Beta-blockade in Unruptured Intracranial Aneurysm (BBLURAN)

Subarachnoid haemorrhage is a devastating type of stroke, with high mortality and morbidity rate. In approximately 85% of cases, it is caused by an intracranial aneurysm rupture. Majority of patients with diagnosed intracranial aneurysm are eligible for interventional treatment, however, some patients are managed conservatively. Currently, the only recommendations for patients with conservatively managed intracranial aneurysms, are routine imaging follow-ups and minimization of rupture risk factors. There are no medications proven to decrease risk of aneurysm rupture, that might be prescribed to such patients. In preliminary study the investigators found that patients with intracranial aneurysms who took β-blockers had significantly smaller aneurysm rupture rate and dome size, as well as more favorable hemodynamic parameters. No other antihypertensive drugs showed similar associations. Therefore, in this project the investigators aim to further analyze the impact of β-blocker intake on fate of intracranial aneurysm and find possible explanations for its protective role. The investigators aim to perform a randomised, double-blind, placebo-controlled clinical trial. One hundred patients with unruptured intracranial aneurysm, , qualified to conservative management will be enrolled. Two arms (50 patients each) will be receiving nebivolol or matching placebo. Treatment in each arm will last 12 months. The following examinations will be performed at baseline and at 6 and 12 months: clinical assessment, angio-MRI with vessel wall imaging, Doppler ultrasound to extract blood flow waveforms from Internal Carotid Artery, Vertebral Artery Middle Cerebral Artery, Anterior Cerebral Artery and Posterior Cerebral Artery, as well as blood samples. Based on the results the investigators will assess changes in aneurysm size and wall contrast enhancement. The investigators will also analyze levels of possible aneurysm growth biomarkers in peripheral blood. Additionally, the investigators will prepare three-dimensional models of the artery harbouring aneurysm and perform patient-specific computer modelling of blood flow through such artery to assess hemodynamic parameters of aneurysm dome. All obtained measurements will be compared at baseline and at 6 and 12 months. The investigators hypothesize that, in comparison to the placebo group, β-blocker therapy in patients with unruptured intracranial aneurysm will contribute to favorable changes in hemodynamic parameters of aneurysm dome, decrease wall degradation process and prevent from aneurysm growth.

Study Overview

• Status: Not yet recruiting
• Conditions: Intracranial Aneurysm
• Intervention / Treatment: Drug: Nebivolol; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 4

Contacts and Locations

Study Locations

• Poland
  • Lesser Poland
    • Kraków, Lesser Poland, Poland, 30-688
      • University Hospital in Krakow
      • Contact: Kornelia M Kliś, MD, PhD; Phone Number: +48 12 400 2450; Email: kornelia.klis@uj.edu.pl
      • Contact: Roger M Krzyżewski, MD, PhD; Phone Number: +48 12 400 2450; Email: roger.krzyzewski@uj.edu.pl
      • Principal Investigator: Kornelia M Kliś, MD, PhD
      • Principal Investigator: Roger M Krzyżewski, MD, PhD
      • Sub-Investigator: Karolina Piotrowicz, MD, PhD
      • Sub-Investigator: Marcin P Surmiak, PhD
      • Sub-Investigator: Borys M Kwinta, MD, PhD
      • Sub-Investigator: Amira Bryll, MD, PhD
      • Principal Investigator: Igor Szydłowski, MD
      • Sub-Investigator: Monika Ryś, MD
      • Sub-Investigator: Ian Perera, MD
      • Principal Investigator: Jerzy Gąsowski, MD, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• freshly (within 12 months) diagnosed unruptured intracranial aneurysm, non-eligible for surgical or endovascular treatment
• age > 18 years
• informed consent

Exclusion Criteria:

• contraindications to β-blockers intake
• previous SAH
• intake of β-blocker currently or in the past
• presence of other intracranial pathology
• history of surgical or endovascular aneurysm treatment
• contraindications for contrast-enhancement MRI examination

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nebivolol arm; Patients randomly assigned to receive active treatment with escalating doses of nebivolol.	Drug: Nebivolol; 12-month intake of medication
Placebo Comparator: Placebo arm; Patients randomly assigned to receive matching placebo tablets.	Drug: Placebo; 12-month intake of matching placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracranial aneurysm growth	Any increase in size of intracranial aneurysm assessed by radiology specialist based on Magnetic Resonance Angiography.	12 months
Intracranial aneurysm rupture	Fatal or non-fatal intracranial aneurysm rupture. Outcome will be determined based on presence of subarachnoid hemorrhage on head Computer Tomography (performed in case on any symptoms).	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality	Death of any cause	12 months
Change in aneurysmal hemodynamic parameters	5% increase or decrease (relative to measurement at baseline) of one or more following parameters: dome fraction very high Oscillatory Shear Index (defined as percentage of aneurysm dome with Oscillatory Shear Index higher than 0.2); dome fraction of very low Wall Shear Stress (defined as percentage of aneurysm dome with Wall Shear Stress lower than 0.5); Surface Vortex Fraction (defined as as percentage of flow with positive Q-criterion in small layer near aneurysm wall) All parameters will be determined based on computer modelling of blood flow in aneurysm dome.	12 months
Change in aneurysm growth biomarkers	Any change in serum levels of one or more biomarkers: IL-1,IL-6, IL-15, TGF- β and MCP-1.	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
5-year all-cause mortality, intracranial aneurysm rupture or necessity of neurosurgical intervention	Yearly follow-up for all-cause mortality or intracranial aneurysm rupture or neurosurgical intervention	5 years

Collaborators and Investigators

• Sponsor: Jagiellonian University
• Collaborators: University Hospital in Krakow

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2025
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: January 6, 2024
• First Submitted That Met QC Criteria: February 6, 2024
• First Posted (Actual): February 8, 2024

Study Record Updates

• Last Update Posted (Actual): February 8, 2024
• Last Update Submitted That Met QC Criteria: February 6, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: randomized clinical trial; intracranial aneurysm; beta-blocker; rupture prevention; hemodynamic analysis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Arterial Diseases; Aneurysm; Intracranial Aneurysm; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Adrenergic Agonists; Adrenergic beta-Agonists; Adrenergic beta-1 Receptor Agonists; Nebivolol
• Other Study ID Numbers: BBLURAN-CMUJ-14062023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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