Clinical trial NCT03356249: Next-Generation Sequencing Diagnostics of Bacteremia in Sepsis
Official title: Next-Generation Sequencing Diagnostics of Bacteremia in Sepsis (Next GeneSiS-Trial) - Study Protocol for a Prospective, Observational, Non-interventional, Multicenter, Clinical Trial
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Sepsis
Septic Shock
Keywords: Sepsis
Septic shock
Next-Generation Sequencing
Bacteremia
Lead sponsor: University Hospital Heidelberg
Sponsor class: OTHER
Collaborators: name: Fraunhofer Institute for Interfacial Engineering and Biotechnology
name: Dietmar Hopp Stiftung GmbH
First posted: 2017-11-29
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with sepsis or septic shock according to the new sepsis definitions (Sepsis-3) with an onset \<24h are eligible for study inclusion.

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: 2 years
measure: 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)
timeFrame: 2 years
measure: 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)
timeFrame: 2 years
measure: 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)
timeFrame: 2 years
measure: 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)
timeFrame: 2 years
Secondary outcomes:
measure: Plausibility [%] (of the NGS-based SIQ-score)
timeFrame: 2,5 years
measure: Changes in therapy [%] (that may have occurred if the NGS-based SIQ-score had been available for clinical use)
timeFrame: 2,5 years
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: RWTH Aachen University
city: Baden-Baden
country: Germany
facility: Klinikum Mittelbaden Baden-Baden Balg
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Bielefeld
country: Germany
facility: Evangelisches Krankenhaus Bethel gGmbH
city: Bonn
country: Germany
facility: University Hospital Bonn
city: Bremerhaven
country: Germany
facility: Klinikum Bremerhaven Reinkenheide gGmbH
city: Duesseldorf
country: Germany
facility: Duesseldorf University Hospital
city: Essen
country: Germany
facility: University Hospital Essen
city: Frankfurt
country: Germany
facility: University Hospital Frankfurt
city: Göttingen
country: Germany
facility: University Medical Center Göttingen
city: Hannover
country: Germany
facility: Medical School Hannover
city: Heidelberg
country: Germany
facility: University Hospital Heidelberg
city: Heidenheim
country: Germany
facility: Kliniken Landkreis Heidenheim gGmbH
city: Köln
country: Germany
facility: University Hospital Köln
city: Leipzig
country: Germany
facility: University Hospital Leipzig
city: Luckau
country: Germany
facility: Evangelisches Krankenhaus Luckau gGmbH
city: Munich
country: Germany
facility: University Hospital rechts der Isar
city: Regensburg
country: Germany
facility: University Hospital of Regensburg
city: Rostock
country: Germany
facility: University of Rostock
city: Tübingen
country: Germany
facility: University Hospital Tübingen
city: Ulm
country: Germany
facility: Ulm University Medical Center
Study officials:
affiliation: University Hospital, Essen
name: Thorsten Brenner, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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):1796. doi: 10.3390/ijms18081796.
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.
citation: Brenner T, Decker SO, Grumaz S, Stevens P, Bruckner T, Schmoch T, Pletz MW, Bracht H, Hofer S, Marx G, Weigand MA, Sohn K; TIFOnet Critical Care Trials Group. Next-generation sequencing diagnostics of bacteremia in sepsis (Next GeneSiS-Trial): Study protocol of a prospective, observational, noninterventional, multicenter, clinical trial. Medicine (Baltimore). 2018 Feb;97(6):e9868. doi: 10.1097/MD.0000000000009868.