Next-Generation Sequencing Diagnostics of Bacteremia in Sepsis

Sepsis Clinical Trial

— NextGeneSiS  

Official title:

Next-Generation Sequencing Diagnostics of Bacteremia in Sepsis (Next GeneSiS-Trial) - Study Protocol for a Prospective, Observational, Non-interventional, Multicenter, Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03356249
• Other study ID #: S-084/2017
• Status: Completed
• Start date: March 1, 2019
• Est. completion date: September 30, 2021

Study information

• Verified date: May 2022
• Source: University Hospital Heidelberg
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Sepsis remains a major challenge, even in modern intensive care medicine. The identification of the causative pathogen is crucial for an early optimization of the antimicrobial treatment regime in patients with sepsis. In this context, culture-based diagnostic procedures (e.g. blood cultures) represent the standard of care, although they are associated with relevant limitations. Therefore, culture independent methods (e.g. Next-Generation Sequencing (NGS)) seem to be an attractive alternative. By the identification of circulating cell-free DNA in the blood and the use of the quantitative sepsis indicating quantifier (SIQ) score, causing pathogens can be identified and potential contaminations can be excluded.

The goal of the presented study is therefore, to assess the diagnostic performance of a NGS-based approach for the detection of relevant infecting organisms in a big cohort of septic patients (n=500). Moreover, the plausibility of this NGS-based approach will be estimated by a panel of independent clinical specialists, retrospectively identifying potential changes in patients´ management based on NGS results.

Description:

Sepsis remains a major challenge, even in modern intensive care medicine. The identification of the causative pathogen is crucial for an early optimization of the antimicrobial treatment regime in patients with sepsis. In this context, culture-based diagnostic procedures (e.g., blood cultures) represent the standard of care, although they are associated with relevant limitations. Accordingly, culture-independent molecular diagnostic procedures might be of help for the identification of the causative pathogen in infected patients. Especially the concept of an unbiased sequence analysis of circulating cell-free DNA (cfDNA) from plasma samples of septic patients by next-generation sequencing (NGS) has recently been identified to be a promising diagnostic platform for critically ill patients suffering from bloodstream infections. Although this new approach might be more sensitive and specific than culture-based state-of-the-art technologies, additional clinical trials are needed to exactly define the performance as well as clinical value of a NGS-based approach.

Next GeneSiS is a prospective, observational, non-interventional, multicenter study to assess the diagnostic performance of a NGS-based approach for the detection of relevant infecting organisms in patients with suspected or proven sepsis (according to recent sepsis definitions [sepsis-3]) by the use of the quantitative sepsis indicating quantifier (SIQ) score in comparison to standard (culture-based) microbiological testings. Moreover, the clinical value of this NGS-based approach will be estimated by a panel of independent clinical specialists, retrospectively identifying potential changes in patients´ management based on NGS results. Further subgroup analyses will focus on the clinical value especially for patients suffering from a failure of empiric treatment within the first three days after onset (as assessed by (1.) death of the patient or lack of improvement of the patient´s clinical condition (in terms of an inadequate decrease of SOFA-score) or (2.) persistent high procalcitonin levels).

This prospective, observational, non-interventional, multicenter study trial for the first time investigates the performance as well as the clinical value of a NGS based approach for the detection of bacteremia in patients with sepsis and may therefore be a pivotal step toward the clinical use of NGS in this indication.

Two sets of blood cultures (2x aerobic / 2x anaerobic) will be collected at study inclusion (=Onset) as well as 72 hours afterwards (=72h). In parallel, plasma samples for NGS-based measurements need to be obtained as described previously. Further blood samples for NGS-based measurements can be collected whenever physicians order blood cultures (2x aerobic / 2x anaerobic) because of the clinical suspicion of a bloodstream infection (BSI) within the first 3 days after study inclusion. Results of microbiological routine diagnostics in specimens different from blood (e.g. body fluid, tissue, bronchoalveolar lavage, endotracheal aspirate) will be used for further analyses when they are obtained within a timeframe of ≤72 hours prior or after the timepoints for NGS-based measurements. Clinical data collection and (if possible) PCT measurements will be performed at Onset as well as at 72h after study inclusion. The final outcome evaluation of patients will be performed at 28 days.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 500
• Est. completion date: September 30, 2021
• Est. primary completion date: August 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

• Age =18yr

• Informed consent

• Sepsis (with an onset =24h): Patients with a life-threatening organ dysfunction caused by a dysregulated host response to a suspected or proven infection. Organ dysfunction can be identified as an acute change in total SOFA score =2 points consequent to the infection. Patients can also be promptly identified at the bedside with qSOFA, ie, alteration in mental status, systolic blood pressure =100mmHg, or respiratory rate =22/min.

• or Septic shock (with an onset =24h): Patients with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain mean arterial pressure (MAP) =65mmHg and having a serum lactate level >2mmol/L (18mg/dL) despite adequate volume resuscitation.

Exclusion Criteria:

• Age =18yr

• Refusal to give consent

• Patient will probably be discharged from the ICU within the first 72h following inclusion

• Palliative treatment intent

• Clinician is not committed to aggressive treatment

• Death is deemed imminent and inevitable

• Patients who had previously been included, but are readmitted to the ICU during the same hospitalization, will not be included a second time.

Related Conditions & MeSH terms

• Bacteremia
• Sepsis
• Septic Shock
• Shock, Septic
• Toxemia

Intervention

Diagnostic Test:
• Next-Generation Sequencing
In 500 patients with suspected or proven sepsis or septic shock (according to the Sepsis-3 definitions), patients´ characteristics and routine blood parameters will be determined at sepsis onset as well as 72 hours afterwards. At the same time points, 2 sets of blood cultures and one blood tube for Next-Generation Sequencing (NGS)-diagnostics will be collected. An evaluation of outcome will be performed at 28 days after sepsis onset.

Locations

Country	Name	City	State
Germany	RWTH Aachen University	Aachen
Germany	Klinikum Mittelbaden Baden-Baden Balg	Baden-Baden
Germany	Charité - Universitätsmedizin Berlin	Berlin
Germany	Evangelisches Krankenhaus Bethel gGmbH	Bielefeld
Germany	University Hospital Bonn	Bonn
Germany	Klinikum Bremerhaven Reinkenheide gGmbH	Bremerhaven
Germany	Duesseldorf University Hospital	Duesseldorf
Germany	University Hospital Essen	Essen
Germany	University Hospital Frankfurt	Frankfurt
Germany	University Medical Center Göttingen	Göttingen
Germany	Medical School Hannover	Hannover
Germany	University Hospital Heidelberg	Heidelberg
Germany	Kliniken Landkreis Heidenheim gGmbH	Heidenheim
Germany	University Hospital Köln	Köln
Germany	University Hospital Leipzig	Leipzig
Germany	Evangelisches Krankenhaus Luckau gGmbH	Luckau
Germany	University Hospital rechts der Isar	Munich
Germany	University Hospital of Regensburg	Regensburg
Germany	University of Rostock	Rostock
Germany	University Hospital Tübingen	Tübingen
Germany	Ulm University Medical Center	Ulm

Sponsors (3)

Lead Sponsor	Collaborator
University Hospital Heidelberg	Dietmar Hopp Stiftung GmbH, Fraunhofer Institute for Interfacial Engineering and Biotechnology

Country where clinical trial is conducted

Germany, 

References & Publications (2)

Decker SO, Sigl A, Grumaz C, Stevens P, Vainshtein Y, Zimmermann S, Weigand MA, Hofer S, Sohn K, Brenner T. Immune-Response Patterns and Next Generation Sequencing Diagnostics for the Detection of Mycoses in Patients with Septic Shock-Results of a Combined Clinical and Experimental Investigation. Int J Mol Sci. 2017 Aug 18;18(8). pii: E1796. doi: 10.3390/ijms18081796. — View Citation

Grumaz S, Stevens P, Grumaz C, Decker SO, Weigand MA, Hofer S, Brenner T, von Haeseler A, Sohn K. Next-generation sequencing diagnostics of bacteremia in septic patients. Genome Med. 2016 Jul 1;8(1):73. doi: 10.1186/s13073-016-0326-8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Sensitivity [%] (of the NGS-based SIQ-score in comparison to blood culture diagnostics, as the goldstandard for the identification of the causative pathogen in sepsis)	Proportion of positives that are correctly identified as such.	2 years
Primary	Specificity [%] (of the NGS-based SIQ-score in comparison to blood culture diagnostics, as the goldstandard for the identification of the causative pathogen in sepsis)	Proportion of negatives that are correctly identified as such.	2 years
Primary	Positive predictive value [%] (of the NGS-based SIQ-score in comparison to blood culture diagnostics, as the goldstandard for the identification of the causative pathogen in sepsis)	Proportion of positives that are true positive.	2 years
Primary	Negative predictive value [%] (of the NGS-based SIQ-score in comparison to blood culture diagnostics, as the goldstandard for the identification of the causative pathogen in sepsis)	Proportion of negatives that are true negative.	2 years
Primary	Cohen's kappa coefficient [no measuring unit; 0</=k</=1] (of the NGS-based SIQ-score in comparison to blood culture diagnostics, as the goldstandard for the identification of the causative pathogen in sepsis)	Measurement of the interobserver agreement between both items.	2 years
Secondary	Plausibility [%] (of the NGS-based SIQ-score)	Using a majority rule, SIQ-score results will be evaluated for plausibility by a panel of three independent clinical specialists not associated with the study site. Therefore, the panel will be provided with clinical case summaries, NGS results and standard-of-care results from all samples tested. Results of microbiological routine diagnostics in specimens different from blood (e.g. body fluid, tissue, bronchoalveolar lavage, endotracheal aspirate) will be included when they have been obtained within a timeframe of =72 hours prior or after the timepoints for NGS-based measurements.	2,5 years
Secondary	Changes in therapy [%] (that may have occurred if the NGS-based SIQ-score had been available for clinical use)	Using a majority rule, the clinical value of the NGS-based approach will be estimated by a panel of three independent clinical specialists not associated with the study site, retrospectively identifying potential changes in patients´ management based on NGS results. Therefore, the panel will be provided with clinical case summaries, NGS results and standard-of-care results from all samples tested. Results of microbiological routine diagnostics in specimens different from blood (e.g. body fluid, tissue, bronchoalveolar lavage, endotracheal aspirate) will be included when they have been obtained within a timeframe of =72 hours prior or after the timepoints for NGS-based measurements. To identify potential changes in antimicrobial management that may have occurred if the results from the NGS technology had been available for clinical use, the panel will be provided with a special questionnaire.	2,5 years