Plasma Inducible Nitric Oxide Synthase (iNOS) Assay and Sepsis Study

Sepsis Clinical Trial

— PliNOSa® Test  

Official title:

Evaluation of the PliNOSa® Test as an Aid in the Risk Assessment for the Onset of Sepsis

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01371929
• Other study ID #: RDAbs 11-001
• Secondary ID: 1RC3GM093717-01
• Status: Terminated
• Start date: February 4, 2013
• Est. completion date: September 30, 2015

Study information

• Verified date: November 2023
• Source: Research & Diagnostic Antibodies
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The primary objective is to demonstrate that the plasma inducible nitric oxide synthase (iNOS) assay (PliNOSa® test) has an acceptable relative risk ratio for predicting the onset of sepsis within 72 hours of testing when performed on the first day a patient is admitted or transferred to the intensive care unit (ICU) and is considered to be at risk of becoming septic. The PliNOSa® test measures inducible nitric oxide synthase (iNOS) in plasma and uses a pre-determined iNOS cut-off value to identify patients at risk for the onset of the sepsis pathology.

Description:

At present, an accurate and definitive clinical test to predict early the onset of the sepsis pathology does not exist. At least 7 million people per year enter into the early stages of the sepsis pathology, which will lead to more than 250,000 deaths per year in the USA and more than 750,000 worldwide. An early, accurate, and reliable test that can assess an intensive care unit (ICU) patient's risk of becoming septic would be a major medical breakthrough. A large unmet clinical laboratory need exists for a test that can aid physicians in assessing their patient's risk for the onset of the sepsis pathology. The current culture procedures suffer from a number of problems. (1) They are slow. The first answer is obtained only after 24 hours of culture, and an absolute answer requires a minimum of 48 hours of culture. (2) Blood culture only yields positive results (i.e. sepsis is present) in approximately 28% of patients who become septic, thus over 70% of the patients do not yield positive blood cultures. Everyone in the sepsis field agrees that better IVD tests for the sepsis pathology are desperately needed. Our PliNOSa IVD test based upon the presence of iNOS in plasma should identify those patients as being at risk for developing sepsis since our assay is not dependent upon the culturing of live bacteria or other micro-organisms.

Sepsis develops from a variety of bacterial and fungal sources stemming from the patient's inability to fight infection, and is commonly acquired while recovering from severe injuries and surgery in hospitals. An early, accurate, and reliable clinical diagnostics test for the onset of sepsis currently does not exist, but an enormous clinical laboratory need does exist. In January 2008, Levenson reviewed the current status of the clinical diagnosis of sepsis and concluded [1] that none of the currently FDA cleared risk-assessment tests work well and [2] that new biomarkers specific for the sepsis pathology would be a major medical breakthrough. In 2000, the Institute of Medicine of the National Academy of Science estimated the cost to the US healthcare system to be $17 - 29 billion annually. The presence in plasma of a normally intracellular protein, inducible nitric oxide synthase (iNOS), has been found to be an early and accurate biomarker for the onset of the sepsis pathology. Data gathered using our in vitro diagnostic (IVD) test to analyze more than 1,200 blood samples collected during our clinical studies on 350 study subjects (295 ICU patients and 55 healthy volunteers) demonstrated that iNOS is present only in plasma samples obtained from people suffering from the onset of sepsis. In our three clinical studies, the latter two of which were partially funded by the NIH, our candidate IVD test for plasma iNOS was found to predict the onset of sepsis 24 - 72 hours before the appearance of the physiological symptoms of the pathology.

The superiority of plasma iNOS as compared to other potential biochemical markers of SIRS (pre-sepsis) and sepsis was assessed using the data from our third clinical study. Four cohorts from this study were analyzed for the plasma levels for four potential biomarkers of the sepsis pathology: iNOS, procalcitonin (PCT), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFα). The four cohorts are (1) 36 normal healthy individuals as Group A; (2) critically injured patients who remained SIRS and septic negative throughout the entire study period as Group B; (3) critically ill patients who became septic during the study period, with their plasma levels 24 hours before the symptoms of sepsis were recognized by the attending doctors as Group C; and (4) confirmed septic patients who were enrolled in our study and had not received antibiotics prior to their enrollment as Group D. Only plasma iNOS was found to differentiate between non-septic critically ill patients (Group B) and the critically ill patients who were developing sepsis (Group C) or were already septic (Group D). The plasma level of procalcitonin, one of the FDA cleared IVD tests, was not specific for sepsis since a number of normal healthy volunteers and many of the non-SIRS and non-septic patients had elevated plasma levels of procalcitonin (PCT).

To summarize, infections in intensive care units and other hospital settings can be caused by different types of organisms, such as bacteria and fungi. These infections annually cause more than 7,000,000 cases of SIRS (pre-sepsis) that can deteriorate to sepsis, severe sepsis with organ dysfunction, and septic shock with multiple organ failure. To date, three clinical studies have been conducted on this project in which 295 ICU patients and 55 healthy volunteers have been enrolled and studied. The data obtained during these prior clinical studies clearly demonstrate that a measurable increase in the plasma level of iNOS occurs during the onset of the sepsis pathology. The main focus of this research proposal is to gather the data needed to obtain FDA clearance to market our new PliNOSa® test by demonstrating in a statistically significant number of critically ill ICU patients that the presence of iNOS in plasma is a reliable early biomarker as a risk assessment aid for the onset of sepsis.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 166
• Est. completion date: September 30, 2015
• Est. primary completion date: September 30, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male or female

• 18 years of age or older

• May be designated Do Not Attempt to Resuscitate / Do Not Intubate (DNAR / DNI) if they are committed to FULL CARE

• Study subject or their legal representative must have read, understood and provided written informed consent after the clinical study has been fully explained and their questions answered

• Subject must be admitted to or transferred to an Intensive Care Unit (ICU) and expected to require ICU-level of Care >24 hours for any of the following reasons:

• Following a surgical procedure

• Following a traumatic injury

• For threatened or actual respiratory failure

• For hemodynamic instability

• Subject is considered to be at risk of developing sepsis during the next 72 hours based upon his/her clinical presentation

• Must have an in-dwelling line from which blood can be drawn.

Exclusion Criteria:

• Cannot be already septic, severely septic or in septic shock as defined by a recent positive culture (< 48 hrs) plus 2 or more of the signs and symptoms of sepsis listed in Table 1, "Diagnostic Criteria for Sepsis" in Levy MM, et al (2003) Crit Care Med, 31#4:1250-1256.

• Cannot be moribund (not expected to survive 48 hours)

• Cannot be expected to be discharged from the ICU in under 3 days

• Cannot be pregnant

• Cannot be a prisoner

Related Conditions & MeSH terms

• Sepsis
• Septic Shock
• Severe Sepsis
• Toxemia

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Research & Diagnostic Antibodies	National Institute of General Medical Sciences (NIGMS)

References & Publications (11)

Azevedo LC, Janiszewski M, Pontieri V, Pedro Mde A, Bassi E, Tucci PJ, Laurindo FR. Platelet-derived exosomes from septic shock patients induce myocardial dysfunction. Crit Care. 2007;11(6):R120. doi: 10.1186/cc6176. — View Citation

Gambim MH, do Carmo Ade O, Marti L, Verissimo-Filho S, Lopes LR, Janiszewski M. Platelet-derived exosomes induce endothelial cell apoptosis through peroxynitrite generation: experimental evidence for a novel mechanism of septic vascular dysfunction. Crit Care. 2007;11(5):R107. doi: 10.1186/cc6133. — View Citation

Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G; SCCM/ESICM/ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003 Apr;31(4):1250-6. doi: 10.1097/01.CCM.0000050454.01978.3B. — View Citation

Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014 Apr;20(4):195-203. doi: 10.1016/j.molmed.2014.01.007. Epub 2014 Feb 24. — View Citation

Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003 Apr 17;348(16):1546-54. doi: 10.1056/NEJMoa022139. — View Citation

Mortaza S, Martinez MC, Baron-Menguy C, Burban M, de la Bourdonnaye M, Fizanne L, Pierrot M, Cales P, Henrion D, Andriantsitohaina R, Mercat A, Asfar P, Meziani F. Detrimental hemodynamic and inflammatory effects of microparticles originating from septic rats. Crit Care Med. 2009 Jun;37(6):2045-50. doi: 10.1097/CCM.0b013e3181a00629. — View Citation

Sands KE, Bates DW, Lanken PN, Graman PS, Hibberd PL, Kahn KL, Parsonnet J, Panzer R, Orav EJ, Snydman DR, Black E, Schwartz JS, Moore R, Johnson BL Jr, Platt R; Academic Medical Center Consortium Sepsis Project Working Group. Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA. 1997 Jul 16;278(3):234-40. — View Citation

Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A, Rubenfeld G, Kahn JM, Shankar-Hari M, Singer M, Deutschman CS, Escobar GJ, Angus DC. Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):762-74. doi: 10.1001/jama.2016.0288. Erratum In: JAMA. 2016 May 24-31;315(20):2237. — View Citation

Tse MT. Trial watch: Sepsis study failure highlights need for trial design rethink. Nat Rev Drug Discov. 2013 May;12(5):334. doi: 10.1038/nrd4016. No abstract available. — View Citation

Webber RJ, Rodriguez JG, Webber DS, Dunnebacke TH. Development, characterization, and epitope mapping of a panel of twenty-four monoclonal antibodies specific for human inducible nitric oxide synthase. Hybridoma (Larchmt). 2005 Feb;24(1):6-13. doi: 10.1089/hyb.2005.24.6. — View Citation

Webber RJ, Sweet RM, Webber DS. Inducible Nitric Oxide Synthase in Circulating Microvesicles: Discovery, Evolution, and Evidence as a Novel Biomarker and the Probable Causative Agent for Sepsis. J Appl Lab Med. 2019 Jan;3(4):698-711. doi: 10.1373/jalm.2018.026377. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evaluation of the PliNOSa test for a Positive Percent Agreement greater than 75% or a Negative Percent Agreement greater than 75% for predicting in ICU patients the onset of sepsis diagnosed within 72 hours of a plasma sample collected on study day 1.	A successful result (rejection of the null hypothesis) will be achieved if the Positive Percent Agreement is greater than 75% or the Negative Percent Agreement is greater than 75%.	First 72 hours after entry into the ICU