Biomarkers in Patients With Flesh-eating Bacterial Infections

Necrotizing Soft Tissue Infection Clinical Trial

— BIONEC  

Official title:

Biomarkers in Necrotizing Soft Tissue Infections - Aspects of the Innate Immune Response

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02180906
• Other study ID #: BIONEC1-MBH-2014
• Status: Completed
• Phase: N/A
• First received: June 29, 2014
• Last updated: February 14, 2016
• Start date: February 2013
• Est. completion date: February 2016

Study information

• Verified date: February 2016
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: The Danish National Committee on Biomedical Research EthicsDenmark: Mental Health Services in the Capital Region of Denmark
• Study type: Observational

Clinical Trial Summary

The purpose of this study is to investigate the immune response in patients with necrotizing soft tissue infections (NSTI). The investigation will focus on inflammatory and vasoactive biomarkers as prognostic markers of severity and mortality at admission to Rigshospitalet and the following 3 days

Description:

Necrotizing soft tissue infection (NSTI) is a complex, multi-factorial disease with diverse microbiological etiology and varying co-morbidities. The rapidly spreading infection may cause extensive soft tissue damage, limb loss, and multiple organ failure. The incidence of NSTIs has increased over the past years and the fatality rates are still high despite increased focus on these patients (20-30%). The extensive inflammatory response is thought to be a main course of death. However, it is unknown which biomarkers that are responsible for the deleterious effects and how these molecular mediators are modulated during the infection and treatment regimes. Thus, there is a need for novel insight into the immune system disturbances in order to improve outcome of NSTIs.

Location: Copenhagen University Hospital, Rigshospitalet, Denmark.

Design: Observational cohort study.

Cohort: NSTI patients in Denmark.

Controls: 50-100 Patients undergoing elective, orthopedic surgery at Rigshospitalet.

Biomarkers: The investigators will focus on three major groups of biomarkers: Acute-phase proteins, cytokines and vasoactive biomarkers.

Sample size calculations:

1. Acute-phase proteins: The investigators expect a mean PTX3-concentration at admission at 120 nmol/L in patients without septic shock and a mean PTX3-concentration at 210 nmol/L in patients with septic shock. With an estimated standard deviation at 100 nmol/L, the inclusion of 52 patients will be able to detect a significant difference with a statistical power of 90% at a 5% significance level. Since the groups are unequal the investigators will need to include 82 patients (N'=52(1+4)^2/4*4).

2. Cytokines: In a pilot study with seven NSTI patients, the investigators found a minimal clinically relevant difference in IL-6 concentration in NSTI patients with LRINEC < 6 and ≥ 6 to be 1050 pg/ml. With an estimated standard deviation at 2000 pg/ml, the inclusion of 114 patients will be able to detect a significant difference with a statistical power of 80% at a 5% significance level.

3. Vasoactive proteins: The investigators expect a mean NOx-concentration at admission at 90 μmol/L in patients without septic shock and a mean NOx-concentration at 145 μmol/Lin patients with septic shock. With an estimated standard deviation at 70 μmol/L, the inclusion of 70 patients will be able to detect a significant difference with a statistical power of 90% at a 5% significance level. Since the groups are unequal the investigators will need to include 110 patients (N'=70(1+4)^2/4*4).

Data: Data will be handled according to the National Data Protection Agency. All original records (incl. consent forms and questionnaires) will be archived at trial site for 15 years. The National Data Protection Agency has approved the biobank (2007-58-0015, J. nr. 30-1282).

Ethics: The trial will adhere to the Helsinki Declaration and Danish law. The National Ethics Committee and the Regional Ethics Committee have approved the inclusion of the NSTI patients (CVK-1211709) and the control patients, including biomarker analyses (H-2-2014-071).

Biomarker analyses, data extraction and interpretation will be performed once the recruiting of participants has ended.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 169
• Est. completion date: February 2016
• Est. primary completion date: February 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria for patients with NSTI:

• Necrotizing soft tissue infection based on surgical findings

• Age >18 years

• Admitted to/planned to be admitted to the ICU at Rigshospitalet and/or operated for NSTI at Rigshospitalet

Exclusion Criteria for patients with NSTI:

• Patients who at the operating theatre were categorized as non-NSTI patients

Inclusion Criteria for control patients:

• Patients undergoing elective orthopedic surgery (non-pathologic fractures, joint replacement surgery, back surgery) at Rigshospitalet

• Age >18 years

Exclusion Criteria for control patients:

• Patients with ongoing infections

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Bacterial Infections
• Communicable Diseases
• Fasciitis
• Fasciitis, Necrotizing
• Fournier Gangrene
• Gangrene
• Gas Gangrene
• Infection
• Necrotizing Fasciitis
• Necrotizing Soft Tissue Infection
• Soft Tissue Infections

Locations

Country	Name	City	State
Denmark	Copenhagen University Hospital, Rigshospitalet	Copenhagen

Sponsors (2)

Lead Sponsor	Collaborator
Ole Hyldegaard	Seventh Framework Programme

Country where clinical trial is conducted

Denmark, 

References & Publications (7)

Bastrup-Birk S, Skjoedt MO, Munthe-Fog L, Strom JJ, Ma YJ, Garred P. Pentraxin-3 serum levels are associated with disease severity and mortality in patients with systemic inflammatory response syndrome. PLoS One. 2013 Sep 9;8(9):e73119. doi: 10.1371/journal.pone.0073119. eCollection 2013. — View Citation

Golger A, Ching S, Goldsmith CH, Pennie RA, Bain JR. Mortality in patients with necrotizing fasciitis. Plast Reconstr Surg. 2007 May;119(6):1803-7. — View Citation

Hasham S, Matteucci P, Stanley PR, Hart NB. Necrotising fasciitis. BMJ. 2005 Apr 9;330(7495):830-3. Review. Erratum in: BMJ. 2005 May 14;330(7500):1143. — View Citation

Muller B, Peri G, Doni A, Torri V, Landmann R, Bottazzi B, Mantovani A. Circulating levels of the long pentraxin PTX3 correlate with severity of infection in critically ill patients. Crit Care Med. 2001 Jul;29(7):1404-7. — View Citation

Panacek EA, Marshall JC, Albertson TE, Johnson DH, Johnson S, MacArthur RD, Miller M, Barchuk WT, Fischkoff S, Kaul M, Teoh L, Van Meter L, Daum L, Lemeshow S, Hicklin G, Doig C; Monoclonal Anti-TNF: a Randomized Controlled Sepsis Study Investigators. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med. 2004 Nov;32(11):2173-82. — View Citation

Su YC, Chen HW, Hong YC, Chen CT, Hsiao CT, Chen IC. Laboratory risk indicator for necrotizing fasciitis score and the outcomes. ANZ J Surg. 2008 Nov;78(11):968-72. doi: 10.1111/j.1445-2197.2008.04713.x. — View Citation

Sultan HY, Boyle AA, Sheppard N. Necrotising fasciitis. BMJ. 2012 Jul 20;345:e4274. doi: 10.1136/bmj.e4274. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	PTX3, NOx and IL-6 as early markers of disease severity in NSTI patients with and without septic shock	Primary analysis: Association between PTX3-, NOx-, and IL6-concentration and septic shock (PTX3, NOx) or LRINEC = 6 (IL-6) in NSTI patients at time of admission to Rigshospitalet	Admission, first 24 hours	No
Secondary	Mortality		28, 90, 180 days	Yes
Secondary	Amputation rate	At any anatomical site	During ICU admission (expected average of 8 days)	Yes
Secondary	ICU-scoring systems	SAPS II (day 1) APACHE II (day 1) SOFA, GCS excluded (day 1-7), Anaya-score	During ICU admission (expected average of 8 days)	No
Secondary	Multiple organ failure		During ICU admission (expected average of 8 days)	Yes
Secondary	Number of debridements		During ICU admission (expected average of 8 days)	Yes
Secondary	Microbial etiology	Tissue and blood samples	During ICU admission (expected average of 8 days)	No
Secondary	Time from admission to primary hospital until first surgery/debridement		2 days	No
Secondary	Ventilator treatment, renal replacement therapy, vasopressor treatment during stay at ICU		During ICU admission (expected average of 8 days)	No
Secondary	Steroid treatment (injection/oral intake) up to development of NSTI		Up to 7 days before surgical diagnose at primary hospital	No
Secondary	Inflammatory biomarkers	Secondary analysis: The association between inflammatory biomarkers such as CRP, procalcitonin, mannose-binding-lectin and ficolin-1,2,3, cytokines and septic shock, LRINEC = 6 and SAPS II at admission and the following 3 days	Admission and the following 3 days	No
Secondary	Vasoactive biomarkers	Secondary analysis: The association between vasoactive biomarkers such as NOx (nitrite, NO2-, and nitrate, NO3-,), L-arginine, asymmetric dimethylarginine, hydrogen sulfide, reactive oxygen species, ICAM-1, E-selectin and septic shock, LRINEC = 6 and SAPS II at admission and the following 3 days	Admission and the following 3 days	No
Secondary	The effects of immunoglobulin on inflammatory biomarkers	A subgroup analysis will be performed on patients randomized to immunoglobulin or saline as immunoglobulin might affect the biomarker response (PTX3, NO, IL-6). The randomized double-blinded study was initiated April 2014 and registered at ClinicalTrials.gov (NCT02111161).	Admission and the following 3 days	No
Secondary	Biomarkers and Severity of disease	Subgroup analysis: Systemic inflammatory response syndrome, sepsis, severe sepsis and septic shock will be diagnosed according to standardized criteria (American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee) and the biomarkers will be investigated to see if there is a correlation between disease severity and mortality in these groups.	Admission and the following 3 days	No

External Links

•   Research website: INFECT-study. Further description of funding from EU 7th Framework Programme