Trial document




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  DRKS00015705

Trial Description

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Title

Next-Generation Sequencing diagnostics of bacteremia in Pediatric Sepsis

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Trial Acronym

Next-GeneSiPS

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URL of the Trial

[---]*

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Brief Summary in Lay Language

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. The identification of a pathogen and its susceptibility testing usually requires up to several days. Within this timeframe, an empiric antibiotic therapy needs to be performed, which entails the risks of either being ineffective or covering a too broad spectrum of pathogens with subsequent undesired changes of the intestinal microbiota. 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. In the Next GeneSIS-Trial (DRKS00011911) we therefore assess the diagnostic performance of a NGS-based approach for the detection of relevant infecting organisms in a big cohort of adult patients (n=500) with sepsis or septic shock. In addition to the Next GeneSiS-Trial, the aim of the here presented Next-GeneSiPS Trial is to evaluate the performance of the SIQ-score in neonats, infants and toddlers (n=150). Moreover, the plausability 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.

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Brief Summary in Scientific Language

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 GeneSiPS 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 150 neonats, infants and toddlers (50 neonats (d1-28), 50 infants (d29 - <1 year) and 50 toddlers (1year – 5 years) with suspected or proven sepsis (according to the pediatric sepsis defnitions) 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 independant clinical specialists, retrospectively indentifying 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). The Next-GeneSiPS Trial is supplementary to the Next-GeneSiS Trial (DRKS00011911) which has an almost identical protocol and includes 500 adult patients with sepsis or septic shock.

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 1-2 blood cultures (2x aerobic / 2x anaerobic) because of the clinical suspicion of a blood stream 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, broncoalveolar 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.

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Do you plan to share individual participant data with other researchers?

Yes

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Description IPD sharing plan:

Once the study has been completed and the database has been closed, the anonymized data could be requested from the director of studies for secondary evaluations.

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Organizational Data

  •   DRKS00015705
  •   2018/10/24
  •   [---]*
  •   yes
  •   Approved
  •   S-605/2018, Ethik-Kommission I der Medizinischen Fakultät Heidelberg
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Secondary IDs

  • [---]*
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Health Condition or Problem studied

  •   R65.1 -  Systemic Inflammatory Response Syndrome of infectious origin with organ failure
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Interventions/Observational Groups

  •   In 40 infants and toddlers (20 infants (d29 - <1 year) and 20 toddlers (1year – 5 years) with suspected or proven severe sepsis or septic shock (according to the pediatric sepsis definitions), patients characteristics and routine blood parameters will be determined at sepsis onset as well as 72h afterwards. At the same time points, 2 sets of blood cultures and one blood tube for NGS-diagnostics will be collected. An evaluation of outcome will be perfomed at 28 days after sepsis onset.
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Characteristics

  •   Non-interventional
  •   Other
  •   Single arm study
  •   Open (masking not used)
  •   [---]*
  •   Uncontrolled/Single arm
  •   Diagnostic
  •   Single (group)
  •   N/A
  •   N/A
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Primary Outcome

For the evaluation of NGS-performance (sensitivity, specificity, positive predictive value, negative predictive value), results of the NGS-based approach for each sample will be compared with those obtained using conventional microbiology methods for the same sample. Moreover, interobserver agreement will be assessed by the calculation of Cohens Kappa. 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.

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Secondary Outcome

1.) Diagnostic or prognostic value of host nucleosome positioning patterns derived from plasma cell free DNA in infants and toddlers with suspected or proven severe sepsis or septic shock, 2.) Diagnostic value of host expression profiles including RNA-derived biomarkers in infants and toddlers with suspected or proven severe sepsis or septic shock, 3.) Diagnostic or prognostic value of methylglyoxal (MG)-derived carbonylstress in infants and toddlers with suspected or proven severe sepsis or septic shock, 4.) Evaluation of antimicrobial resistance patterns and virulence factors, 5.) Evaluation of process times for NGS-based measurements

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Planned
  •   2021/06/01
  •   150
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   1   Days
  •   5   Years
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Additional Inclusion Criteria

- Age ≤ 28 days and <6 years
- Informed consent by parent(s) or legal guardian

Severe Sepsis (with an onset ≤24h):
- Infants and toddlers with severe sepsis can be identified with a clinical construct of sepsis (Infection + ≥ 2 criteria of a systemic inflammatory syndrome (SIRS)) together with clinical signs of an organ failure.

or Septic shock (with an onset ≤24h):
- Infants and toddlers with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain mean arterial pressure (MAP ≥ 40 mmHg+1,5mmHg x age [years]) despite adequate volume resuscitation

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Exclusion Criteria

[---]*

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Addresses

  • start of 1:1-Block address primary-sponsor
    • Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen
    • Mr.  Prof. Dr.  Thorsten  Brenner 
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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    • Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen
    • Mr.  Prof. Dr.  Thorsten  Brenner 
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
    end of 1:1-Block address scientific-contact
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    • Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen
    • Mr.  Prof. Dr.  Thorsten  Brenner 
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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Sources of Monetary or Material Support

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    • Klinik für Anästhesiologie, Universitätsklinikum Heidelberg
    • Mr.  Prof. Dr.  Thorsten  Brenner 
    • Im Neuenheimer Feld 110
    • 69120  Heidelberg
    • Germany
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Status

  •   Recruiting planned
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.