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

Sepsis Clinical Trial

— PEPPER  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03334006
• Other study ID #: 15-167
• Status: Recruiting
• Phase: Phase 2
• Start date: November 20, 2017
• Est. completion date: March 2028

Study information

• Verified date: April 2024
• Source: RWTH Aachen University
• Contact: Katharina Alack, Dr. rer. nat.
• Email: PEPPER[@]ukaachen.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: March 2028
• Est. primary completion date: September 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Peritonitis
• Sepsis
• Septic Shock

Intervention

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

Locations

Country	Name	City	State
Austria	Medizinische Universität Wien, Klinische Abteilung für Allgemeine Anästhesie und Intensivmedizin	Wien
Germany	Uniklinik RWTH Aachen, Klinik für Operative Intensivmedizin und Intermediate Care	Aachen
Germany	Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Klinik für Anästesiologie, Intensivmedizin und Schmerztherapie	Bochum
Germany	Klinikum Westfalen, Knappschaftskrankenhaus Dortmund, Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie	Dortmund
Germany	Universitätsklinikum Carl Gustav Carus, Klinik und Poliklinik für Anästhesiologie und Intensivtherapie	Dresden
Germany	Universitätsklinikum Düsseldorf, Klinik für Anästhesiologie	Düsseldorf
Germany	Universitätsklinikum Essen, Klinik für Anästhesiologie und Intensivmedizin	Essen	Nordrhein-Westfalen
Germany	Universitätklinikum Frankfurt, Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie	Frankfurt
Germany	Universitätsklinikum Freiburg, Klinik für Allgemein- und Viszeralchirurgie	Freiburg
Germany	Universitätsklinikum Hamburg-Eppendorf, Zentrum für Anästhesiologie und Intensivmedizin	Hamburg
Germany	Medizinische Hochschule Hannover, Zentrum für Anästhesiologie und Intensivmedizin	Hannover
Germany	Universitätsklinikum Heidelberg, Anästhesiologische Klinik	Heidelberg
Germany	Klinikum Magdeburg, Klinik für Intensivmedizin	Magdeburg
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie	Mainz
Germany	Klinikum der Universität München, Klinikum der Universität München, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie	München
Germany	Heinrich-Braun-Klinikum gGmbH, Klinik für Anästhesie, Intensivmedizin, Notfallmedizin und Schmerztherapie	Zwickau

Sponsors (2)

Lead Sponsor	Collaborator
RWTH Aachen University	Biotest

Countries where clinical trial is conducted

Austria,  Germany, 

References & Publications (37)

Adamzik M, Frey UH, Mohlenkamp S, Scherag A, Waydhas C, Marggraf G, Dammann M, Steinmann J, Siffert W, Peters J. Aquaporin 5 gene promoter--1364A/C polymorphism associated with 30-day survival in severe sepsis. Anesthesiology. 2011 Apr;114(4):912-7. doi: 10.1097/ALN.0b013e31820ca911. — View Citation

Alejandria MM, Lansang MA, Dans LF, Mantaring JB 3rd. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev. 2013 Sep 16;2013(9):CD001090. doi: 10.1002/14651858.CD001090.pub2. — View Citation

Bermejo-Martin JF, Rodriguez-Fernandez A, Herran-Monge R, Andaluz-Ojeda D, Muriel-Bombin A, Merino P, Garcia-Garcia MM, Citores R, Gandia F, Almansa R, Blanco J; GRECIA Group (Grupo de Estudios y Analisis en Cuidados Intensivos). Immunoglobulins IgG1, IgM and IgA: a synergistic team influencing survival in sepsis. J Intern Med. 2014 Oct;276(4):404-12. doi: 10.1111/joim.12265. Epub 2014 May 29. — View Citation

Beyer K, Menges P, Kessler W, Heidecke CD. [Pathophysiology of peritonitis]. Chirurg. 2016 Jan;87(1):5-12. doi: 10.1007/s00104-015-0117-6. German. — View Citation

Brunkhorst FM. [Sepsismarker--what is useful?]. Dtsch Med Wochenschr. 2008 Nov;133(48):2512-5. doi: 10.1055/s-0028-1100949. Epub 2008 Nov 19. No abstract available. German. — View Citation

Casserly B, Phillips GS, Schorr C, Dellinger RP, Townsend SR, Osborn TM, Reinhart K, Selvakumar N, Levy MM. Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med. 2015 Mar;43(3):567-73. doi: 10.1097/CCM.0000000000000742. — View Citation

Cavazzuti I, Serafini G, Busani S, Rinaldi L, Biagioni E, Buoncristiano M, Girardis M. Early therapy with IgM-enriched polyclonal immunoglobulin in patients with septic shock. Intensive Care Med. 2014 Dec;40(12):1888-96. doi: 10.1007/s00134-014-3474-6. Epub 2014 Sep 13. — View Citation

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. — View Citation

Christ-Crain M, Stolz D, Bingisser R, Muller C, Miedinger D, Huber PR, Zimmerli W, Harbarth S, Tamm M, Muller B. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med. 2006 Jul 1;174(1):84-93. doi: 10.1164/rccm.200512-1922OC. Epub 2006 Apr 7. — View Citation

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. — View Citation

Giamarellos-Bourboulis EJ, Apostolidou E, Lada M, Perdios I, Gatselis NK, Tsangaris I, Georgitsi M, Bristianou M, Kanni T, Sereti K, Kyprianou MA, Kotanidou A, Armaganidis A; Hellenic Sepsis Study Group. Kinetics of circulating immunoglobulin M in sepsis: relationship with final outcome. Crit Care. 2013 Oct 21;17(5):R247. doi: 10.1186/cc13073. — View Citation

Goris RJ, te Boekhorst TP, Nuytinck JK, Gimbrere JS. Multiple-organ failure. Generalized autodestructive inflammation? Arch Surg. 1985 Oct;120(10):1109-15. doi: 10.1001/archsurg.1985.01390340007001. — View Citation

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. — View Citation

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. — View Citation

Janssens U. [Treatment of sepsis and septic shock with immunoglobulins]. Dtsch Med Wochenschr. 2014 Jan;139(5):178. doi: 10.1055/s-0032-1329177. Epub 2014 Jan 21. No abstract available. German. — View Citation

Koo DJ, Zhou M, Chaudry IH, Wang P. The role of adrenomedullin in producing differential hemodynamic responses during sepsis. J Surg Res. 2001 Feb;95(2):207-18. doi: 10.1006/jsre.2000.6013. — View Citation

Kujath P., Rodloff Peritonitis UNI-MED, 2001 ISBN 3-8999-549-5

Kuster H, Weiss M, Willeitner AE, Detlefsen S, Jeremias I, Zbojan J, Geiger R, Lipowsky G, Simbruner G. Interleukin-1 receptor antagonist and interleukin-6 for early diagnosis of neonatal sepsis 2 days before clinical manifestation. Lancet. 1998 Oct 17;352(9136):1271-7. doi: 10.1016/S0140-6736(98)08148-3. — View Citation

Lefering R, Goris RJ, van Nieuwenhoven EJ, Neugebauer E. Revision of the multiple organ failure score. Langenbecks Arch Surg. 2002 Apr;387(1):14-20. doi: 10.1007/s00423-001-0269-3. Epub 2002 Jan 31. — View Citation

Marino R, Struck J, Maisel AS, Magrini L, Bergmann A, Di Somma S. Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis. Crit Care. 2014 Feb 17;18(1):R34. doi: 10.1186/cc13731. — View Citation

Maruna P, Nedelnikova K, Gurlich R. Physiology and genetics of procalcitonin. Physiol Res. 2000;49 Suppl 1:S57-61. — View Citation

Mebazaa A, Laterre PF, Russell JA, Bergmann A, Gattinoni L, Gayat E, Harhay MO, Hartmann O, Hein F, Kjolbye AL, Legrand M, Lewis RJ, Marshall JC, Marx G, Radermacher P, Schroedter M, Scigalla P, Stough WG, Struck J, Van den Berghe G, Yilmaz MB, Angus DC. Designing phase 3 sepsis trials: application of learned experiences from critical care trials in acute heart failure. J Intensive Care. 2016 Mar 31;4:24. doi: 10.1186/s40560-016-0151-6. eCollection 2016. — View Citation

Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, Weber-Carstens S, Hasper D, Keh D, Zuckermann H, Reinke P, Volk HD. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med. 2009 Oct 1;180(7):640-8. doi: 10.1164/rccm.200903-0363OC. Epub 2009 Jul 9. — View Citation

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. — View Citation

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. — View Citation

Panacek EA, Marshall JC, Albertson TE, Johnson DH, Johnson S, MacArthur RD, Miller M, Barchuk WT, Fischkoff S, Kaul M, Teoh L, Van Meter L, Daum L, Lemeshow S, Hicklin G, Doig C; Monoclonal Anti-TNF: a Randomized Controlled Sepsis Study Investigators. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med. 2004 Nov;32(11):2173-82. doi: 10.1097/01.ccm.0000145229.59014.6c. — View Citation

Reinhart K, Brunkhorst FM, Bone HG, Bardutzky J, Dempfle CE, Forst H, Gastmeier P, Gerlach H, Grundling M, John S, Kern W, Kreymann G, Kruger W, Kujath P, Marggraf G, Martin J, Mayer K, Meier-Hellmann A, Oppert M, Putensen C, Quintel M, Ragaller M, Rossaint R, Seifert H, Spies C, Stuber F, Weiler N, Weimann A, Werdan K, Welte T; German Interdisciplinary Association for Intensive and Emergency Care Medicine; German Sepsis Society. [Prevention, diagnosis, treatment, and follow-up care of sepsis. First revision of the S2k Guidelines of the German Sepsis Society (DSG) and the German Interdisciplinary Association for Intensive and Emergency Care Medicine (DIVI)]. Anaesthesist. 2010 Apr;59(4):347-70. doi: 10.1007/s00101-010-1719-5. No abstract available. German. — View Citation

Rodriguez A, Rello J, Neira J, Maskin B, Ceraso D, Vasta L, Palizas F. Effects of high-dose of intravenous immunoglobulin and antibiotics on survival for severe sepsis undergoing surgery. Shock. 2005 Apr;23(4):298-304. doi: 10.1097/01.shk.0000157302.69125.f8. — View Citation

Schefold JC, von Haehling S, Corsepius M, Pohle C, Kruschke P, Zuckermann H, Volk HD, Reinke P. A novel selective extracorporeal intervention in sepsis: immunoadsorption of endotoxin, interleukin 6, and complement-activating product 5a. Shock. 2007 Oct;28(4):418-25. doi: 10.1097/shk.0b013e31804f5921. — View Citation

Tamayo E, Fernandez A, Almansa R, Carrasco E, Goncalves L, Heredia M, Andaluz-Ojeda D, March G, Rico L, Gomez-Herreras JI, de Lejarazu RO, Bermejo-Martin JF. Beneficial role of endogenous immunoglobulin subclasses and isotypes in septic shock. J Crit Care. 2012 Dec;27(6):616-22. doi: 10.1016/j.jcrc.2012.08.004. Epub 2012 Oct 22. — View Citation

Thair SA, Walley KR, Nakada TA, McConechy MK, Boyd JH, Wellman H, Russell JA. A single nucleotide polymorphism in NF-kappaB inducing kinase is associated with mortality in septic shock. J Immunol. 2011 Feb 15;186(4):2321-8. doi: 10.4049/jimmunol.1002864. Epub 2011 Jan 21. — View Citation

Ueda S, Nishio K, Minamino N, Kubo A, Akai Y, Kangawa K, Matsuo H, Fujimura Y, Yoshioka A, Masui K, Doi N, Murao Y, Miyamoto S. Increased plasma levels of adrenomedullin in patients with systemic inflammatory response syndrome. Am J Respir Crit Care Med. 1999 Jul;160(1):132-6. doi: 10.1164/ajrccm.160.1.9810006. — View Citation

Van Snick J. Interleukin-6: an overview. Annu Rev Immunol. 1990;8:253-78. doi: 10.1146/annurev.iy.08.040190.001345. No abstract available. — View Citation

Wang P, Ba ZF, Cioffi WG, Bland KI, Chaudry IH. The pivotal role of adrenomedullin in producing hyperdynamic circulation during the early stage of sepsis. Arch Surg. 1998 Dec;133(12):1298-304. doi: 10.1001/archsurg.133.12.1298. — View Citation

Weigelt JA. Empiric treatment options in the management of complicated intra-abdominal infections. Cleve Clin J Med. 2007 Aug;74 Suppl 4:S29-37. doi: 10.3949/ccjm.74.suppl_4.s29. — View Citation

Wong PF, Gilliam AD, Kumar S, Shenfine J, O'Dair GN, Leaper DJ. Antibiotic regimens for secondary peritonitis of gastrointestinal origin in adults. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD004539. doi: 10.1002/14651858.CD004539.pub2. — View Citation

Zhu Y, Qiu HB, Liu JT, Wang Y, Lin HY, Xu Y, Jiang L, Shi Y, Zhu X, Ning B, Cheng R, Xie ZY, Ma PL. [Effect of endothelial nitric oxide synthase gene polymorphisms upon disease severity and outcome in septic patients]. Zhonghua Yi Xue Za Zhi. 2010 Apr 6;90(13):906-11. Chinese. — View Citation

* Note: There are 37 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 points are distributed per organ: Normal organ function: 0 points; organ dysfunction: 1 point; single organ failure: 2 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 points.	7 days
Secondary	Death within 28 days	Evaluation of death within 28-days.	28 days
Secondary	Death within 90 days	Evaluation of death within 90-days.	90 days
Secondary	Change in MOF Score from baseline to day 5	Change in MOF Score from baseline to day 5.	5 days
Secondary	Multi-Organ Failure (i.e., > 4 MOF points) on Day 7	MOF (i.e., > 4 MOF points) on Day 7 Day 7	7 days