Complement Inhibition: Attacking the Overshooting Inflammation @Fter Traumatic Brain Injury (CIAO@TBI)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Traumatic Brain Injury; Trauma, Head
• Intervention / Treatment: Drug: Placebo; Drug: C1 Inhibitor, Human

• Study Type: Interventional
• Enrollment (Anticipated): 106
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Inge van Erp, BSc; Phone Number: +31(0)715262109; Email: i.a.m.van_erp@lumc.nl

Study Locations

• Netherlands
  • Den Haag, Netherlands
    • Recruiting
    • Haaglanden Medisch Centrum
    • Contact: Wilco Peul
  • Leiden, Netherlands
    • Recruiting
    • Leiden University Medical Center
    • Contact: Wilco Peul
  • Rotterdam, Netherlands
    • Not yet recruiting
    • Erasmus Medical Center
    • Contact: Wilco Peul

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Takeda; Netherlands Brain Foundation
• Investigators: Principal Investigator: Wilco Peul, MD, MPH, PhD, MBa, Leiden University Medical Center

Publications and helpful links

General Publications

• Fluiter K, Opperhuizen AL, Morgan BP, Baas F, Ramaglia V. Inhibition of the membrane attack complex of the complement system reduces secondary neuroaxonal loss and promotes neurologic recovery after traumatic brain injury in mice. J Immunol. 2014 Mar 1;192(5):2339-48. doi: 10.4049/jimmunol.1302793. Epub 2014 Jan 31.
• van Erp IAM, van Essen TA, Fluiter K, van Zwet E, van Vliet P, Baas F, Haitsma I, Verbaan D, Coert B, de Ruiter GCW, Moojen WA, van der Jagt M, Peul WC. Safety and efficacy of C1-inhibitor in traumatic brain injury (CIAO@TBI): study protocol for a randomized, placebo-controlled, multi-center trial. Trials. 2021 Dec 4;22(1):874. doi: 10.1186/s13063-021-05833-1.

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2021
• Primary Completion (Anticipated): July 1, 2023
• Study Completion (Anticipated): July 1, 2024

Study Registration Dates

• First Submitted: July 17, 2020
• First Submitted That Met QC Criteria: July 24, 2020
• First Posted (Actual): July 28, 2020

Study Record Updates

• Last Update Posted (Actual): September 13, 2021
• Last Update Submitted That Met QC Criteria: September 6, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Safety; Efficacy; Neuroinflammation; Traumatic Brain Injury; C1-inhibitor
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Craniocerebral Trauma; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Complement C1 Inhibitor Protein
• Other Study ID Numbers: NL7255105823

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes