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

Sepsis Clinical Trial

— PROVIDE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03332225
• Other study ID #: PROVIDE
• Secondary ID: 2017-002171-26
• Status: Completed
• Phase: Phase 2
• Start date: December 15, 2017
• Est. completion date: December 31, 2019

Study information

• Verified date: July 2020
• Source: Hellenic Institute for the Study of Sepsis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: December 31, 2019
• Est. primary completion date: December 31, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Immune System Diseases
• Macrophage Activation Syndrome
• Sepsis
• Toxemia

Intervention

Drug:
• Anakinra
Treatment with anakinra
• Recombinant human interferon-gamma
Treatment with recombinant human interferon-gamma
• Placebo
Treatment with Placebo

Locations

Country	Name	City	State
Greece	Intensive Care Unit, Alexandroupolis University Hospital	Alexandroupolis
Greece	1st Department of Pulmonary Medicine and Intensive Care Unit	Athens
Greece	2nd Department of Critical Care Medicine	Athens	Haidari
Greece	4th Department of Internal Medicine	Athens	Haidari
Greece	Intensive Care Unit, Center for Accident Rehabilitation (KAT) of Athens	Athens	Kifissia
Greece	Intensive Care Unit, "Latsio", Thriasio Elefsis General Hospital	Elefsína
Greece	Intensive Care Unit, Ioannina University Hospital	Ioánnina	Ioannina
Greece	Department of Internal Medicine, Larissa University Hospital	Larissa
Greece	Intensive Care Unit, "Koutlimbaneio & Triantafylleio" Larissa General Hospital	Larissa
Greece	Department of Internal Medicine, Patras University Hospital	Patras	Rion
Greece	Intensive Care Unit, "Tzanio" Piraeus General Hospital	Piraeus
Greece	Intensive Care Unit, "Aghios Dimitrios" Thessaloniki General Hospital	Salónica
Greece	Intensive Care Unit, "G.Gennimatas" Thessaloniki General Hospital	Salónica

Sponsors (1)

Lead Sponsor	Collaborator
Hellenic Institute for the Study of Sepsis

Country where clinical trial is conducted

Greece, 

References & Publications (12)

Calandra 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. Rev — View Citation

Christ-Crain M, Jaccard-Stolz D, Bingisser R, Gencay MM, Huber PR, Tamm M, Müller B. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lance — View Citation

Döcke 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. — View Citation

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 — View Citation

Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O'Grady NP, Bartlett JG, Carratalà 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 Wit — View Citation

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, Armagani — View Citation

Leentjens 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. d — View Citation

Opal 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 — View Citation

Pontikis 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 exte — View Citation

Shakoory 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 — View Citation

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 C — View Citation

Zilberberg 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. Review. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mortality	Mortality will be compared between the groups of treatment	28 days
Secondary	Mortality	Mortality will be compared between the groups of treatment	90 days
Secondary	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	28 days
Secondary	Time to infection resolution	The time to infection resolution will be compared between the groups of treatment	28 days
Secondary	Duration of hospitalisation	The duration of hospitalisation will be compared between the groups of treatment	28 days
Secondary	Number of secondary infections	The number of secondary infections will be compared between the groups of treatment	28 days
Secondary	Cytokine stimulation	Cytokine stimulation from peripheral blood mononuclear cells will be compared between the groups of treatment	4 days
Secondary	Cytokine stimulation	Cytokine stimulation from peripheral blood mononuclear cells will be compared between the groups of treatment	7 days
Secondary	Gene expression	Gene expression of peripheral blood mononuclear cells will be compared between the groups of treatment	7 days
Secondary	Gut microbiome changes	Gut microbiome changes will be compared between the groups of treatment	7 days
Secondary	Epigenetic changes	Epigenetic changes of circulating monocytes will be compared between the groups of treatment	7 days
Secondary	Classification of the immune function	Classification of the immune function of screened patients not characterized with MALS neither with hypo-inflammation	28 days