Complement Inhibition: Attacking the Overshooting Inflammation @Fter Subarachnoid Hemorrhage (CIAO@SAH) (CIAO@SAH)

A Phase II Trial on the Safety and Efficacy of C1 Inhibitor for the Acute Management of Subarachnoid Hemorrhage

Aneurysmal subarachnoid hemorrhage (SAH) can lead to devastating outcomes for patients, like cognitive decline. This is caused by early brain injury (EBI) followed by delayed cerebral ischemia (DCI). Neuroinflammation, triggered by the complement system, has been investigated to be a key mediator in the pathophysiology of EBI and DCI. Inhibition of the complement system is therefore considered to be a potentially important new treatment for SAH.

This trial aims to study the safety and efficacy of C1-inhibitor Cinryze, an approved inhibitor of the complement system, compared to placebo in patients with SAH. By temporarily blocking the complement system we hypothesize limitation of delayed cerebral ischemia and a more favourable clinical outcome for SAH patients due to a decrease in the inflammatory response.

Study Overview

• Status: Not yet recruiting
• Conditions: Subarachnoid Hemorrhage, Aneurysmal
• Intervention / Treatment: Drug: C1 Esterase Inhibitor Injection [Cinryze]; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 128
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Daan de Groot, MD; Phone Number: 088 979 7900; Email: daan.de.groot@haaglandenmc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Confirmed diagnosis of aneurysmal subarachnoid hemorrhage on CT-scan;
• Age ≥ 18 years on admission;
• WFNS grade 1-5.

Exclusion Criteria:

• Subarachnoid hemorrhage deemed most likely of 'peri mesencephalic' origin after consideration of history, clinical examination and radiological findings (including angiographic imaging); (not originated from an aneurysm and patients have by definition a favourable clinical outcome)
• Subarachnoid hemorrhage deemed most likely of post-traumatic origin after consideration of history, clinical examination and radiological findings (including angiographic imaging); (does not occur spontaneous)
• Participation in another clinical therapeutic study;
• Patients with definite infaust prognosis on arrival and/or expected death within 24 hours of admission
• Patients with a known hereditary complement deficiency (including hereditary angioedema);
• Patients with a history of sensibility to blood products or C1-inhibitor;
• Patients with a history of thrombosis (when known at time of inclusion);
• Pregnant woman

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
Experimental: C1-esterase inhibitor (Cinryze); One group receiving study medication (C1-esterase inhibitor Cinryze)	Drug: C1 Esterase Inhibitor Injection [Cinryze]; C1 Esterase Inhibitor Injection [Cinryze]; Other Names: Cinryze
Placebo Comparator: Placebo; One group receiving placebo medication	Drug: Placebo; Sodium Chloride /physiological saline (0.9%) in equal volume dosed intravenous

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with delayed cerebral ischemia (DCI)	Defined as either a new focal neurological impairment, or a decrease of at least 2 points on the Glasgow Coma Scale. This should last for at least 1 hour, is not apparent immediately after aneurysm occlusion, and cannot be attributed to other causes by means of clinical assessment, CT or MRI scanning of the brain, and appropriate laboratory studies.	To be determined between day 4 and day 14 of admission
Number of participants with complications during hospitalization.	Complication rate during hospitalization	Up to 1 year after admission

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with cerebral infarction on brain CT		at 14 days after admission
Number of participants dying	Mortality rate	Up to 1 year after admission
Neurological condition measured by Glasgow Coma Scale	Measured daily, minimum value of 3, maximal value of 15, higher scores mean a better outcome	During the first 14 days
Complement activity markers measured in serum and CSF	WIESLAB, C3b/C, C4b/C, C5b-9 ELISA assays, CH50/AC50	Before IV administration of C1-INH or placebo, and after 48 hours and 96 hours after IV administration
Inflammatory markers measured in serum and CSF	TNF-alpha, intraleukins	Before IV administration of C1-INH or placebo, and after 48 hours and 96 hours after IV administration
Number of days in the hospital	Hospital length of stay	Up to 1 year
Number of ICU days	ICU length of stay	Up to 1 year
Number of ventilator days	Ventilator days	Up to 1 year
Clinical outcome	Modified Ranking Scale, minimum value 0, maximum value 6, higher score means worse outcome	At 6 months
Clinical outcome	Glasgow Outcome Scale Extended, minimum value 1, maximum value 8, higher score means better outcome	At 6 months
Clinical outcome	Barthel Index, minimum value 0, maximum value 100, higher score means better outcome	At 6 months
Clinical outcome	Montreal Cognitive assessment, minimum value 0, maximum value 30, higher score means better outcome	At 6 months
Clinical outcome	Quality of Life (EQ-5D-5l), minimum value -0.51, maximum value 1, higher score means better outcome	At 6 months

Collaborators and Investigators

• Sponsor: Haaglanden Medical Centre
• Collaborators: Takeda; Leiden University Medical Center
• Investigators: Principal Investigator: Wouter Moojen, MD PHD, Haaglanden Medisch Centrum

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2027

Study Registration Dates

• First Submitted: March 22, 2024
• First Submitted That Met QC Criteria: April 5, 2024
• First Posted (Actual): April 11, 2024

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: April 5, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Subarachnoid Hemorrhage; 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: NL76082.058.20

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