Effect of C1-esterase Inhibitor on Systemic Inflammation in Trauma Patients With a Femur or Pelvic Fracture (CAESAR)

Trauma and major operation are associated with an excessive inflammation reaction due to tissue injury. This overwhelming immune response is considered to be a major risk factor in the pathogenesis of late inflammatory complications such as acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS) and sepsis.

The investigators hypothesize that administration of C1-esterase inhibitor (C1-INH) will attenuate the humane inflammatory response and, thereby, reduce the risk of inflammatory complications due to surgical interventions in trauma patients with a femur or pelvic fracture

Study Overview

• Status: Terminated
• Conditions: Sepsis; Inflammation; Trauma; Multiple Organ Dysfunction Syndrome
• Intervention / Treatment: Drug: C1-esterase inhibitor; Other: Saline 0.9%

Detailed Description

Systemic inflammation in response to a femur or pelvic fracture and fixation is associated with complications, such as acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS). The injury itself, but also the additional fixation procedure give a release of pro-inflammatory cytokines, in particular interleukin (IL)-6. This results in an aggravation of the initial systemic inflammatory response, and will cause in some patients an increased risk on the development of inflammatory complications, like ARDS and MODS. Which can lead to higher morbidity, mortality and prolonged hospital stay.

Various strategies, such as damage control orthopedics, have been proposed to prevent these complications. Another strategy is to decrease the inflammatory reaction caused by the surgical procedure, and by interventions focused on inhibition of the innate inflammatory response. This will lower the risk of complications.

A promising candidate is the endogenously produced serum protein C1-esterase inhibitor (C1-INH). This protein is an acute phase protein, produced by the liver in response to inflammatory conditions. C1-INH is a major inactivator of the complement system, but important additional anti-inflammatory properties have been demonstrated. A previous study of from our laboratory showed that administration of the drug C1-INH significantly reduced the concentration of circulating pro-inflammatory cytokines such as IL-6, during human experimental endotoxemia. Treatment with C1-INH has been proven to be safe in treatment with humans, even in high dosages and in pregnant patients with C1-INH deficiency.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3508 GA
    • University Medical Centre Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Multi trauma patients
• Femur or pelvic fracture
• Injury Severity Score (ISS) ≥ 18
• Age 18-80 yrs

Exclusion Criteria:

• Congenital C1-inhibitor deficiency
• Use of immune suppressants
• Pregnancy
• Known hypersensitivity for blood products
• Fixation of femur fracture with external fixation or osteosynthesis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: C1-esterase inhibitor; C1-esterase inhibitor, 100 U/kg bodyweight	Drug: C1-esterase inhibitor; C1-esterase inhibitor 200 U/kg infusion over 30 minutes, just before the start of the femur or pelvic fixation operation.; Other Names: Cetor® (RVG 19303)
Placebo Comparator: Saline 0.9%	Other: Saline 0.9%; Infusion, just before the start of the femur or pelvic fixation operation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Delta Interleukine-6	6 hours after C1-INH administration

Secondary Outcome Measures

Outcome Measure	Time Frame
Cytokines and other markers of inflammation	up to 12 days after C1-INH administration
Neutrophil redistribution and phenotype	Up to 12 days after C1-INH administration
C1-inhibitor and complement concentration and activity	Up to 12 days after C1-INH administration
Hemodynamic response	Up to 12 days after C1-INH administration

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Collaborators: Prothya Biosolutions
• Investigators: Principal Investigator: Luke P Leenen, MD, PhD, UMC Utrecht

Publications and helpful links

General Publications

• Heeres M, Visser T, van Wessem KJ, Koenderman AH, Strengers PF, Koenderman L, Leenen LP. The effect of C1-esterase inhibitor on systemic inflammation in trauma patients with a femur fracture - The CAESAR study: study protocol for a randomized controlled trial. Trials. 2011 Oct 11;12:223. doi: 10.1186/1745-6215-12-223.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): February 1, 2015
• Study Completion (Actual): February 1, 2015

Study Registration Dates

• First Submitted: January 12, 2011
• First Submitted That Met QC Criteria: January 12, 2011
• First Posted (Estimate): January 13, 2011

Study Record Updates

• Last Update Posted (Estimate): February 4, 2015
• Last Update Submitted That Met QC Criteria: February 3, 2015
• Last Verified: February 1, 2015

More Information

Terms related to this study

• Keywords: Systemic inflammation; Sepsis; Cytokines; Trauma; Multiple Organ Dysfunction Syndrome; C1-esterase inhibitor
• Additional Relevant MeSH Terms: Pathologic Processes; Fractures, Bone; Leg Injuries; Shock; Femoral Fractures; Hip Injuries; Inflammation; Wounds and Injuries; Hip Fractures; Multiple Organ Failure; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Complement C1 Inhibitor Protein; Complement C1 Inactivator Proteins; Complement C1s
• Other Study ID Numbers: 34932