SepsisPhase 2ImmunoSepNCT04990232
Personalized Immunotherapy in Sepsis
A Phase 2 study testing Anakinra or rhIFNγ in people with Sepsis, run by Hellenic Institute for the Study of Sepsis at 35 sites in 6 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sepsis
- What is being tested?
- Anakinra or rhIFNγ
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 280 participants
- Where
- 35 sitesin 6 countries
- Study dates
- 29 Jul 2021to 27 Apr 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 15Show fewer
- 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.
Trial locations and contacts
35 sites in 6 countries.
35 sites in 6 countries
Greece29 sites
Intensive Care Unit, Alexandroupolis University Hospital
Alexandroupoli, Alexandroupolis, 68100
1st Department of Pulmonary Medicine and Intensive Care Unit
Athens, Athens, 11527
3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens SOTIRIA
Athens, Athens, 11527
New Intensive Care Unit, SOTIRIA Athens General Hospital of Chest Diseases
Athens, Athens, 11527
2nd Department of Critical Care Medicine, ATTIKON University Hospital
Athens, Haidari, 12462
Intensive Care Unit, Center for Accident Rehabilitation (KAT) of Athens
Athens, Kifissia, 14561
1ST Department of Internal Medicine, Evangelismos General Hospital
Athens, 10676
General Hospital of Athens LAIKO - Intensive Care Unit
Athens, 11527
Intensive Care Unit of Center for Respiratory Failure, General Hospital of Chest Diseases of Athens SOTIRIA
Athens, 11527
4th Department of Internal Medicine, "Attikon" University Hospital, National and Kapodistrian University of Athens, Medical School
Athens, 12462
Intensive Care Unit, General Hospital ASKLEPIEIO Voulas
Athens, 16673
2nd Department of Internal Medicine, Attikon University Hospital
Athens
5th Department of Internal Medicine, Evangelismos General Hospital
Athens
General Oncological Hospital of Kifisia Oi Agioi Anargyroi - Clinic of Intensive Care and Pulmonary Diseases Department of Nursing, University of Athens
Athens
Greece Intensive Care Unit General Hospital of Athens Korgialeneio
Athens
Intensive Care Unit, "Latsio", Thriasio Elefsis General Hospital
Elefsina, 19600
Greece Intensive Care Unit University General Hospital of Heraklion
Heraklion
Intensive Care Unit, Ioannina University Hospital
Ioannina, Ioannina, 45500
General Hospital of Karditsa Intensive Care Unit
Karditsa, 43100
Department of Internal Medicine, Larissa University Hospital
Larissa, Larissa, 41334
Intensive Care Unit, "Koutlimbaneio & Triantafylleio" Larissa General Hospital
Larissa, 41221
Intensive Care Unit, TZANEIO Piraeus General Hospital
Piraeus, Piraeus, 18536
Intensive Care Unit, 424 General Military Training Hospital
Thessaloniki, Thessaloniki, 56429
Intensive Care Unit, Agios Dimitrios General Hospital
Thessaloniki, 54 634
Intensive Care Unit, G. Gennimatas General Hospital
Thessaloniki, 546 35
Intensive Care Unit, Theageneio Oncological Hospital of Thessaloniki
Thessaloniki, 546 39
Intensive Care Unit, Ippokrateion General Hospital
Thessaloniki, 546 42
Department of Anesthesiology and Intensive Care Medicine, University General Hospital of Thessaloniki AHEPA
Thessaloniki, 54636
General Hospital of Thessaloniki, Papageorgiou- Intensive Care Unit
Thessaloniki, 56429
Netherlands2 sites
Department of Internal Medicine and Infectious Diseases, Amsterdam Medical Center
Amsterdam, Amsterdam, 1105 AZ
Intensive Care Unit, University Medical Center Radboud
Nijmegen, Nijmegen, 6525 GA
Italy1 site
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Rome, Rome, 00168
Romania1 site
Infectious Diseases Department, "Iuliu Hatieganu'' University of Medicine and Pharmacy Cluj-Napoca
Cluj-Napoca, Cluj-Napoca
Switzerland1 site
Intensive Care Unit, Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne, Lausanne, CH-1011
About this study
Official title: 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.
Read the 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.
- Conditions
- Sepsis
- Being tested
- Anakinra or rhIFNγ, Placebo
- Medical subject headings
- Sepsis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Anakinra or rhIFNγDrug
Also called Imukin, Kineret
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.
PlaceboDrug
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
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Anakinra or rhIFNγ |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mean total Sequential Organ Failure Assessment score
Difference in the mean total Sequential Organ Failure Assessment score between the two arms
Measured: 9 days
Secondary outcomes (4)
28-day mortality
Difference in mortality between the two arms
Measured: 28 days
90-day mortality
Difference in mortality between the two arms
Measured: 90 days
Mean total Sequential Organ Failure Assessment score
Difference in the mean total Sequential Organ Failure Assessment score between the two arms
Measured: 15 days
Reversal of hyper-inflammation (decrease of ferritin) or immunoparalysis (increase of Quantibrite)
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)
Measured: 15 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Aug 2021
- Study start29 Jul 2021
- Primary completion6 Feb 2024
- Study completion27 Apr 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for SepsisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- multicentre and multinational, double-blind, double-dummy randomized clinical trial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 280 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hellenic Institute for the Study of Sepsis
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Evagelos Giamarellos-Bourboulis, MD, PhD, Study chair, Hellenic Institute for the Study of Sepsis
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04990232
- Sponsor's protocol ID
- ImmunoSep
- Acronym
- ImmunoSep
- Status last verified
- Jan 2025
- First submitted
- 29 Jul 2021
- Last updated
- 19 Mar 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
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. 2026 Mar 3;335(9):775-786. doi: 10.1001/jama.2025.24175.
PubMed 41359996Giamarellos-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.
PubMed 36867758Kotsaki 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.
PubMed 36600424
Study at a glance
From the registry record, last updated by the sponsor on 19 Mar 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Personalized Immunotherapy in Sepsis: a Multicentre and Multinational, Double-blind, Double-dummy Randomized Clinical Trial
- ClinicalTrials.gov ID
- NCT04990232
- Acronym / sponsor ID
- ImmunoSep / ImmunoSep
- Conditions
- Sepsis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 280 participants (actual)
- Lead sponsor
- Hellenic Institute for the Study of SepsisUniversity, hospital or other
- Study start
- 29 Jul 2021 (actual)
- Primary completion
- 6 Feb 2024 (actual)
- Study completion
- 27 Apr 2024 (actual)
- First posted
- 4 Aug 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- multicentre and multinational, double-blind, double-dummy randomized clinical trial
| Arm | Type | Receives |
|---|---|---|
| Standard of care | Placebo comparator | Drug: PlaceboPatients 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. |
| Immunotherapy | Experimental | Drug: Anakinra or rhIFNγPatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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).
Key exclusion criteria (15 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Anakinra or rhIFNγAlso: Imukin, KineretIn 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. | Drug | Immunotherapy |
| Placebo20ml (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 | Standard of care |
Primary outcome
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
4 secondary outcomes
28-day mortality
Time frame: 28 days
90-day mortality
Time frame: 90 days
Mean total Sequential Organ Failure Assessment score
Time frame: 15 days
Reversal of hyper-inflammation (decrease of ferritin) or immunoparalysis (increase of Quantibrite)
Time frame: 15 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Mar 2025.
- Derived from this study: PubMed 41359996Giamarellos-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. 2026 Mar 3;335(9):775-786. doi: 10.1001/jama.2025.24175.
- Derived from this study: PubMed 36867758Giamarellos-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.
- Derived from this study: PubMed 36600424Kotsaki 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.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Evagelos Giamarellos-Bourboulis, MD, PhD study chair
Hellenic Institute for the Study of Sepsis
35 sites in 6 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Anakinra or rhIFNγ in people with Sepsis, run by Hellenic Institute for the Study of Sepsis at 35 sites in 6 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 35 sites in Greece, Netherlands, Germany, Italy, Romania and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mean total Sequential Organ Failure Assessment score (time frame: 9 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04990232, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Mar 2025.