Clinical trial NCT03334006: Prospective, Randomized Trial of Personalized Medicine With Pentaglobin® After Surgical Infectious Source Control in Patients With Peritonitis
Official title: Prospective, Randomized Trial of Personalized Medicine With Pentaglobin® After Surgical Infectious Source Control in Patients With Peritonitis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Peritonitis
Sepsis
Septic Shock
Keywords: Pentaglobin®
Personalized Medicine
Lead sponsor: RWTH Aachen University
Sponsor class: OTHER
Collaborators: name: Biotest
First posted: 2017-11-07
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The control group receives a Standard-of-Care treatment. The intervention group is additionally treated with IgGAM (Pentaglobin®) as an add on treatment to Standard-of-Care.

The preparation to be provided contains (per ml solution) 50 mg human plasma proteins, of which \>95% are immunoglobulins: IgM 6 mg, IgA 6 mg and IgG 38 mg. The IgG subclass distribution is IgG1 \~63%, IgG2 \~26%, IgG3 \~4%, IgG4 \~7%.

Pentaglobin® is administered by continuous intravenous infusion over a period of 5 day of 0.4 ml/kg body weight/hour until the total dose of 7mL/kg body weight/day is reached.
Primary purpose: TREATMENT

Brief summary: The aim of this prospective, randomized, controlled trial is to provide evidence for adjuvant IgGAM treatment with regard to

1. Improvement of patient outcomes for peritonitis. Improvement in outcome will be determined by scores such as MOF, SOFA and survival.
2. Identification of biomarkers (including immunoglobulin levels, HLA-DR, Nf-kB1 and other immunological biomarkers) to identify patient subpopulations that benefit most from IgGAM treatment. These patients will form the basis for a further randomized, controlled, double-blind Phase III trial (RCT) to demonstrate the benefit of this treatment.
3. In addition, these biomarkers could help to guide a targeted, i.e. "personalized", adjuvant therapy with Pentaglobin® (IgGAM) in the indication of peritonitis.

Detailed description: The aim of this prospective, randomized, controlled trial is to provide evidence for adjuvant IgGAM treatment with regard to

1. Improvement of patient outcomes for peritonitis. Improvement in outcome will be determined by scores such as MOF, SOFA and survival.
2. Identification of biomarkers (including immunoglobulin levels, HLA-DR, Nf-kB1 and other immunological biomarkers) to identify patient subpopulations that benefit most from IgGAM treatment. These patients will form the basis for a further randomized, controlled, double-blind Phase III trial (RCT) to demonstrate the benefit of this treatment.
3. In addition, these biomarkers could help to guide a targeted, i.e. "personalized", adjuvant therapy with Pentaglobin® (IgGAM) in the indication of peritonitis.

The control group receives Standard-of-Care treatment. The intervention group is additionally treated with IgGAM (Pentaglobin®) as an add-on treatment to Standard-of-Care.

Pentaglobin® is administered by continuous intravenous infusion over a period of 5 days of 0.4ml/kg body weight/hour until the total dose of 7mL/kg body weight/day is reached.

Primary outcome: Change in Multiple Organ Failure (MOF) score (measured in lung, heart, kidney, liver, blood) from baseline to day 7 after surgical infectious source control in the context of peritonitis.

The MOF score is determined in the morning. The following score points are distributed per organ: Normal organ function: 0 score points; organ dysfunction: 1 score point; single organ failure: 2 score points. A score \> 4 in the sum of the 5 organs indicates multiple organ failure. Patients who died before the MOF score was obtained are assigned a score of 10 score points.

Secondary outcome:

* Death within 28 days
* Death within 90 days
* Change in MOF score from baseline to day 5
* Multi-organ Failure ( \> 4 MOF score points on day 7)

Exploratory objectives:

* Effects of Pentaglobin® therapy on the SOFA score (determined in the organs lung, CNS, circulation, liver, coagulation and kidney).
* Interaction of the biomarkers "NF-kB1" (steady), "CRP (≥ 70 mg/L), IgA (\< 150 mg/dl), IgG (\< 300 mg/dl), IgM (\< 35 mg/dl) and HLA-DR expression (≤ 8,000 molecules per monocyte) with therapy in terms of change in MOF score from baseline to days 5 and 7 and death within 28 and 90 days.

Eligibility criteria: Inclusion Criteria:

1. The patient is diagnosed with secondary or quaternary peritonitis
2. The time of the surgical infectious source control is within 6 hours of indication (defined as date and time of registration for surgical or minimal invasive procedure).
3. Sepsis and / or septic shock (according to the current sepsis guideline of the German Sepsis Society).
4. SOFA Score ≥ 8
5. The concentration of IL-6 is ≥ 1000 pg / ml
6. Treatment with antibiotics is started within 12 hours of admission to the Intensive Care Unit
7. The informed consent form has been signed by the patient and / or by his legal representative (such as his spouse, an health care proxy authorized or a legal representative) or by a consultant physician

Exclusion criteria

1. Patients with a life expectancy of less than 90 days due to medical conditions unrelated to peritonitis nor with sepsis and / or septic shock.
2. For female patients : The patient is pregnant or breastfeeding
3. The patient is a minor (\< 18 years of age).
4. The patient has known chronic renal dysfunction requiring dialysis (creatinine ≥ 3.4 mg / dl or creatinine clearance ≤ 30 mL / min / 1.73 m2).
5. The patient has acute, primarily non-infectious pancreatitis or mediastinitis
6. The patient has a BMI\> 40.
7. The patient has any contraindication to study drug.
8. The patient has participated in another clinical trial within the last 30 days.
9. The patient is in a dependent or employment relationship with the sponsor or investigator.
10. The patient is institutionalized by court or government order

Primary outcomes:
measure: Change in Multiple Organ Failure (MOF) score (measured in lung, heart, kidney, liver, blood) from baseline to day 7 after surgical infectious source control in the context of peritonitis.
timeFrame: 7 days
Secondary outcomes:
measure: Death within 28 days
timeFrame: 28 days
measure: Death within 90 days
timeFrame: 90 days
measure: Change in MOF Score from baseline to day 5
timeFrame: 5 days
measure: Multi-Organ Failure (i.e., > 4 MOF points) on Day 7
timeFrame: 7 days
Other outcomes:
Locations:
city: Wien
country: Austria
facility: Medizinische Universität Wien, Klinische Abteilung für Allgemeine Anästhesie und Intensivmedizin
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen, Universitätsklinik für Anästhesiologie und Intensivmedizin
state: Baden-Württemberg
city: Essen
country: Germany
facility: Universitätsklinikum Essen, Klinik für Anästhesiologie und Intensivmedizin
state: Nordrhein-Westfalen
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen, Klinik für Operative Intensivmedizin und Intermediate Care
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin, Klinik für Anästhesiologie mit Schwerpunkt operative Intensivmedizin
city: Bochum
country: Germany
facility: Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Klinik für Anästesiologie, Intensivmedizin und Schmerztherapie
city: Dortmund
country: Germany
facility: Klinikum Westfalen, Knappschaftskrankenhaus Dortmund, Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus, Klinik und Poliklinik für Anästhesiologie und Intensivtherapie
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf, Klinik für Anästhesiologie
city: Frankfurt
country: Germany
facility: Universitätklinikum Frankfurt, Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg, Klinik für Allgemein- und Viszeralchirurgie
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf, Zentrum für Anästhesiologie und Intensivmedizin
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Zentrum für Anästhesiologie und Intensivmedizin
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg, Anästhesiologische Klinik
city: Magdeburg
country: Germany
facility: Klinikum Magdeburg, Klinik für Intensivmedizin
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie
city: München
country: Germany
facility: Klinikum der Universität München, Klinikum der Universität München, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg, Klinik für Anästhesiologie und operative Intensivmedizin
city: Zwickau
country: Germany
facility: Heinrich-Braun-Klinikum gGmbH, Klinik für Anästhesie, Intensivmedizin, Notfallmedizin und Schmerztherapie
Study officials:
affiliation: RWTH Aachen University
name: Gernot Marx, Univ.-Prof.
role: PRINCIPAL_INVESTIGATOR
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