A Trial of Validation and Restoration of Immune Dysfunction in Severe Infections and Sepsis (PROVIDE)
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ClinicalTrials.gov Identifier: NCT03332225 |
Recruitment Status :
Completed
First Posted : November 6, 2017
Last Update Posted : July 29, 2020
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
Sepsis Macrophage Activation Syndrome | Drug: Anakinra Drug: Recombinant human interferon-gamma Drug: Placebo | Phase 2 |

Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 36 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Intervention Model Description: | Treatment with recombinant human interferon-gamma or anakinra |
Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
Primary Purpose: | Treatment |
Official Title: | A Personalized Randomized Trial of Validation and Restoration of Immune Dysfunction in Severe Infections and Sepsis |
Actual Study Start Date : | December 15, 2017 |
Actual Primary Completion Date : | December 31, 2019 |
Actual Study Completion Date : | December 31, 2019 |

Arm | Intervention/treatment |
---|---|
Experimental: Anakinra
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
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Drug: Anakinra
Treatment with anakinra
Other Name: Kineret |
Placebo Comparator: IV Placebo
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
Treatment with Placebo
Other Name: Saline Solution |
Experimental: Recombinant human interferon-gamma
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
Treatment with recombinant human interferon-gamma
Other Name: Imukin |
- Mortality [ Time Frame: 28 days ]Mortality will be compared between the groups of treatment
- Mortality [ Time Frame: 90 days ]Mortality will be compared between the groups of treatment
- Time to decrease of SOFA score by more than 50% [ Time Frame: 28 days ]The time to decrease of SOFA score by more than 50% will be compared between the groups of treatment
- Time to infection resolution [ Time Frame: 28 days ]The time to infection resolution will be compared between the groups of treatment
- Duration of hospitalisation [ Time Frame: 28 days ]The duration of hospitalisation will be compared between the groups of treatment
- Number of secondary infections [ Time Frame: 28 days ]The number of secondary infections will be compared between the groups of treatment
- Cytokine stimulation [ Time Frame: 4 days ]Cytokine stimulation from peripheral blood mononuclear cells will be compared between the groups of treatment
- Cytokine stimulation [ Time Frame: 7 days ]Cytokine stimulation from peripheral blood mononuclear cells will be compared between the groups of treatment
- Gene expression [ Time Frame: 7 days ]Gene expression of peripheral blood mononuclear cells will be compared between the groups of treatment
- Gut microbiome changes [ Time Frame: 7 days ]Gut microbiome changes will be compared between the groups of treatment
- Epigenetic changes [ Time Frame: 7 days ]Epigenetic changes of circulating monocytes will be compared between the groups of treatment
- Classification of the immune function [ Time Frame: 28 days ]Classification of the immune function of screened patients not characterized with MALS neither with hypo-inflammation

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- 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%
Exclusion Criteria:
- 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
- Pregnancy or lactation. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03332225
Greece | |
2nd Department of Critical Care Medicine | |
Athens, Haidari, Greece, 12462 | |
4th Department of Internal Medicine | |
Athens, Haidari, Greece, 12462 | |
Intensive Care Unit, Ioannina University Hospital | |
Ioánnina, Ioannina, Greece, 45500 | |
Intensive Care Unit, Center for Accident Rehabilitation (KAT) of Athens | |
Athens, Kifissia, Greece, 14561 | |
Department of Internal Medicine, Patras University Hospital | |
Patras, Rion, Greece, 26504 | |
Intensive Care Unit, Alexandroupolis University Hospital | |
Alexandroupolis, Greece, 68100 | |
1st Department of Pulmonary Medicine and Intensive Care Unit | |
Athens, Greece, 11527 | |
Intensive Care Unit, "Latsio", Thriasio Elefsis General Hospital | |
Elefsína, Greece, 19600 | |
Intensive Care Unit, "Koutlimbaneio & Triantafylleio" Larissa General Hospital | |
Larissa, Greece, 41221 | |
Department of Internal Medicine, Larissa University Hospital | |
Larissa, Greece, 41334 | |
Intensive Care Unit, "Tzanio" Piraeus General Hospital | |
Piraeus, Greece, 18536 | |
Intensive Care Unit, "Aghios Dimitrios" Thessaloniki General Hospital | |
Salónica, Greece, 54634 | |
Intensive Care Unit, "G.Gennimatas" Thessaloniki General Hospital | |
Salónica, Greece, 54635 |
Principal Investigator: | Antonios Papadopoulos, MD, PhD | National Kapodistrian University of Athens, Medical School |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: | Hellenic Institute for the Study of Sepsis |
ClinicalTrials.gov Identifier: | NCT03332225 |
Other Study ID Numbers: |
PROVIDE 2017-002171-26 ( EudraCT Number ) |
First Posted: | November 6, 2017 Key Record Dates |
Last Update Posted: | July 29, 2020 |
Last Verified: | July 2020 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | No |
Studies a U.S. FDA-regulated Device Product: | No |
sepsis macrophage activation syndrome immunoparalysis |
anakinra recombinant human interferon-gamma HLA-DR |
Sepsis Toxemia Immune System Diseases Macrophage Activation Syndrome Pathologic Processes Infections Systemic Inflammatory Response Syndrome Inflammation Lymphoproliferative Disorders |
Immunoproliferative Disorders Interferons Interferon-gamma Interleukin 1 Receptor Antagonist Protein Antineoplastic Agents Antiviral Agents Anti-Infective Agents Antirheumatic Agents |