Complement Inhibition: Attacking the Overshooting Inflammation @Fter Traumatic Brain Injury

Study Overview
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Brief Summary
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Severe Traumatic Brain Injury (s-TBI) is a major cause of death and disability across all ages. Besides the primary impact, the pathophysiologic process of major secondary brain damage consists of a neuroinflammation response that critically leads to irreversible brain damage in the first days after the trauma. A key catalyst in this inflammatory process is the complement system. Inhibiting the complement system is therefore considered to be a potentially important new treatment for TBI, as has been shown in animal studies. This trial aims to study the safety and efficacy of C1-inhibitor compared to placebo in TBI patients. By temporarily blocking the complement system we hypothesize limitation of secondary brain injury and more favourable clinical outcome for TBI patients due to a decrease in the posttraumatic neuroinflammatory response.

Official Title
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A Phase II Trial on the Safety and Efficacy of C1 Inhibitor for the Acute Management of Severe Traumatic Brain Injury

Conditions
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Traumatic Brain Injury, Trauma, Head

Intervention / Treatment
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* Drug: C1 Inhibitor, Human
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age at admission ≥ 18 years and < 65 years; Clinical diagnosis of traumatic brain injury with GCS < 13 (with intracranial deviations); Catheter placement for monitoring and management of increased ICP for at least 24 hours; Exclusion Criteria: A clear, non-traumatic cause of low GCS (e.g. toxic, cardial) on admission; Not expected to survive more than 24 hours after admission; Brain death on arrival in the participating centers; Severe pre-trauma disability, defined as being dependent on other people; Known prior history of sensibility to blood products or Cinryze; Patients with a history of hereditary angioedema; Patients with a history of thrombosis; Pregnant women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: C1-inhibitor<br>One dose 6000 IU C1-inhibitor intravenously | Drug: C1 Inhibitor, Human<br>* 6000 IU C1-INH<br>* Other names: Cinryze;|
| Placebo Comparator: Placebo<br>0.9% saline | Drug: Placebo<br>* 0.9% saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Therapy Intensity Level (TIL) Scale | TIL differentiated for various treatment modalities aimed at prevention or control of raised Intracranial Pressure (ICP) and/or for CPP management (0 to 38 points) | First four ICU days | 
| Glasgow Outcome Scale Extended (GOSE) | Functional outcome (minimum score = 1, maximum score = 8) | At 6 months after trauma | 
| Complication rate | Adverse and serious adverse events related possibly related to study medication | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial pressure (ICP) burden | Minutes of ICP>20 mm Hg | First four ICU days | 
| CT scan midline shift | in mm | Up to 1 year | 
| Mortality |  | Up to 1 year after trauma | 
| Glasgow Outcome Scale Extended (GOSE) | Functional outcome (minimum score = 1, maximum score = 8) | At discharge (an average of 14 days), 3 and 12 months after trauma | 
| QoLiBri | Quality of Life | At 3, 6 and 12 months after trauma | 
| SF-36 | Health-related quality of life | At 3, 6 and 12 months after trauma | 
| EQ-5D-5L | Health-related quality of life | At 6 and 12 months after trauma | 
| ICU length of stay | in days | Up to 1 year | 
| Ventilator days | in days | Up to 1 year | 
| Hospital length of stay | in days | Up to 1 year | 
| Hospital disposition | Discharged to home, rehabilitation or nursery home | Up to 1 year | 
| UCH-L1 and GFAP biomarkers |  | Baseline (Before adminstration of investigational product ) and 6, 12, 24, 48, 72 and 96 hours after adminstration of investigational product | 
| Complement activation | WIESLAB, C3b/C, C4b/C, C5b-9 ELISA assays, CH50/AC50 | Baseline (Before adminstration of investigational product ) and 6, 12, 24, 48, 72 and 96 hours after adminstration of investigational product | 
| Coagulation cascade activation | PT, aPPT, PLT, D-dimer, fibrinogen | Baseline (Before adminstration of investigational product ) and 6, 12, 24, 48, 72 and 96 hours after adminstration of investigational product | 
| Inflammatory markers | TNF-alpha, intraleukins | Baseline (Before adminstration of investigational product ) and 6, 12, 24, 48, 72 and 96 hours after adminstration of investigational product | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, C1-inhibitor, Neuroinflammation, Efficacy, Traumatic Brain Injury