Optimization of Sepsis Therapy Based on Patient-specific Digital Precision Diagnostics (DigiSep)

March 28, 2022 updated by: University Hospital, Essen

Sepsis is triggered by an infection and represents one of the greatest challenges of modern intensive care medicine. With regard to a targeted antimicrobial treatment strategy, the earliest possible pathogen detection is of crucial importance. Until now, culture-based detection methods represent the diagnostic gold standard, although they are characterized by numerous limitations. Culture-independent molecular diagnostic procedures may represent a promising alternative. In particular, the concept of plasmatic detection of circulating, free DNA employing next-generation sequencing (NGS) has shown to be suitable for the detection of disease-causing pathogens in patients with bloodstream infections.

The DigiSep-Trial is a randomized, controlled, interventional, multicenter trial to characterize the effect of the combination of NGS-based digital precision diagnostics, standard-of-care microbiological analyses and optional expert exchanges compared to solely standard-of-care microbiological analyses 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 (Desirability of Outcome Ranking / Response Adjusted for Duration of Antibiotic Risk) score (representing a combined endpoint including the criteria (1) inpatient admission time, (2) consumption of antibiotics, (3) mortality and (4) acute renal failure (ARF)) can be significantly improved, by application of an additional NGS-based diagnostic concept. We also aim to investigate whether the new diagnostic procedure is cost-effective. It is postulated that the inpatient admission time, mortality rate, incidence of ARF, the duration of antimicrobial therapy as well as the costs of complications and outpatient aftercare can be reduced. Moreover, a significant improvement in the quality of life (QoL) of the affected patients can be expected.

Extensive preparatory work suggests that NGS-based diagnostics have higher specificity and sensitivity compared to standard-of-care microbiological analyses for detecting bloodstream infections. This preliminary work for the DigiSep-Trial with the help of an interventional study design provides the optimal basis to establish this new concept as part of the national standard based on the best possible evidence.

Study Overview

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

410

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

      • Berlin, Germany
        • Not yet recruiting
        • University Hospital Charité
        • Contact:
    • Baden-Württemberg
      • Heidelberg, Baden-Württemberg, Germany
      • Heidenheim, Baden-Württemberg, Germany
      • Konstanz, Baden-Württemberg, Germany
        • Not yet recruiting
        • Konstanz Hospital
        • Contact:
      • Tübingen, Baden-Württemberg, Germany
      • Ulm, Baden-Württemberg, Germany
    • Bayern
      • München, Bayern, Germany
        • Not yet recruiting
        • University Hospital TU München
        • Contact:
      • Regensburg, Bayern, Germany
        • Not yet recruiting
        • University Hospital Regensburg
        • Contact:
      • Würzburg, Bayern, Germany
        • Not yet recruiting
        • University Hospital Würzburg
        • Contact:
    • Brandenburg
      • Luckau, Brandenburg, Germany
        • Not yet recruiting
        • Klinik Evangelisches Krankenhaus Luckau gGmbH
        • Contact:
    • Hessen
      • Frankfurt, Hessen, Germany
        • Not yet recruiting
        • University Hospital Frankfurt
        • Contact:
      • Wiesbaden, Hessen, Germany
    • Mecklenburg-Vorpommern
      • Rostock, Mecklenburg-Vorpommern, Germany
    • Niedersachsen
      • Göttingen, Niedersachsen, Germany
        • Not yet recruiting
        • University Hospital Göttingen
        • Contact:
      • Hannover, Niedersachsen, Germany
    • Nordrhein-Westfalen
      • Aachen, Nordrhein-Westfalen, Germany
        • Not yet recruiting
        • University Hospital Aachen
        • Contact:
      • Bielefeld, Nordrhein-Westfalen, Germany
        • Not yet recruiting
        • Klinik Evangelisches Krankenhaus Bethel gGmbH Bielefeld
        • Contact:
          • Friedhelm Bach, MD
          • Phone Number: 79102 +49 521 772
          • Email: ains@evkb.de
      • Bonn, Nordrhein-Westfalen, Germany
        • Not yet recruiting
        • University Hospital Bonn
        • Contact:
      • Düsseldorf, Nordrhein-Westfalen, Germany
      • Essen, Nordrhein-Westfalen, Germany
      • Köln, Nordrhein-Westfalen, Germany
        • Not yet recruiting
        • University Hospital Köln
        • Contact:
    • Sachsen
      • Leipzig, Sachsen, Germany

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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)

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 1
Standard diagnostics
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 of sepsis / septic shock
Experimental: 2
Standard diagnostics + NGS
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 of sepsis / septic shock

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Desirability of Outcome Ranking / Response Adjusted for Duration of Antibiotic Risk-Score
Time Frame: 28 days
DOOR/RADAR-score [points], (min. 1, max. 5), a lower score indicates a better outcome
28 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease severity
Time Frame: at 90 and 180 days
Long term mortality [%]
at 90 and 180 days
Disease severity
Time Frame: at 28, 90, and 180 days
Hospital length of stay [days]
at 28, 90, and 180 days
Degree of organ dysfunction/-failure
Time Frame: at 28, 90, and 180 days
Duration of mechanical ventilation [days]
at 28, 90, and 180 days
Degree of organ dysfunction/-failure
Time Frame: during 28 days
Length of time until shock resolution [hours]
during 28 days
Degree of organ dysfunction/-failure
Time Frame: at 28, 90, and 180 days
Ongoing need for renal replacement therapy [%]
at 28, 90, and 180 days
Microbiological outcome
Time Frame: at 28, 90, and 180 days
Cumulative need for anti-infective drugs [days]
at 28, 90, and 180 days
Microbiological outcome
Time Frame: during 28 days
Beginning of a targeted anti-infective treatment regimen [days]
during 28 days
Health economic outcome
Time Frame: at 28, 90, and 180 days
Utilization of healthcare ressources (outpatient and inpatient) [Euro]
at 28, 90, and 180 days
Health economic outcome
Time Frame: at 28, 90, and 180 days
Policyholder costs (outpatient and inpatient) [Euro]
at 28, 90, and 180 days
Economic outcome
Time Frame: at 28, 90, and 180 days
Disease-related absence from work [days]
at 28, 90, and 180 days
Quality-of-life (QoL) based on VR-36 questionnaire
Time Frame: 90 and 180 days
VR-36 questionnaire [points] including 2 summary components, 8 scales, 36 items, a higher score indicates a higher Quality-of-Life (QoL)
90 and 180 days
Quality-of-life (QoL) based on EQ-5D-5L questionnaire
Time Frame: at 0, 90 and 180 days
EQ-5D-5L questionnaire [points] including 10 items, a higher score indicates a higher Quality-of-Life (QoL)
at 0, 90 and 180 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 16, 2022

Primary Completion (Anticipated)

February 28, 2024

Study Completion (Anticipated)

August 31, 2024

Study Registration Dates

First Submitted

September 21, 2020

First Submitted That Met QC Criteria

September 25, 2020

First Posted (Actual)

October 1, 2020

Study Record Updates

Last Update Posted (Actual)

March 29, 2022

Last Update Submitted That Met QC Criteria

March 28, 2022

Last Verified

March 1, 2022

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

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.

IPD Sharing Supporting Information Type

  • Study Protocol
  • Statistical Analysis Plan (SAP)
  • Informed Consent Form (ICF)
  • Clinical Study Report (CSR)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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