Trial document




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  DRKS00022782

Trial Description

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Title

Optimization of sepsis therapy based on patient-specific digital precision diagnostics

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Trial Acronym

DigiSep - Trial

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URL of the Trial

http://digisep.de

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Brief Summary in Lay Language

Sepsis is a disease which is triggered by an infection and represents one of the most significant challenges of modern intensive care medicine. With regard to targeted therapy, the earliest possible detection of pathogens is of crucial importance. Numerous limitations characterize previous detection methods. In this context, the concept of detecting free DNA in circulating bloodstream, utilizing next-generation sequencing (NGS) appears to be a promising diagnostic method. Our preliminary work suggests that NGS-based diagnostics have higher accuracy and sensitivity compared to conventional methods. The DigiSep trial is intended to characterize the effect of the combination of NGS and culture-based standard diagnostics compared to a purely culture-based standard diagnosis in the clinical picture of sepsis / septic shock. The study examines in 410 patients (n = 205 per arm) with sepsis / septic shock whether the so-called DOOR-RADAR score (Desirability of Outcome Ranking / Response Adjusted for Duration of Antibiotic Risk Score) can be significantly improved, by application of NGS. We also aim to study whether the new procedure is cost-effective. It is assumed that the inpatient duration of admission, mortality rate, the incidence of acute renal failure, the length of anti-infective therapy as well as the costs of complications or the costs of outpatient aftercare can be reduced. A significant improvement in the quality of life of the affected patients can be additionally expected.
As part of the study, the essential data is collected once at the time of sepsis. The culture-based diagnostics include the guideline-based collection of 2 blood culture sets at the beginning of the study, and three days later. Simultaneously, blood samples will be obtained for NGS-based pathogen diagnostics. Additional sampling for NGS-based diagnostics can be made up to day 14 after the start of the study based on clinical indication for the collection of further blood cultures as established by the attending physician. The aforementioned culture vs NGS-based pathogen diagnostic is also accompanied by extended immunological monitoring of blood samples as well as an NGS-based gene expression analysis. The associated sampling takes place at the begin of the study, 3, 7 and 14 days after the onset of sepsis. Routine microbiological findings from other sample materials (e.g. surgical swabs and samples, drainage secretions, tracheal secretions, tissue samples) are included in the evaluation if these were collected three days before or after the collection of plasma samples for NGS-based diagnostics. The clinical data collection is also carried out at the onset of sepsis and 3, 7 and 14 days later, in the same way as the samples as mentioned earlier. The final survey is carried out 28 days after the onset of sepsis.

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Brief Summary in Scientific Language

Sepsis is a disease which is triggered by an infection and represents one of the greatest challenges of modern intensive care medicine. With regard to targeted anti-microbial therapy, the earliest possible pathogen detection is of crucial importance. Until now, culture-based detection methods represent the gold standard for diagnosis, although numerous limitations characterize these. In this context, culture-independent molecular biological processes are an alternative. In particular, the concept of serum detection of circulating, free DNA employing next-generation sequencing (NGS) seems to represent a promising diagnostic procedure in patients with bloodstream infections. The applicant's extensive preparatory work suggests that NGS-based diagnostics using the SIQ score have higher specificity and sensitivity compared to traditional culture-based methods for detecting bloodstream infections. This preliminary work for the DigiSep trial with the help of interventional study design provides the optimal basis to establish this new concept as part of the national standard based on the best possible evidence. The DigiSep trial is intended to characterize the effect of the combination of digital precision diagnostics, expert exchange and culture-based standard diagnostics compared to a purely culture-based conventional diagnosis in the clinical picture of sepsis / septic shock. The study examines in 410 patients (n = 205 per arm) with sepsis / septic shock whether the so-called DOOR-RADAR score (Desirability of Outcome Ranking / Response Adjusted for Duration of Antibiotic Risk Score) can be significantly improved, by application of the NGS. We also aim to also study whether the new procedure is cost-effective. It is postulated that the inpatient admission time, mortality rate, incidence of acute renal failure (ARF), the duration of anti-microbial therapy as well as the costs of complications and outpatient aftercare can be reduced. Also, a significant improvement in the quality of life of the affected patients can be expected.
As part of the study, the essential data is collected once at the time of sepsis (= onset). The culture-based diagnostics include the guideline-oriented collection of 2 blood culture sets (2 x aerobic / 2 x anaerobic) to the onset and three days later. At the same time, serum samples are obtained for NGS-based pathogen diagnostics. Additional sampling for NGS-based diagnostics can be made up to day 14 after onset or whenever the attending physician establishes a clinical indication for the collection of further blood cultures. The aforementioned cultures vs NGS-based pathogen diagnostics are also accompanied by extended immunological monitoring from blood plasma samples as well as an NGS-based transcriptome analysis. The associated sampling takes place at the time of onset, 3, 7 and 14 days after the beginning of sepsis. Routine microbiological findings from other biological samples (e.g. surgical swabs, drainage secretions, tracheal secretions, tissue samples) are included in the evaluation if these were collected three days before or after the extraction of serum samples for NGS-based diagnostics. The clinical data collection is also carried out at the time of sepsis (= onset), 3, 7 and 14 days later, analogous to the above-mentioned sample collection. The final outcome evaluation takes place 28 days (= 28 d) after the onset of sepsis. The study-related burden on the individual study patient includes a total of 17 ml of whole blood for NGS-based diagnostics, the four samples of 7.5 ml of whole blood for immunological monitoring and the four samples of 2.7 ml of whole blood for transcriptome analysis. The minimum total volume, therefore, amounts to the collection of approximately 75 ml of whole blood within the first 14 days after the onset of sepsis. The sampling takes place with the collection of the blood cultures or within the framework of the daily routine blood samples so that no further venous punctures are required here. Infection parameters such as procalcitonin (PCT) are carried out within the framework of daily regular blood collection and therefore, do not require any additional vascular punctures. The same principle applies to the collection of blood cultures which are routinely obtained as part of standard diagnostics in patients with suspected or proven sepsis. The required blood samples of two 40 ml of whole blood (each two sets of 2 x aerobic / 2 x anaerobic = 4 x 10 ml = 40 ml) therefore do not represent any additional burden due to the study. A further additional burden for the patient concerning invasive procedures or examinations is not expected in the study.

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

Yes

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Description IPD sharing plan:

Researchers with access to data are limited to the project partners involved. Researchers will receive pseudonymized data sets for data evaluations. A prerequisite for the transfer of the data to the project partners is the written consent of the patients.

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Organizational Data

  •   DRKS00022782
  •   2020/08/25
  •   2020/10/01
  •   yes
  •   Approved
  •   20-9352-BO, Ethik-Kommission der Medizinischen Fakultät der Universität Duisburg-Essen
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Secondary IDs

  •   /NCT04571801  (ClinicalTrials.gov Identifier)
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Health Condition or Problem studied

  •   A41 -  Other sepsis
  •   R65.1 -  Systemic Inflammatory Response Syndrome of infectious origin with organ failure
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Interventions/Observational Groups

  •   Only standard diagnostics (Microbial diagnostics by means of standard culture methods + optional consultation of experts in the field of infectious diseases) within the first 72 h after diagnosis
  •   Standard diagnostics + NGS (Microbial diagnostics using standard culture methods + Next Generation Sequencing + optional consultation of experts in the field of infectious diseases) within the first 72 h after diagnosis
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Characteristics

  •   Interventional
  •   [---]*
  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Active control (effective treament of control group)
  •   Diagnostic
  •   Parallel
  •   N/A
  •   N/A
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Primary Outcome

DOOR/RADAR (Desirability of Outcome Ranking / Response Adjusted for Duration of Antibiotic Risk)-Score after 28 days.

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Secondary Outcome

-Mortality rate after 90 and 180 days
- Duration of ventilation
- Time to resolution of Sepsis
- Requirement for follow-up continuous renal replacement therapy
- Total hospital stay
- Cumulative time of antibiotic requirement
- Time at the beginning of the targeted antibiotic
-Use of therapeutic services (outpatient and inpatient)
- Time out of work
- Insurance costs (inpatient and outpatient)
- Health-related survey of quality of life

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
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Recruitment

  •   Actual
  •   2022/03/16
  •   410
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

All patients who develop sepsis or septic shock within < 24 h in accordance with the new sepsis definition (Sepsis-3) in the above-mentioned participating centers and consent to participation in the study will be included.
General inclusion criteria:
- written consent by the study participant or a legally appointed representative
- Age >18 years
Sepsis:
- Life-threatening organ dysfunction due to a dysregulated immune response on the basis of a suspected or proven infection
- Detection of organ dysfunction indicated by SOFA score of ≥ 2 points Alternative:
Change of the quick (q) SOFA score of 2 points as an indication of a sepsis
Or septic shock:
-Persistent hypotension despite adequate volume substitution, which necessitates the use of vasopressors, to maintain an arterial medium pressure of > 65 mmHg
-serum lactate > 2 mmol/l (18 mg/dl)

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Exclusion Criteria

- Age < 18 years
- Refusal to participate in the study
- Probable discharge of the patient from the intensive care unit within the first 72 h of initial study inclusion
- Palliative therapy approach
- Death of the patient is already foreseeable or inevitable at trial inclusion
- Patients who have already been included in the study but require re-admission to the intensive care unit cannot be included a second time

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Addresses

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    • Universitätsklinikum EssenKlinik für Anästhesiologie und Intensivmedizin
    • Mr.  Univ.-Prof. Dr.  Thorsten  Brenner 
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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    • Universitätsklinikum EssenKlinik für Anästhesiologie und Intensivmedizin
    • Mr.  Univ.-Prof. Dr.  Thorsten  Brenner 
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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    • Universitätsklinikum EssenKlinik für Anästhesiologie und Intensivmedizin
    • Mr.  Univ.-Prof. Dr.   Thorsten  Brenner 
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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Sources of Monetary or Material Support

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    • Universitätsklinikum EssenKlinik für Anästhesiologie und Intensivmedizin
    • Mr.  Univ.-Prof. Dr.  Thorsten  Brenner 
    • Hufelandstr. 55
    • 45147  Essen
    • Germany
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Status

  •   Recruiting ongoing
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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.