Sepsis Clinical Trial
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.
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.
;
Status | Clinical Trial | Phase | |
---|---|---|---|
Active, not recruiting |
NCT05095324 -
The Biomarker Prediction Model of Septic Risk in Infected Patients
|
||
Completed |
NCT02714595 -
Study of Cefiderocol (S-649266) or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens
|
Phase 3 | |
Completed |
NCT03644030 -
Phase Angle, Lean Body Mass Index and Tissue Edema and Immediate Outcome of Cardiac Surgery Patients
|
||
Completed |
NCT02867267 -
The Efficacy and Safety of Ta1 for Sepsis
|
Phase 3 | |
Completed |
NCT04804306 -
Sepsis Post Market Clinical Utility Simple Endpoint Study - HUMC
|
||
Recruiting |
NCT05578196 -
Fecal Microbial Transplantation in Critically Ill Patients With Severe Infections.
|
N/A | |
Terminated |
NCT04117568 -
The Role of Emergency Neutrophils and Glycans in Postoperative and Septic Patients
|
||
Completed |
NCT03550794 -
Thiamine as a Renal Protective Agent in Septic Shock
|
Phase 2 | |
Completed |
NCT04332861 -
Evaluation of Infection in Obstructing Urolithiasis
|
||
Completed |
NCT04227652 -
Control of Fever in Septic Patients
|
N/A | |
Enrolling by invitation |
NCT05052203 -
Researching the Effects of Sepsis on Quality Of Life, Vitality, Epigenome and Gene Expression During RecoverY From Sepsis
|
||
Terminated |
NCT03335124 -
The Effect of Vitamin C, Thiamine and Hydrocortisone on Clinical Course and Outcome in Patients With Severe Sepsis and Septic Shock
|
Phase 4 | |
Recruiting |
NCT04005001 -
Machine Learning Sepsis Alert Notification Using Clinical Data
|
Phase 2 | |
Completed |
NCT03258684 -
Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Sepsis and Septic Shock
|
N/A | |
Recruiting |
NCT05217836 -
Iron Metabolism Disorders in Patients With Sepsis or Septic Shock.
|
||
Completed |
NCT05018546 -
Safety and Efficacy of Different Irrigation System in Retrograde Intrarenal Surgery
|
N/A | |
Completed |
NCT03295825 -
Heparin Binding Protein in Early Sepsis Diagnosis
|
N/A | |
Not yet recruiting |
NCT06045130 -
PUFAs in Preterm Infants
|
||
Not yet recruiting |
NCT05361135 -
18-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in S. Aureus Bacteraemia
|
N/A | |
Not yet recruiting |
NCT05443854 -
Impact of Aminoglycosides-based Antibiotics Combination and Protective Isolation on Outcomes in Critically-ill Neutropenic Patients With Sepsis: (Combination-Lock01)
|
Phase 3 |