SepsisPhase 2PROVIDENCT03332225
A Trial of Validation and Restoration of Immune Dysfunction in Severe Infections and Sepsis
A Phase 2 study testing Anakinra and Recombinant human interferon-gamma in people with Sepsis and Macrophage Activation Syndrome, run by Hellenic Institute for the Study of Sepsis at 13 sites in Greece.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sepsis, Macrophage Activation Syndrome
- What is being tested?
- Anakinra and Recombinant human interferon-gamma
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 36 participants
- Where
- 13 sitesGreece
- Study dates
- 15 Dec 2017to 31 Dec 2019
- 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
- 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%
Who cannot join
- 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.
Show all 14Show fewer
- 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
Trial locations and contacts
13 sites in 1 country.
13 sites in 1 country
Greece13 sites
Intensive Care Unit, Alexandroupolis University Hospital
Alexandroupoli, 68100
2nd Department of Critical Care Medicine
Athens, Haidari, 12462
4th Department of Internal Medicine
Athens, Haidari, 12462
Intensive Care Unit, Center for Accident Rehabilitation (KAT) of Athens
Athens, Kifissia, 14561
1st Department of Pulmonary Medicine and Intensive Care Unit
Athens, 11527
Intensive Care Unit, "Latsio", Thriasio Elefsis General Hospital
Elefsina, 19600
Intensive Care Unit, Ioannina University Hospital
Ioannina, Ioannina, 45500
Intensive Care Unit, "Koutlimbaneio & Triantafylleio" Larissa General Hospital
Larissa, 41221
Department of Internal Medicine, Larissa University Hospital
Larissa, 41334
Department of Internal Medicine, Patras University Hospital
Pátrai, Rion, 26504
Intensive Care Unit, "Tzanio" Piraeus General Hospital
Piraeus, 18536
Intensive Care Unit, "Aghios Dimitrios" Thessaloniki General Hospital
Thessaloniki, 54634
Intensive Care Unit, "G.Gennimatas" Thessaloniki General Hospital
Thessaloniki, 54635
About this study
Official title: A Personalized Randomized Trial of Validation and Restoration of Immune Dysfunction in Severe Infections and Sepsis
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.
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 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.
- Conditions
- Sepsis, Macrophage Activation Syndrome
- Being tested
- Anakinra, Recombinant human interferon-gamma, Placebo
- Keywords
- sepsis, macrophage activation syndrome, immunoparalysis, anakinra, recombinant human interferon-gamma, HLA-DR
- Medical subject headings
- Sepsis, Macrophage Activation Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AnakinraDrug
Also called Kineret
Treatment with anakinra
Recombinant human interferon-gammaDrug
Also called Imukin
Treatment with recombinant human interferon-gamma
PlaceboDrug
Also called Saline Solution
Treatment with Placebo
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: 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 Receives: Drug: Recombinant human interferon-gamma |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mortality
Mortality will be compared between the groups of treatment
Measured: 28 days
Secondary outcomes (11)
Mortality
Mortality will be compared between the groups of treatment
Measured: 90 days
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
Measured: 28 days
Time to infection resolution
The time to infection resolution will be compared between the groups of treatment
Measured: 28 days
Duration of hospitalisation
The duration of hospitalisation will be compared between the groups of treatment
Measured: 28 days
Number of secondary infections
The number of secondary infections will be compared between the groups of treatment
Measured: 28 days
Cytokine stimulation
Cytokine stimulation from peripheral blood mononuclear cells will be compared between the groups of treatment
Measured: 4 days
Cytokine stimulation
Cytokine stimulation from peripheral blood mononuclear cells will be compared between the groups of treatment
Measured: 7 days
Gene expression
Gene expression of peripheral blood mononuclear cells will be compared between the groups of treatment
Measured: 7 days
Gut microbiome changes
Gut microbiome changes will be compared between the groups of treatment
Measured: 7 days
Epigenetic changes
Epigenetic changes of circulating monocytes will be compared between the groups of treatment
Measured: 7 days
Classification of the immune function
Classification of the immune function of screened patients not characterized with MALS neither with hypo-inflammation
Measured: 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Nov 2017
- Study start15 Dec 2017
- Primary completion31 Dec 2019
- Study completion31 Dec 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (15)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
- Treatment with recombinant human interferon-gamma or anakinra
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 36 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hellenic Institute for the Study of Sepsis
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Antonios Papadopoulos, MD, PhD, Principal investigator, National Kapodistrian University of Athens, Medical School
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03332225
- Sponsor's protocol ID
- PROVIDE
- Other IDs
- 2017-002171-26, 2017
- Acronym
- PROVIDE
- Status last verified
- Jul 2020
- First submitted
- 27 Oct 2017
- Last updated
- 29 Jul 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.
PubMed 26903338Opal SM, Fisher CJ Jr, Dhainaut JF, Vincent JL, Brase R, Lowry SF, Sadoff JC, Slotman GJ, Levy H, Balk RA, Shelly MP, Pribble JP, LaBrecque JF, Lookabaugh J, Donovan H, Dubin H, Baughman R, Norman J, DeMaria E, Matzel K, Abraham E, Seneff M. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med. 1997 Jul;25(7):1115-24. doi: 10.1097/00003246-199707000-00010.
PubMed 9233735Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, Cron RQ, Opal SM. Interleukin-1 Receptor Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial. Crit Care Med. 2016 Feb;44(2):275-81. doi: 10.1097/CCM.0000000000001402.
PubMed 26584195Kyriazopoulou 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.
PubMed 28918754Leentjens J, Kox M, Koch RM, Preijers F, Joosten LA, van der Hoeven JG, Netea MG, Pickkers P. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med. 2012 Nov 1;186(9):838-45. doi: 10.1164/rccm.201204-0645OC. Epub 2012 Jul 19.
PubMed 22822024Docke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, Volk HD, Kox W. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med. 1997 Jun;3(6):678-81. doi: 10.1038/nm0697-678.
PubMed 9176497Calandra T, Cohen J; International Sepsis Forum Definition of Infection in the ICU Consensus Conference. The international sepsis forum consensus conference on definitions of infection in the intensive care unit. Crit Care Med. 2005 Jul;33(7):1538-48. doi: 10.1097/01.ccm.0000168253.91200.83.
PubMed 16003060Christ-Crain M, Jaccard-Stolz D, Bingisser R, Gencay MM, Huber PR, Tamm M, Muller B. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet. 2004 Feb 21;363(9409):600-7. doi: 10.1016/S0140-6736(04)15591-8.
PubMed 14987884Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O'Grady NP, Bartlett JG, Carratala J, El Solh AA, Ewig S, Fey PD, File TM Jr, Restrepo MI, Roberts JA, Waterer GW, Cruse P, Knight SL, Brozek JL. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016 Sep 1;63(5):e61-e111. doi: 10.1093/cid/ciw353. Epub 2016 Jul 14.
PubMed 27418577Zilberberg MD, Shorr AF. Ventilator-associated pneumonia: the clinical pulmonary infection score as a surrogate for diagnostics and outcome. Clin Infect Dis. 2010 Aug 1;51 Suppl 1:S131-5. doi: 10.1086/653062.
PubMed 20597663Giamarellos-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.
PubMed 27856268Pontikis K, Karaiskos I, Bastani S, Dimopoulos G, Kalogirou M, Katsiari M, Oikonomou A, Poulakou G, Roilides E, Giamarellou H. Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drug-resistant carbapenemase-producing Gram-negative bacteria. Int J Antimicrob Agents. 2014 Jan;43(1):52-9. doi: 10.1016/j.ijantimicag.2013.09.010. Epub 2013 Oct 16.
PubMed 24183799Kranidioti 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.
PubMed 39418210Leventogiannis 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.
PubMed 36384100Karakike E, Giamarellos-Bourboulis EJ. Macrophage Activation-Like Syndrome: A Distinct Entity Leading to Early Death in Sepsis. Front Immunol. 2019 Jan 31;10:55. doi: 10.3389/fimmu.2019.00055. eCollection 2019.
PubMed 30766533
Study at a glance
From the registry record, last updated by the sponsor on 29 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Personalized Randomized Trial of Validation and Restoration of Immune Dysfunction in Severe Infections and Sepsis
- ClinicalTrials.gov ID
- NCT03332225
- Acronym / sponsor ID
- PROVIDE / PROVIDE
- Conditions
- Sepsis, Macrophage Activation Syndrome
- Keywords
- sepsis, macrophage activation syndrome, immunoparalysis, anakinra, recombinant human interferon-gamma, HLA-DR
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 36 participants (actual)
- Lead sponsor
- Hellenic Institute for the Study of SepsisUniversity, hospital or other
- Study start
- 15 Dec 2017 (actual)
- Primary completion
- 31 Dec 2019 (actual)
- Study completion
- 31 Dec 2019 (actual)
- First posted
- 6 Nov 2017 (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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- Treatment with recombinant human interferon-gamma or anakinra
| Arm | Type | Receives |
|---|---|---|
| Anakinra | Experimental | Drug: AnakinraTreatment 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 |
| IV Placebo | Placebo comparator | Drug: PlaceboTreatment 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 |
| Recombinant human interferon-gamma | Experimental | Drug: Recombinant human interferon-gammaTreatment 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (14 listed)
- 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
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 |
|---|---|---|
| AnakinraAlso: KineretTreatment with anakinra | Drug | Anakinra |
| Recombinant human interferon-gammaAlso: ImukinTreatment with recombinant human interferon-gamma | Drug | Recombinant human interferon-gamma |
| PlaceboAlso: Saline SolutionTreatment with Placebo | Drug | IV Placebo |
Primary outcome
Mortality
Time frame: 28 days
Mortality will be compared between the groups of treatment
11 secondary outcomes
Mortality
Time frame: 90 days
Time to decrease of SOFA score by more than 50%
Time frame: 28 days
Time to infection resolution
Time frame: 28 days
Duration of hospitalisation
Time frame: 28 days
Number of secondary infections
Time frame: 28 days
Cytokine stimulation
Time frame: 4 days
Cytokine stimulation
Time frame: 7 days
Gene expression
Time frame: 7 days
Gut microbiome changes
Time frame: 7 days
Epigenetic changes
Time frame: 7 days
Classification of the immune function
Time frame: 28 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 29 Jul 2020.
- Results publication: PubMed 26903338Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.
- Results publication: PubMed 9233735Opal SM, Fisher CJ Jr, Dhainaut JF, Vincent JL, Brase R, Lowry SF, Sadoff JC, Slotman GJ, Levy H, Balk RA, Shelly MP, Pribble JP, LaBrecque JF, Lookabaugh J, Donovan H, Dubin H, Baughman R, Norman J, DeMaria E, Matzel K, Abraham E, Seneff M. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med. 1997 Jul;25(7):1115-24. doi: 10.1097/00003246-199707000-00010.
- Results publication: PubMed 26584195Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, Cron RQ, Opal SM. Interleukin-1 Receptor Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial. Crit Care Med. 2016 Feb;44(2):275-81. doi: 10.1097/CCM.0000000000001402.
- Results publication: PubMed 28918754Kyriazopoulou 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.
- Results publication: PubMed 22822024Leentjens J, Kox M, Koch RM, Preijers F, Joosten LA, van der Hoeven JG, Netea MG, Pickkers P. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med. 2012 Nov 1;186(9):838-45. doi: 10.1164/rccm.201204-0645OC. Epub 2012 Jul 19.
- Results publication: PubMed 9176497Docke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, Volk HD, Kox W. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med. 1997 Jun;3(6):678-81. doi: 10.1038/nm0697-678.
- Results publication: PubMed 16003060Calandra T, Cohen J; International Sepsis Forum Definition of Infection in the ICU Consensus Conference. The international sepsis forum consensus conference on definitions of infection in the intensive care unit. Crit Care Med. 2005 Jul;33(7):1538-48. doi: 10.1097/01.ccm.0000168253.91200.83.
- Results publication: PubMed 14987884Christ-Crain M, Jaccard-Stolz D, Bingisser R, Gencay MM, Huber PR, Tamm M, Muller B. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet. 2004 Feb 21;363(9409):600-7. doi: 10.1016/S0140-6736(04)15591-8.
- Results publication: PubMed 27418577Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O'Grady NP, Bartlett JG, Carratala J, El Solh AA, Ewig S, Fey PD, File TM Jr, Restrepo MI, Roberts JA, Waterer GW, Cruse P, Knight SL, Brozek JL. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016 Sep 1;63(5):e61-e111. doi: 10.1093/cid/ciw353. Epub 2016 Jul 14.
- Results publication: PubMed 20597663Zilberberg MD, Shorr AF. Ventilator-associated pneumonia: the clinical pulmonary infection score as a surrogate for diagnostics and outcome. Clin Infect Dis. 2010 Aug 1;51 Suppl 1:S131-5. doi: 10.1086/653062.
- Results publication: PubMed 27856268Giamarellos-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.
- Results publication: PubMed 24183799Pontikis K, Karaiskos I, Bastani S, Dimopoulos G, Kalogirou M, Katsiari M, Oikonomou A, Poulakou G, Roilides E, Giamarellou H. Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drug-resistant carbapenemase-producing Gram-negative bacteria. Int J Antimicrob Agents. 2014 Jan;43(1):52-9. doi: 10.1016/j.ijantimicag.2013.09.010. Epub 2013 Oct 16.
- Individual participant dataSharing planned: No
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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.
Antonios Papadopoulos, MD, PhD principal investigator
National Kapodistrian University of Athens, Medical School
13 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Anakinra and Recombinant human interferon-gamma in people with Sepsis and Macrophage Activation Syndrome, run by Hellenic Institute for the Study of Sepsis at 13 sites in Greece.
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 7 inclusion and 14 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 29 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in Greece. 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?
Mortality (time frame: 28 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 NCT03332225, which also lists 15 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 29 Jul 2020.