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

Primary Purpose

Sepsis, Macrophage Activation Syndrome

Status
Completed
Phase
Phase 2
Locations
Greece
Study Type
Interventional
Intervention
Anakinra
Recombinant human interferon-gamma
Placebo
Sponsored by
Hellenic Institute for the Study of Sepsis
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sepsis focused on measuring sepsis, macrophage activation syndrome, immunoparalysis, anakinra, recombinant human interferon-gamma, HLA-DR

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • 2nd Department of Critical Care Medicine
  • 4th Department of Internal Medicine
  • Intensive Care Unit, Ioannina University Hospital
  • Intensive Care Unit, Center for Accident Rehabilitation (KAT) of Athens
  • Department of Internal Medicine, Patras University Hospital
  • Intensive Care Unit, Alexandroupolis University Hospital
  • 1st Department of Pulmonary Medicine and Intensive Care Unit
  • Intensive Care Unit, "Latsio", Thriasio Elefsis General Hospital
  • Intensive Care Unit, "Koutlimbaneio & Triantafylleio" Larissa General Hospital
  • Department of Internal Medicine, Larissa University Hospital
  • Intensive Care Unit, "Tzanio" Piraeus General Hospital
  • Intensive Care Unit, "Aghios Dimitrios" Thessaloniki General Hospital
  • Intensive Care Unit, "G.Gennimatas" Thessaloniki General Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Experimental

Arm Label

Anakinra

IV Placebo

Recombinant human interferon-gamma

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

Mortality
Mortality will be compared between the groups of treatment

Secondary Outcome Measures

Mortality
Mortality will be compared between the groups of treatment
Time to decrease of SOFA score by more than 50%
The time to decrease of SOFA score by more than 50% will be compared between the groups of treatment
Time to infection resolution
The time to infection resolution will be compared between the groups of treatment
Duration of hospitalisation
The duration of hospitalisation will be compared between the groups of treatment
Number of secondary infections
The number of secondary infections will be compared between the groups of treatment
Cytokine stimulation
Cytokine stimulation from peripheral blood mononuclear cells will be compared between the groups of treatment
Cytokine stimulation
Cytokine stimulation from peripheral blood mononuclear cells will be compared between the groups of treatment
Gene expression
Gene expression of peripheral blood mononuclear cells will be compared between the groups of treatment
Gut microbiome changes
Gut microbiome changes will be compared between the groups of treatment
Epigenetic changes
Epigenetic changes of circulating monocytes will be compared between the groups of treatment
Classification of the immune function
Classification of the immune function of screened patients not characterized with MALS neither with hypo-inflammation

Full Information

First Posted
October 27, 2017
Last Updated
July 28, 2020
Sponsor
Hellenic Institute for the Study of Sepsis
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1. Study Identification

Unique Protocol Identification Number
NCT03332225
Brief Title
A Trial of Validation and Restoration of Immune Dysfunction in Severe Infections and Sepsis
Acronym
PROVIDE
Official Title
A Personalized Randomized Trial of Validation and Restoration of Immune Dysfunction in Severe Infections and Sepsis
Study Type
Interventional

2. Study Status

Record Verification Date
July 2020
Overall Recruitment Status
Completed
Study Start Date
December 15, 2017 (Actual)
Primary Completion Date
December 31, 2019 (Actual)
Study Completion Date
December 31, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hellenic Institute for the Study of Sepsis

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.
Detailed Description
Sepsis is a life-threatening organ dysfunction that results from the dysregulated host response to an infection. Accumulating knowledge suggests that this dysregulated host response has a broad spectrum where some patients lie to the two extremes of this spectrum whereas the majority of patients lie in between. The first extreme encompasses patients who are dominated from a hyper-inflammatory response to an infectious insult. On the other extreme lie patients who do not have any hyper-inflammatory response; instead these patients are dominated by an exhausted immune response to an infectious stimulus. The remaining patients have features of both hyper- and hypo-inflammatory responses. Randomized clinical trials (RCTs) that have investigated the effects of immunotherapy in sepsis have all failed to establish beneficial effects for the patients. The reasons for that are multiple but one of the most important is the current notion that sepsis is a complex disorder with heterogeneity regarding patient characteristics. Thus, it is necessary to try and find ways to personalise the immunomodulatory treatment of sepsis. In the clinical trial proposed here, two personalised approaches will be investigated. Some 25 years ago, there were high expectations of the blockade of interleukin (IL)-1 in sepsis using the human recombinant IL-1 receptor antagonist, anakinra. The expectations were based on animal experiments as well as positive results in a single-centre clinical trial. However, in a large international trial, anakinra did not show benefit over placebo. Still, it became clear from this study, enrolling 906 patients that intravenous anakinra was a very safe drug: there was neither excess mortality in these critically ill patients, nor increased susceptibility to secondary infections. In a post-hoc analysis of this trial published in 2016, it was demonstrated that a subgroup of 34 patients showed a clinical picture compatible with macrophage activation syndrome. Since bone marrow was not performed in these patients, the investigators prefer to call this macrophage activation like syndrome (MALS). MALS is a dreaded complication with a mortality rate in the order of 70%. The post-hoc analysis showed that patients receiving anakinra had 30% significant survival benefit compared to those receiving placebo. From these data it can be concluded that it is important to recognize patients with this complication of sepsis and that anakinra might be a beneficial drug. A survey of the database of sepsis patients in the Hellenic Sepsis Study Group revealed that 5% of the patients with septic shock suffered from MALS. It was found in this study that MAS can be easily and reliably diagnosed by measuring ferritin in the blood. A cut off of 4.420ng/ml had specificity more than 97%. Another important clinical phenomenon in sepsis is that patients may run into a phase of immunoparalysis. In this situation, the immune cells do not produce any more proinflammatory cytokines and switch to production of anti-inflammatory cytokines such as IL-10; they also loose important functional markers such HLA-DR. Patients with immunoparalysis have a 50% risk of dying in the subsequent 28 days. There is evidence from preclinical studies and from the endotoxin challenge model in human volunteers that immunoparalysis is reversible at least to some extent. The best candidate drug for this would be interferon gamma (IFNγ). Immunosuppression established in healthy volunteers after experimental endotoxemia was reversed after administration of recombinant human interferon-gamma (rhIFNγ). rhIFNγ was also investigated for this purpose in nine patients at septic shock in a small open-label and non-randomized clinical trial; reversal of immunoparalysis was achieved. The extensive experience with IFNγ teaches that it is a safe drug, the main side effect being fever and flu-like syndrome, which can be mitigated by premedication with a prostaglandin inhibitor like paracetamol. In patients with autoimmune diseases like systemic lupus erythematosus (SLE) and multiple sclerosis flares of the disease induced by IFNγ have been described. So these diseases are contraindications for the drug. The purpose of this study is to investigate in a randomised placebo-controlled clinical trial with a double-dummy design in patients with septic shock, whether personalised immunotherapy directed against either MALS or immunoparalysis is able to change the perspective for these critically ill patients. MALS is considered as a more direct life-threatening manifestation of sepsis than immunoparalysis. For that reason all patients will be randomised with evidence of MALS for anakinra or placebo, irrespective the state of immunity as measured by HLA-DR positivity. 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 allocated to placebo or immunotherapy treatment according to their needs.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sepsis, Macrophage Activation Syndrome
Keywords
sepsis, macrophage activation syndrome, immunoparalysis, anakinra, recombinant human interferon-gamma, HLA-DR

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Treatment with recombinant human interferon-gamma or anakinra
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
36 (Actual)

8. Arms, Groups, and Interventions

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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Antonios Papadopoulos, MD, PhD
Organizational Affiliation
National Kapodistrian University of Athens, Medical School
Official's Role
Principal Investigator
Facility Information:
Facility Name
2nd Department of Critical Care Medicine
City
Athens
State/Province
Haidari
ZIP/Postal Code
12462
Country
Greece
Facility Name
4th Department of Internal Medicine
City
Athens
State/Province
Haidari
ZIP/Postal Code
12462
Country
Greece
Facility Name
Intensive Care Unit, Ioannina University Hospital
City
Ioánnina
State/Province
Ioannina
ZIP/Postal Code
45500
Country
Greece
Facility Name
Intensive Care Unit, Center for Accident Rehabilitation (KAT) of Athens
City
Athens
State/Province
Kifissia
ZIP/Postal Code
14561
Country
Greece
Facility Name
Department of Internal Medicine, Patras University Hospital
City
Patras
State/Province
Rion
ZIP/Postal Code
26504
Country
Greece
Facility Name
Intensive Care Unit, Alexandroupolis University Hospital
City
Alexandroupolis
ZIP/Postal Code
68100
Country
Greece
Facility Name
1st Department of Pulmonary Medicine and Intensive Care Unit
City
Athens
ZIP/Postal Code
11527
Country
Greece
Facility Name
Intensive Care Unit, "Latsio", Thriasio Elefsis General Hospital
City
Elefsína
ZIP/Postal Code
19600
Country
Greece
Facility Name
Intensive Care Unit, "Koutlimbaneio & Triantafylleio" Larissa General Hospital
City
Larissa
ZIP/Postal Code
41221
Country
Greece
Facility Name
Department of Internal Medicine, Larissa University Hospital
City
Larissa
ZIP/Postal Code
41334
Country
Greece
Facility Name
Intensive Care Unit, "Tzanio" Piraeus General Hospital
City
Piraeus
ZIP/Postal Code
18536
Country
Greece
Facility Name
Intensive Care Unit, "Aghios Dimitrios" Thessaloniki General Hospital
City
Salónica
ZIP/Postal Code
54634
Country
Greece
Facility Name
Intensive Care Unit, "G.Gennimatas" Thessaloniki General Hospital
City
Salónica
ZIP/Postal Code
54635
Country
Greece

12. IPD Sharing Statement

Plan to Share IPD
No
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A Trial of Validation and Restoration of Immune Dysfunction in Severe Infections and Sepsis

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