A Trial of Validation and Restoration of Immune Dysfunction in Severe Infections and Sepsis

NCT03332225 | Completed Phase 2

• 2 other identifiers: PROVIDE2017-002171-26
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 13

Brief Summary

The aim of the study is to conduct one RCT of personalized immunotherapy in sepsis targeting patients who lie either on the predominantly hyper-inflammatory arm or on the predominantly hypo-inflammatory arm of the spectrum of the host response. These patients will be selected by the use of a panel of biomarkers and laboratory findings and they will be randomly allocated to placebo or immunotherapy treatment according to their needs.

Conditions

Sepsis; Macrophage Activation Syndrome

Keywords

sepsis; macrophage activation syndrome; immunoparalysis; anakinra; recombinant human interferon-gamma; HLA-DR

Outcome Measures

Primary Outcomes (1)

• Mortality

  Mortality will be compared between the groups of treatment

  28 days

Secondary Outcomes (11)

• Mortality

  90 days

• Time to decrease of SOFA score by more than 50%

  28 days

• Time to infection resolution

  28 days

• Duration of hospitalisation

  28 days

• Number of secondary infections

  28 days

Study Arms (3)

Anakinra

EXPERIMENTAL

Treatment with iv anakinra 200 mg three times daily (every eight hours) for seven days and sc 1ml N/S 0.9% every other day for 15 days

Drug: Anakinra

IV Placebo

PLACEBO COMPARATOR

Treatment with iv 1ml N/S 0.9% three times daily (every eight hours) for seven days and sc 1ml N/S 0.9% every other day for 15 days

Drug: Placebo

Recombinant human interferon-gamma

EXPERIMENTAL

Treatment with sc recombinant human interferon-gamma every other day for a total of 15 days and with iv 1ml N/S 0.9% three times daily (every eight hours) for seven days

Drug: Recombinant human interferon-gamma

Interventions

Anakinra DRUG

Treatment with anakinra

Also known as: Kineret

Anakinra

Recombinant human interferon-gamma DRUG

Treatment with recombinant human interferon-gamma

Also known as: Imukin

Recombinant human interferon-gamma

Placebo DRUG

Treatment with Placebo

Also known as: Saline Solution

IV Placebo

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
• Male or female gender
• In case of women, unwillingness to remain 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 or hospital-acquired pneumonia or ventilator-associated pneumonia or primary bacteremia or acute cholangitis
• Sepsis defined by the Sepsis-3 definitions.
• Patients with laboratory diagnosis of MALS or hypo-inflammation (immune-paralysis) based on two consecutive blood sampling with 24 hours apart. MALS is defined as the presence of ferritin \>4,420 ng/ml and hypo-inflammation as HLA-DR expression on CD14-monocytes (co-expression) less than 30%

You may not qualify if:

• Age below 18 years
• Denial for written informed consent
• Acute pyelonephritis or intraabdominal infection other than AC, meningitis or skin infection. It is explicitly stated that in the case of a patient with both AC and any other type of intraabdominal infection, the patient cannot be enrolled.
• Any stage IV malignancy
• Any do not resuscitate decision
• 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 IV intake of corticosteroids at a daily dose equal or greater than 0.4 mg 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 (13)

2nd Department of Critical Care Medicine

Athens, Haidari, 12462, Greece

Location

4th Department of Internal Medicine

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, Patras University Hospital

Pátrai, Rion, 26504, Greece

Location

Intensive Care Unit, Alexandroupolis University Hospital

Alexandroupoli, 68100, Greece

Location

1st Department of Pulmonary Medicine and Intensive Care Unit

Athens, 11527, Greece

Location

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

Elefsina, 19600, Greece

Location

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

Larissa, 41221, Greece

Location

Department of Internal Medicine, Larissa University Hospital

Larissa, 41334, Greece

Location

Intensive Care Unit, "Tzanio" Piraeus General Hospital

Piraeus, 18536, Greece

Location

Intensive Care Unit, "Aghios Dimitrios" Thessaloniki General Hospital

Thessaloniki, 54634, Greece

Location

Intensive Care Unit, "G.Gennimatas" Thessaloniki General Hospital

Thessaloniki, 54635, Greece

Location

Related Publications (15)

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• Kyriazopoulou E, Leventogiannis K, Norrby-Teglund A, Dimopoulos G, Pantazi A, Orfanos SE, Rovina N, Tsangaris I, Gkavogianni T, Botsa E, Chassiou E, Kotanidou A, Kontouli C, Chaloulis P, Velissaris D, Savva A, Cullberg JS, Akinosoglou K, Gogos C, Armaganidis A, Giamarellos-Bourboulis EJ; Hellenic Sepsis Study Group. Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis. BMC Med. 2017 Sep 18;15(1):172. doi: 10.1186/s12916-017-0930-5.

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• Giamarellos-Bourboulis EJ, Tsaganos T, Tsangaris I, Lada M, Routsi C, Sinapidis D, Koupetori M, Bristianou M, Adamis G, Mandragos K, Dalekos GN, Kritselis I, Giannikopoulos G, Koutelidakis I, Pavlaki M, Antoniadou E, Vlachogiannis G, Koulouras V, Prekates A, Dimopoulos G, Koutsoukou A, Pnevmatikos I, Ioakeimidou A, Kotanidou A, Orfanos SE, Armaganidis A, Gogos C; Hellenic Sepsis Study Group. Validation of the new Sepsis-3 definitions: proposal for improvement in early risk identification. Clin Microbiol Infect. 2017 Feb;23(2):104-109. doi: 10.1016/j.cmi.2016.11.003. Epub 2016 Nov 14.

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• Kranidioti E, Ricano-Ponce I, Antonakos N, Kyriazopoulou E, Kotsaki A, Tsangaris I, Markopoulou D, Rovina N, Antoniadou E, Koutsodimitropoulos I, Dalekos GN, Vlachogianni G, Akinosoglou K, Koulouras V, Komnos A, Kontopoulou T, Dimopoulos G, Netea MG, Kumar V, Giamarellos-Bourboulis EJ. Modulation of Metabolomic Profile in Sepsis According to the State of Immune Activation. Crit Care Med. 2024 Nov 1;52(11):e536-e544. doi: 10.1097/CCM.0000000000006391. Epub 2024 Aug 23.

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• Leventogiannis K, Kyriazopoulou E, Antonakos N, Kotsaki A, Tsangaris I, Markopoulou D, Grondman I, Rovina N, Theodorou V, Antoniadou E, Koutsodimitropoulos I, Dalekos G, Vlachogianni G, Akinosoglou K, Koulouras V, Komnos A, Kontopoulou T, Prekates A, Koutsoukou A, van der Meer JWM, Dimopoulos G, Kyprianou M, Netea MG, Giamarellos-Bourboulis EJ. Toward personalized immunotherapy in sepsis: The PROVIDE randomized clinical trial. Cell Rep Med. 2022 Nov 15;3(11):100817. doi: 10.1016/j.xcrm.2022.100817.

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MeSH Terms

Conditions

Sepsis; Macrophage Activation Syndrome

Interventions

Interleukin 1 Receptor Antagonist Protein; Saline Solution

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Antonios Papadopoulos, MD, PhD

  National Kapodistrian University of Athens, Medical School

  PRINCIPAL INVESTIGATOR

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: Treatment with recombinant human interferon-gamma or anakinra

Study Record Dates

• First Submitted: October 27, 2017
• First Posted: November 6, 2017
• Study Start: December 15, 2017
• Primary Completion: December 31, 2019
• Study Completion: December 31, 2019
• Last Updated: July 29, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

GR (13)