Personalized Immunotherapy in Sepsis

NCT04990232 | Completed Phase 2

• 1 other identifier: ImmunoSep
• Study Type: interventional
• Target: 280
• Locations: 6 countries
• Sites: 35

Brief Summary

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.

Conditions

Sepsis

Outcome Measures

Primary Outcomes (1)

• Mean total Sequential Organ Failure Assessment score

  Difference in the mean total Sequential Organ Failure Assessment score between the two arms

  9 days

Secondary Outcomes (4)

• 28-day mortality

  28 days

• 90-day mortality

  90 days

• Mean total Sequential Organ Failure Assessment score

  15 days

• Reversal of hyper-inflammation (decrease of ferritin) or immunoparalysis (increase of Quantibrite)

  15 days

Other Outcomes (1)

• Resolution of infection-reversal of all signs and symptoms of the initial infection

  15 days

Study Arms (2)

Standard of care

PLACEBO COMPARATOR

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

Immunotherapy

EXPERIMENTAL

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

Interventions

Anakinra or rhIFNγ DRUG

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.

Also known as: Imukin, Kineret

Immunotherapy

Placebo DRUG

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

Standard of care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Hellenic Institute for the Study of Sepsis: lead

Study Sites (35)

Intensive Care Unit, Jena University Hospital

Jena, Jena, 07747, Germany

Location

Intensive Care Unit, Alexandroupolis University Hospital

Alexandroupoli, Alexandroupolis, 68100, Greece

Location

1st Department of Pulmonary Medicine and Intensive Care Unit

Athens, Athens, 11527, Greece

Location

3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens SOTIRIA

Athens, Athens, 11527, Greece

Location

New Intensive Care Unit, SOTIRIA Athens General Hospital of Chest Diseases

Athens, Athens, 11527, Greece

Location

2nd Department of Critical Care Medicine, ATTIKON University Hospital

Athens, Haidari, 12462, Greece

Location

Intensive Care Unit, Ioannina University Hospital

Ioannina, Ioannina, 45500, Greece

Location

Intensive Care Unit, Center for Accident Rehabilitation (KAT) of Athens

Athens, Kifissia, 14561, Greece

Location

Department of Internal Medicine, Larissa University Hospital

Larissa, Larissa, 41334, Greece

Location

Intensive Care Unit, TZANEIO Piraeus General Hospital

Piraeus, Piraeus, 18536, Greece

Location

Intensive Care Unit, 424 General Military Training Hospital

Thessaloniki, Thessaloniki, 56429, Greece

Location

1ST Department of Internal Medicine, Evangelismos General Hospital

Athens, 10676, Greece

Location

General Hospital of Athens LAIKO - Intensive Care Unit

Athens, 11527, Greece

Location

Intensive Care Unit of Center for Respiratory Failure, General Hospital of Chest Diseases of Athens SOTIRIA

Athens, 11527, Greece

Location

4th Department of Internal Medicine, "Attikon" University Hospital, National and Kapodistrian University of Athens, Medical School

Athens, 12462, Greece

Location

Intensive Care Unit, General Hospital ASKLEPIEIO Voulas

Athens, 16673, Greece

Location

2nd Department of Internal Medicine, Attikon University Hospital

Athens, Greece

Location

5th Department of Internal Medicine, Evangelismos General Hospital

Athens, Greece

Location

General Oncological Hospital of Kifisia Oi Agioi Anargyroi - Clinic of Intensive Care and Pulmonary Diseases Department of Nursing, University of Athens

Athens, Greece

Location

Greece Intensive Care Unit General Hospital of Athens Korgialeneio

Athens, Greece

Location

Intensive Care Unit, "Latsio", Thriasio Elefsis General Hospital

Elefsina, 19600, Greece

Location

Greece Intensive Care Unit University General Hospital of Heraklion

Heraklion, Greece

Location

General Hospital of Karditsa Intensive Care Unit

Karditsa, 43100, Greece

Location

Intensive Care Unit, "Koutlimbaneio & Triantafylleio" Larissa General Hospital

Larissa, 41221, Greece

Location

Intensive Care Unit, Agios Dimitrios General Hospital

Thessaloniki, 54 634, Greece

Location

Intensive Care Unit, G. Gennimatas General Hospital

Thessaloniki, 546 35, Greece

Location

Intensive Care Unit, Theageneio Oncological Hospital of Thessaloniki

Thessaloniki, 546 39, Greece

Location

Intensive Care Unit, Ippokrateion General Hospital

Thessaloniki, 546 42, Greece

Location

Department of Anesthesiology and Intensive Care Medicine, University General Hospital of Thessaloniki AHEPA

Thessaloniki, 54636, Greece

Location

General Hospital of Thessaloniki, Papageorgiou- Intensive Care Unit

Thessaloniki, 56429, Greece

Location

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Rome, Rome, 00168, Italy

Location

Department of Internal Medicine and Infectious Diseases, Amsterdam Medical Center

Amsterdam, Amsterdam, 1105 AZ, Netherlands

Location

Intensive Care Unit, University Medical Center Radboud

Nijmegen, Nijmegen, 6525 GA, Netherlands

Location

Infectious Diseases Department, "Iuliu Hatieganu'' University of Medicine and Pharmacy Cluj-Napoca

Cluj-Napoca, Cluj-Napoca, Romania

Location

Intensive Care Unit, Centre Hospitalier Universitaire Vaudois (CHUV)

Lausanne, Lausanne, CH-1011, Switzerland

Location

Related Publications (3)

• Giamarellos-Bourboulis EJ, Kotsaki A, Kotsamidi I, Efthymiou A, Koutsoukou V, Ehler J, Paridou A, Frantzeskaki F, Muller MCA, Pickkers P, Meylan S, Nikolopoulos I, Lupse M, Gavala A, Vlachogianni G, Solomonidi N, Alevizou A, Kondili E, Antoniadou E, Nakou M, Markou N, Hatziagelaki E, Prekates A, Komnos A, Bakkerus L, Slim MA, Dalekos GN, Karapanagiotou A, Ktena S, De Pascale G, Koulouras V, Psarrakis C, Massa E, Dakou K, Pazvanti C, Ioakeimidou A, Tsangaris I, Antonakos N, Vlaar APJ, Anisoglou S, Calandra T, Papaioannou V, Myrianthefs P, Patrani M, Alamanos I, Antonelli M, van der Meer JWM, van der Poll T, Wiersinga WJ, Ntaganou M, Gkeka E, Bauer M, Mouloudi E, Netea MG; ImmunoSep Study Group. Precision Immunotherapy to Improve Sepsis Outcomes: The ImmunoSep Randomized Clinical Trial. JAMA. 2025 Dec 8:e2524175. doi: 10.1001/jama.2025.24175. Online ahead of print.

  PMID: 41359996 DERIVED

• Giamarellos-Bourboulis EJ, Dimopoulos G, Flohe S, Kotsaki A, van der Poll T, Skirecki T, Torres A, Netea MG. THE EUROPEAN SHOCK SOCIETY MEETS THE IMMUNOSEP CONSORTIUM FOR PERSONALIZED SEPSIS TREATMENT. Shock. 2023 Mar 1;59(3S Suppl 1):21-25. doi: 10.1097/SHK.0000000000001955. Epub 2022 Jul 24.

  PMID: 36867758 DERIVED

• Kotsaki A, Pickkers P, Bauer M, Calandra T, Lupse M, Wiersinga WJ, Meylan S, Bloos F, van der Poll T, Slim MA, van Mourik N, Muller MCA, van Vught L, Vlaar APJ, de Nooijer A, Bakkerus L, Weis S, Antonakos N, Netea MG, Giamarellos-Bourboulis EJ. ImmunoSep (Personalised Immunotherapy in Sepsis) international double-blind, double-dummy, placebo-controlled randomised clinical trial: study protocol. BMJ Open. 2022 Dec 20;12(12):e067251. doi: 10.1136/bmjopen-2022-067251.

  PMID: 36600424 DERIVED

MeSH Terms

Conditions

Sepsis

Interventions

Interleukin 1 Receptor Antagonist Protein

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Evagelos Giamarellos-Bourboulis, MD, PhD

  Hellenic Institute for the Study of Sepsis

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: multicentre and multinational, double-blind, double-dummy randomized clinical trial

Study Record Dates

• First Submitted: July 29, 2021
• First Posted: August 4, 2021
• Study Start: July 29, 2021
• Primary Completion: February 6, 2024
• Study Completion: April 27, 2024
• Last Updated: March 19, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Upon publication of manuscript related to this study
• Access Criteria: After contact with sponsor (egiamarel@med.uoa.gr)

Locations

DE (1); RO (1); CH (1); GR (29); NL (2); IT (1)