Prospective, Randomized Trial of Personalized Medicine With Pentaglobin® After Surgical Infectious Source Control in Patients With Peritonitis

Overview

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 0.4 ml/kg body weight/hour until the total dose of 7 ml/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 (\< 700 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.

Interventions

• Drug Pentaglobin®/Standard of Care
  Standard-of-Care treatment + Pentaglobin®

Primary outcome measures

• 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. [Time frame: 7 days]

Secondary outcome measures (4)

• Death within 28 days [Time frame: 28 days]
• Death within 90 days [Time frame: 90 days]
• Change in MOF Score from baseline to day 5 [Time frame: 5 days]
• Multi-Organ Failure (i.e., > 4 MOF points) on day 7 [Time frame: 7 days]

Eligibility criteria

Inclusion criteria

• The patient is diagnosed with secondary or quaternary peritonitis
• 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).
• Sepsis and / or septic shock (according to the current sepsis guideline of the German Sepsis Society).
• SOFA Score ≥ 8
• The concentration of IL-6 is ≥ 1000 pg / ml
• Treatment with antibiotics is started within 12 hours of admission to the Intensive Care Unit
• 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

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Germany · 19 centers

• Universitätsklinikum Tübingen, Universitätsklinik für Anästhesiologie und Intensivmedizin — Tübingen
• Universitätsklinikum Regensburg, Klinik für Anästhesiologie — Regensburg
• Universitätsklinikum Essen, Klinik für Anästhesiologie und Intensivmedizin — Essen
• Charité - Universitätsmedizin Berlin, Klinik für Anästhesiologie mit Schwerpunkt operative — Berlin
• Uniklinik RWTH Aachen, Klinik für Operative Intensivmedizin und Intermediate Care — Aachen
• Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Klinik für Anästhesiologie, Inte — Bochum
• Klinikum Westfalen, Knappschaftskrankenhaus Dortmund, Klinik für Anästhesiologie, operativ — Dortmund
• Universitätsklinikum Carl Gustav Carus, Klinik und Poliklinik für Anästhesiologie und Inte — Dresden
• … and 11 more centers

Austria · 1 center

• Medizinische Universität Wien, Klinische Abteilung für Allgemeine Anästhesie und Intensivm — Vienna

Publications

• Kujath P., Rodloff Peritonitis UNI-MED, 2001 ISBN 3-8999-549-5
• Chang HJ, Lynm C, Glass RM. JAMA patient page. Sepsis. JAMA. 2010 Oct 27;304(16):1856. doi: 10.1001/jama.304.16.1856. No abstract available. PMID 20978264
• Harbarth S, Holeckova K, Froidevaux C, Pittet D, Ricou B, Grau GE, Vadas L, Pugin J; Geneva Sepsis Network. Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med. 2001 Aug 1;164(3):396-402. doi: 10.1164/ajrccm.164.3.2009052. PMID 11500339
• Heyland DK, Muscedere J, Drover J, Jiang X, Day AG; Canadian Critical Care Trials Group. Persistent organ dysfunction plus death: a novel, composite outcome measure for critical care trials. Crit Care. 2011;15(2):R98. doi: 10.1186/cc10110. Epub 2011 Mar 18. PMID 21418560
• Muller B, Becker KL, Schachinger H, Rickenbacher PR, Huber PR, Zimmerli W, Ritz R. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med. 2000 Apr;28(4):977-83. doi: 10.1097/00003246-200004000-00011. PMID 10809269
• Maruna P, Nedelnikova K, Gurlich R. Physiology and genetics of procalcitonin. Physiol Res. 2000;49 Suppl 1:S57-61. PMID 10984072
• Clec'h C, Fosse JP, Karoubi P, Vincent F, Chouahi I, Hamza L, Cupa M, Cohen Y. Differential diagnostic value of procalcitonin in surgical and medical patients with septic shock. Crit Care Med. 2006 Jan;34(1):102-7. doi: 10.1097/01.ccm.0000195012.54682.f3. PMID 16374163
• Monneret G, Doche C, Durand DV, Lepape A, Bienvenu J. Procalcitonin as a specific marker of bacterial infection in adults. Clin Chem Lab Med. 1998 Jan;36(1):67-8. doi: 10.1515/CCLM.1998.012. No abstract available. PMID 9594089

Identifiers

NCT: NCT03334006 · 15-167 · 2024-513526-27-00 · 2016-001788-34

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗