with sepsis have fulminant hyper-inflammation or macrophage activation-like syndrome (MALS) that is an independent clinical condition associated with short-term 10-day mortality. Serum ferritin greater than 4,420 ng/ml had sensitivity 97.1% and negative predictive value 98% for the diagnosis. More than 25 years ago one randomized clinical trial (RCT) was conducted where patients with severe sepsis were randomly assigned to blind treatment with placebo or with the recombinant human interleukin-1 receptor antagonist anakinra. The trial failed to disclose any benefit of anakinra on 28-day mortality. However, a recent post-hoc analysis revealed that patients who had signs of macrophage activation syndrome had significant 30% survival benefit by anakinra treatment.

The immunoparalysis of sepsis is associated with at least 50% risk of death in the subsequent 28 days. There is evidence from preclinical studies and from the endotoxin challenge model in human volunteers that this can be reversed using recombinant human interferon gamma (rhIFNγ). rhIFNγ was administered in nine patients with septic shock in a small open-label clinical trial without placebo comparator; reversal of immunoparalysis was achieved.

It is important to recognize patients with sepsis complicated either with MALS or with immunoparalysis and administer anakinra or rhIFNγ respectively as a potentially beneficial intervention. To this end, a smaller-scale trial was conducted in Greece that was aiming to the personalized management of septic shock. The acronym of this trial was PROVIDE. PROVIDE was conducted between December 2017 and December 2019 in 14 study sites in Greece under the auspices of the European Shock Society. In the PROVIDE trial patients with septic shock due to lower respiratory tract infection, acute cholangitis, or primary bacteremia, were screened on two consecutive days for laboratory signs of fulminant hyper-inflammation or immunoparalysis. Results showed that one single measurement of serum ferritin and the number of human leukocyte antigen-DR (HLA-DR) on monocytes can efficiently classify patients. More precisely, ferritin 4,420 ng/ml diagnoses MALS; and a combination of ferritin >4,420 ng/ml and HLA-DR less than 5000 molecules/monocyte diagnose imunoparalysis. Patients were randomized into double-dummy blind treatment with placebo if randomly assigned to the standard-of-care arm and with anakinra/recombinant human interferon-gamma (rhIFNγ) if randomly assigned to the immunotherapy arm. Thirty-six patients were enrolled and preliminary results derived from the PROVIDE trial further corroborate the use of anakira/rhIFNγ as an innovative, personalized adjunct therapy for sepsis but one larger-scale study with larger number of patients is needed in order to validate findings.

ImmunoSep is a randomized placebo-controlled phase 2 clinical trial with a double-dummy design where the effect of personalized immunotherapy in patients with sepsis and either fulminant hyper-inflammation or immunoparalysis is studied. Hyper-inflammation is considered as a more direct life-threatening manifestation of sepsis than immunoparalysis; for that reason patients with lab findings of both immune states are allocated to the hyper-inflammation treatment arm.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
280

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.
  • Name: Evangelos Giamarellos-Bourboulis, MD, PhD
  • Phone Number: 00302105831994
  • Email: egiamarel@med.uoa.gr

Study Contact Backup

  • Name: Evdoxia Kyriazopoulou, MD, MSc, PhD
  • Phone Number: 00302105832563
  • Email: ekyri@med.uoa.gr

Study Locations

  • Germany
      • Jena, Germany, 07747
        • Intensive Care Unit, Jena University Hospital
  • Greece
      • Alexandroupolis, Greece, 68100
        • Intensive Care Unit, Alexandroupolis University Hospital
      • Athens, Greece, 11527
        • 1st Department of Pulmonary Medicine and Intensive Care Unit
      • Athens, Greece, 12462
        • 4th Department of Internal Medicine, "Attikon" University Hospital, National and Kapodistrian University of Athens, Medical School
      • Athens, Greece
        • 2nd Department of Internal Medicine, Attikon University Hospital
      • Athens, Greece
        • 5th Department of Internal Medicine, Evangelismos General Hospital
      • Athens, Greece, 16673
        • Intensive Care Unit, General Hospital ASKLEPIEIO Voulas
      • Athens, Greece, 10676
        • 1ST Department of Internal Medicine, Evangelismos General Hospital
      • Athens, Greece, 11527
        • 3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens SOTIRIA
      • Athens, Greece, 11527
        • General Hospital of Athens LAIKO - Intensive Care Unit
      • Athens, Greece, 11527
        • Intensive Care Unit of Center for Respiratory Failure, General Hospital of Chest Diseases of Athens SOTIRIA
      • Athens, Greece, 11527
        • New Intensive Care Unit, SOTIRIA Athens General Hospital of Chest Diseases
      • Athens, Greece
        • General Oncological Hospital of Kifisia Oi Agioi Anargyroi - Clinic of Intensive Care and Pulmonary Diseases Department of Nursing, University of Athens
      • Athens, Greece
        • Greece Intensive Care Unit General Hospital of Athens Korgialeneio
      • Elefsína, Greece, 19600
        • Intensive Care Unit, "Latsio", Thriasio Elefsis General Hospital
      • Heraklion, Greece
        • Greece Intensive Care Unit University General Hospital of Heraklion
      • Kardítsa, Greece, 43100
        • General Hospital of Karditsa Intensive Care Unit
      • Larissa, Greece, 41221
        • Intensive Care Unit, "Koutlimbaneio & Triantafylleio" Larissa General Hospital
      • Larissa, Greece, 41334
        • Department of Internal Medicine, Larissa University Hospital
      • Piraeus, Greece, 18536
        • Intensive Care Unit, TZANEIO Piraeus General Hospital
      • Thessaloniki, Greece, 54 634
        • Intensive Care Unit, Agios Dimitrios General Hospital
      • Thessaloniki, Greece, 546 35
        • Intensive Care Unit, G. Gennimatas General Hospital
      • Thessaloniki, Greece, 546 42
        • Intensive Care Unit, Ippokrateion General Hospital
      • Thessaloniki, Greece, 546 39
        • Intensive Care Unit, Theageneio Oncological Hospital of Thessaloniki
      • Thessaloniki, Greece, 54636
        • Department of Anesthesiology and Intensive Care Medicine, University General Hospital of Thessaloniki AHEPA
      • Thessaloniki, Greece, 56429
        • Intensive Care Unit, 424 General Military Training Hospital
      • Thessaloníki, Greece, 56429
        • General Hospital of Thessaloniki, Papageorgiou- Intensive Care Unit
    • Haidari
      • Athens, Haidari, Greece, 12462
        • 2nd Department of Critical Care Medicine, ATTIKON University Hospital
    • Ioannina
      • Ioánnina, Ioannina, Greece, 45500
        • Intensive Care Unit, Ioannina University Hospital
    • Kifissia
      • Athens, Kifissia, Greece, 14561
        • Intensive Care Unit, Center for Accident Rehabilitation (KAT) of Athens
  • Italy
      • Rome, Italy, 00168
        • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
  • Netherlands
      • Amsterdam, Netherlands, 1105 AZ
        • Department of Internal Medicine and Infectious Diseases, Amsterdam Medical Center
      • Nijmegen, Netherlands, 6525 GA
        • Intensive Care Unit, University Medical Center Radboud
  • Romania
      • Cluj-Napoca, Romania
        • Infectious Diseases Department, "Iuliu Hatieganu'' University of Medicine and Pharmacy Cluj-Napoca
  • Switzerland
      • Lausanne, Switzerland, CH-1011
        • Intensive Care Unit, Centre Hospitalier Universitaire Vaudois (CHUV)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age equal to or above 18 years.
  • Both genders.
  • In case of women, unwillingness to become pregnant during the study period.
  • Written informed consent provided by the patient or by one first-degree relative/spouse in case of patients unable to consent.
  • Community-acquired pneumonia (CAP) or hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) or primary bacteremia (BSI).
  • Sepsis defined by the Sepsis-3 definitions. More precisely, sepsis is defined as the presence of total SOFA (sequential organ failure assessment score) equal to 2 or more for patients who are admitted with infection at the emergency department OR as any increase of admission SOFA by 2 or more points for patients already hospitalized.
  • Patients with signs of fulminant hyper-inflammation or sepsis-associated immunoparalysis as defined by ferritin and Quantibrite. Since the state of hyper-inflammation is considered more life-threatening than the state of immunoparalysis, patients with lab findings of both immune states are allocated to treatment targeting hyper-inflammation. It is explicitly stated that patients diagnosed with novel Coronavirus-2 infection (COVID-19) may participate only in the fulminant hyper-inflammation arm
  • Time from classification into sepsis by the Sepsis-3 definitions and start of blind intervention less than 72 hours.

Exclusion Criteria:

  • Age below 18 years.
  • Denial for written informed consent.
  • Acute pyelonephritis or intraabdominal infection, meningitis or skin infection.
  • Any stage IV malignancy.
  • Neutropenia defined as an absolute neutrophil count lower than 1,500/mm3.
  • Any 'do not resuscitate' decision in the hospital.
  • In the case of BSI, patients with blood cultures growing coagulase-negative staphylococci or skin commensals or catheter-related infections cannot be enrolled.
  • Active tuberculosis (TB) as defined by the co-administration of drugs for the treatment of TB.
  • Infection by the human immunodeficiency virus (HIV).
  • Any primary immunodeficiency.
  • Oral or intravenous intake of corticosteroids at a daily dose equal or greater than 0.4 mg/kg prednisone or greater the last 15 days.
  • Any anti-cytokine biological treatment the last one month.
  • Medical history of systemic lupus erythematosus.
  • Medical history of multiple sclerosis or any other demyelinating disorder.
  • Pregnancy or lactation. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Placebo Comparator: Standard of care
Patients will receive the standard type of treatment decided by the attending physicians. They will also receive 20ml (10ml for patients with creatinine clearance lower than 30ml/min) intravenous (IV) 0.9% saline (N/S) three times daily (every eight hours) for 15 days and 0.5 ml subcutaneous (sc) 1ml 0.9% N/S every other day for a total of 15 days.
Drug: Placebo
20ml (10ml for patients with creatinine clearance lower than 30ml/min) intravenous (IV) 0.9% saline (N/S) three times daily (every eight hours) for 15 days and 0.5 ml subcutaneous (sc) 1ml 0.9% N/S every other day for a total of 15 days
Experimental: Immunotherapy
Patients will receive the standard type of treatment decided by the attending physicians. They will also receive IV anakinra 200 mg three times daily (every eight hours) or sc rhIFNγ 100 μg once every other day. More precisely, patients randomized for hyper-inflammation will receive anakinra three times daily (every eight hours) for 15 days and sc 0.5 ml N/S 0.9% every other day for 15 days. Patients having immunoparalysis will receive IV 20 ml N/S 0.9% (10ml for patients with creatinine clearance lower than 30ml/min) three times daily (every eight hours) for 15 days and sc rhIFNγ every other day for 15 days. Especially for patients with creatinine clearance lower than 30 ml/min anakinra will be given half dose (i.e. 100 mg three times daily). Creatinine clearance is calculated by the Cockcroft Gault equation [(140-age in years)/ (72 x serum creatinine in mg/dl) for men; this is multiplied by 0.85 for women.
Drug: Anakinra or rhIFNγ
In hyper-inflammation anakinra three times daily (every eight hours) for 15 days and sc 0.5 ml N/S 0.9% every other day for 15 days. In immunoparalysis IV 20 ml N/S 0.9% (10ml for patients with creatinine clearance lower than 30ml/min) three times daily (every eight hours) for 15 days and sc rhIFNγ every other day for 15 days.
Other Names:
  • Kineret
  • Imukin

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Mean total Sequential Organ Failure Assessment score
Time Frame: 9 days
Difference in the mean total Sequential Organ Failure Assessment score between the two arms
9 days

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
28-day mortality
Time Frame: 28 days
Difference in mortality between the two arms
28 days
90-day mortality
Time Frame: 90 days
Difference in mortality between the two arms
90 days
Mean total Sequential Organ Failure Assessment score
Time Frame: 15 days
Difference in the mean total Sequential Organ Failure Assessment score between the two arms
15 days
Reversal of hyper-inflammation (decrease of ferritin) or immunoparalysis (increase of Quantibrite)
Time Frame: 15 days
Difference in percentage of patients between the two arms with any at least 15% decrease of the baseline serum ferritin (if in hyper-inflammation) and with any Quantibrite to above 8,000 AB/C with serum ferritin below 4,420 ng/ml (if in sepsis-associated immunoparalysis)
15 days

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Resolution of infection-reversal of all signs and symptoms of the initial infection
Time Frame: 15 days
Difference in percentage of patients with resolution of the initial infection between the two arms
15 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Hellenic Institute for the Study of Sepsis

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Chair: Evagelos Giamarellos-Bourboulis, MD, PhD, Hellenic Institute for the Study of Sepsis

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 29, 2021

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 6, 2024

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 27, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 29, 2021

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 29, 2021

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 4, 2021

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 25, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 17, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • ImmunoSep

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

All data will be available within published manuscript. Deidentified patient data can be requested to Sponsor and shared after approval for purposed approved by Sponsor.

IPD Sharing Time Frame

Upon publication of manuscript related to this study

IPD Sharing Access Criteria

After contact with sponsor (egiamarel@med.uoa.gr)

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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