Acetylsalicylic Acid Plus Intensive Blood Pressure Treatment in Patients With Unruptured Intracranial Aneurysms (PROTECT-U)

Prospective Randomized Open-label Trial to Evaluate Risk faCTor Management in Patients With Unruptured Intracranial Aneurysms

Purpose of this study is to assess the hypothesis that a strategy with acetylsalicylic acid (ASA) 100 mg/day, intensive blood pressure treatment (targeted systolic blood pressure below 120 mmHg), and a blood pressure measuring device reduces the risk of aneurysm rupture or growth compared with standard care (i.e. no ASA, blood pressure management according to standard blood pressure management, no blood pressure measuring device)

Study Overview

• Status: Unknown
• Conditions: Unruptured Intracranial Aneurysms
• Intervention / Treatment: Drug: Acetylsalicylic acid; Other: intensive blood pressure control

• Study Type: Interventional
• Enrollment (Anticipated): 776
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany, 52074
    • Recruiting
    • Klinik für Neurochirurgie
    • Contact: Gerrit A Schubert, Prof. Dr.; Phone Number: +49 241 8082420; Email: gschubert@ukaachen.de
    • Contact: Rastislav Pjontek, Dr.; Email: rpjontek@ukaachen.de
    • Principal Investigator: Gerrit A Schubert, Prof. Dr.
  • Berlin, Germany, 13353
    • Recruiting
    • Neurochirurgische Klinik
    • Contact: Peter Vajkoczy, Prof. Dr.; Phone Number: +49 30 450 560900; Email: peter.vajkoczy@charite.de
    • Contact: Lars Wessels, Dr.; Phone Number: 0002 030 450 56; Email: lars.wessels@charite.de
    • Principal Investigator: Peter Vajkoczy, Prof. Dr.
  • Düsseldorf, Germany, 40225
    • Recruiting
    • Neurochirurgische Klinik
    • Contact: Athanasios Petridis, Prof. Dr.; Phone Number: 4514 +49 211810; Email: athanasios.petridis@duesseldorf.de
    • Contact: Kerim Beseoglu, Dr.
  • Erlangen, Germany, 91054
    • Recruiting
    • Neurolgische Klinik
    • Contact: Hagen Huttner, Prof. Dr.; Phone Number: +4991318536597; Email: hagen.huttner@uk-erlangen.de
    • Contact: Bernd Kallmünzer, Dr.; Email: bernd.kallmuenzer@uk-erlangen.de
    • Principal Investigator: Hagen Huttner, Prof. Dr.
  • Essen, Germany, 45147
    • Recruiting
    • Klinik für Neurochirurgie
    • Contact: Ramazan Jabbarli, PD Dr.; Email: ramazan.jabbarli@uk-essen.de
    • Principal Investigator: Ramazan Jabbarli, PhD
  • Göttingen, Germany, 37037
    • Recruiting
    • Klinik für Neurochirurgie
    • Contact: Dorothe Mielke, Prof. Dr.; Email: dorothe.mielke@med.uni-goettingen.de
    • Contact: Katharina Lange; Email: katharina.lange@med.uni-goettingen.de
    • Principal Investigator: Veit Rohde, Prof. Dr.
  • Hamburg, Germany, 20246
    • Recruiting
    • Klinik für Neurochirurgie
    • Contact: Nils O Schmidt, PD Dr.; Email: nschmidt@uke.de
    • Contact: Jan Regelsberger, Prof. Dr.; Email: j.regelsberger@uke.de
    • Principal Investigator: Nils O Schmidt, PD Dr.
  • Heidelberg, Germany, 69120
    • Recruiting
    • Neurologische Universitatsklinik
    • Contact: Peter A Ringleb, Prof. Dr.; Phone Number: 8243 +496221 56-
    • Contact: Elisabeth Beyrle; Phone Number: 8856 +406221 563-; Email: elisabeth.beyrle@med.uni-heidelberg.de
    • Principal Investigator: Peter A Ringleb, Prof. Dr.
  • Mannheim, Germany, 68167
    • Recruiting
    • Department of Neurosurgery, University Hospital Mannheim
    • Contact: Nima Etminan, PD Dr. med.; Phone Number: +49-621-383-2360; Email: nima.etminan@umm.de
    • Contact: Katharina Hackenberg, Dr.med.; Phone Number: +49-621-383-2360; Email: katharina.hackenberg@umm.de
    • Principal Investigator: Nima Etminan, PD Dr.med.
    • Sub-Investigator: Daniel Haenggi, Prof. Dr.med.
  • München, Germany, 81675
    • Active, not recruiting
    • Neurochirurgische Klinik und Poliklinik
  • Münster, Germany, 48149
    • Recruiting
    • Universitätsklinikum Münster
    • Contact: Markus Holling, MD PhD; Phone Number: +49 251 / 83 -47482; Email: hollingm@ukmuenster.de
    • Principal Investigator: Markus Holling, MD PhD
  • Hessen
    • Frankfurt am Main, Hessen, Germany
      • Recruiting
      • Department of Neurology and Neurosurgery, Goethe University
      • Contact: Helmuth Steinmetz, Prof. Dr.; Phone Number: +49 69 6301-5769; Email: helmuth.steinmetz@em.uni-frankfurt.de
      • Contact: Jürgen Konczalla, PD Dr; Email: J.Konczalla@med.uni-frankfurt.de
      • Principal Investigator: Helmuth Steinmetz, Prof. Dr.
• Netherlands
  • Amsterdam, Netherlands, 1105AZ
    • Recruiting
    • AMC Department of Neurology
    • Contact: Yvo B. W. Roos, Prof. Dr.; Phone Number: +31-20-5663942; Email: y.b.roos@amc.uva.nl
    • Contact: Rita Sprengers; Email: r.g.sprengers@amc.uva.nl
    • Principal Investigator: Yvo Roos, Prof. Dr.
  • Groningen, Netherlands
    • Recruiting
    • UMCG
    • Contact: Maarten Uyttenboogaart, Dr.; Email: m.uyttenboogaart@umcg.nl
    • Principal Investigator: Maarten Uyttenboogaart, Dr.
  • Leiden, Netherlands, 2300 RC
    • Recruiting
    • Leiden University Medical Center
    • Contact: Ghislaine Holswilder, MD; Email: g.holswilder@lumc.nl
    • Contact: A van der Meij, MD; Email: a.van_der_meij@lumc.nl
    • Principal Investigator: Marieke JH Wermer, MD PhD FESO
  • Nijmegen, Netherlands, 6500 GS
    • Recruiting
    • Neurochirurgisch Centrum CWZ
    • Contact: Jeroen Boogaarts, Dr.; Email: jeroen.boogaarts@radboudumc.nl
    • Contact: Viktoria Shimanskaya, Dr; Email: vika.shimanskaya@radboudumc.nl
    • Principal Investigator: Jeroen Boogarts, Dr.
  • Rotterdam, Netherlands, 3015 GD
    • Recruiting
    • Erasmus MC
    • Contact: Naziha el Ghannouti; Phone Number: +31 10 704 38 18; Email: n.elghannouti@erasmusmc.nl
    • Principal Investigator: Bob Roozenbeek, MD PhD
  • Utrecht, Netherlands
    • Recruiting
    • UMC
    • Contact: Mervyn D. I. Vergouwen, Dr.; Phone Number: +31 (0)88 755 0455; Email: M.D.I.Vergouwen@umcutrecht.nl
    • Contact: Jacco M. Westeneng; Email: J.M.Westeneng-4@umcutrecht.nl
    • Principal Investigator: Mervyn D. I. Vergouwen, Dr.

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients 18 years or older with an intradural, saccular unruptured aneurysm (UIA) in whom it is decided not to intervene with preventive endovascular or neurosurgical repair of the aneurysm and who are monitored on a regular base for aneurysm growth
• Last aneurysm imaging with either CTA/MRA/DSA within the last 3 months

Exclusion Criteria:

• All non-saccular UIAs or aneurysms related to arteriovenous malformations
• Frequent ASA use and/or indication for a vitamin K antagonist, or direct oral anticoagulant (DOAC) treatment at baseline
• Contra-indication for ASA
• History of hypersensitivity to ASA or to any other drug with similar chemical structure or to any excipient present in the pharmaceutical form of ASA
• Chronic kidney disease stage IV and V (GFR < 30 mL/min/1.73 m2)
• Pregnancy and lactation
• Participation in another clinical trial or observation period of competing trials, respectively
• Life-expectancy <3 years

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Acetylsalicylic acid, BP-target 120; 100 mg ASA plus intensified blood pressure management. Recommended systolic blood pressure 120 mm/Hg	Drug: Acetylsalicylic acid; 100 mg daily as one tablet; Other Names: aspirin; Other: intensive blood pressure control; Patients are encouraged to seek any therapy to have a systolic blood pressure of 120 or below. They will be provided with a blood pressure measurement device and are advised to control blood pressure daily.
No Intervention: standard care; blood pressure management according to guidelines

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
aneurysm rupture or growth	aneurysm rupture (i.e. aneurysmal subarachnoid hemorrhage, SAH) or growth (increase in any aneurysm diameter by ≥1mm) on serial imaging (either two MR or CT angiographies)	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
aneurysm volume	difference of aneurysm volume (in computerized measurements defined as increase of aneurysm volume in computerized measurements by >10% and >3mm3 or aneurysm shape (e.g. development of daughter sac)	36 months
new aneurysm	development of de novo aneurysm on serial imaging	36 months
therapy of aneurysm	clipping/coiling during the study period	36 months
stroke	any ischemic or haemorrhagic stroke, defined as clinical symptoms for stroke AND a compatible lesion on imaging	36 months
myocard infarction	myocardial infarction defined as increase of troponin, creatine-kinase MB and/or presence of new significant Q waves obtained in electrocardiography	36 months
vascular death	vascular death (including fatal stroke, fatal myocardial infarction, sudden death)	36 months
major bleeding	major spontaneous bleeding requiring hospitalisation defined as substantially disabling bleeding, intraocular bleeding leading to the loss of vision, or bleeding necessitating the transfusion of at least 2 units of erythrocyte concentrates	36 months
death	death from all other causes	36 months
achieved blood pressure	any data on blood pressure management used	36 months
Incidence of Treatment-Emergent Adverse and Serious Adverse Events	all adverse and serious adverse events related to the experimental intervention	36 months

Collaborators and Investigators

• Sponsor: Universitätsmedizin Mannheim
• Collaborators: UMC Utrecht; University of Hamburg-Eppendorf; KKS Netzwerk; Schwiete Stiftung, Mannheim, Germany
• Investigators: Principal Investigator: Nima Etminan, PD Dr., UMM, Department of Neurosurgery; Principal Investigator: Mervyn D Vergouwen, MD,PhD, UMC Utrecht, Department of Neurology and Neurosurgery

Publications and helpful links

General Publications

• Vergouwen MD, Rinkel GJ, Algra A, Fiehler J, Steinmetz H, Vajkoczy P, Rutten FH, Luntz S, Hanggi D, Etminan N. Prospective Randomized Open-label Trial to evaluate risk faCTor management in patients with Unruptured intracranial aneurysms: Study protocol. Int J Stroke. 2018 Dec;13(9):992-998. doi: 10.1177/1747493018790033. Epub 2018 Jul 18.

Study record dates

Study Major Dates

• Study Start (Actual): September 21, 2017
• Primary Completion (Anticipated): October 1, 2022
• Study Completion (Anticipated): October 1, 2022

Study Registration Dates

• First Submitted: February 20, 2017
• First Submitted That Met QC Criteria: February 21, 2017
• First Posted (Actual): February 24, 2017

Study Record Updates

• Last Update Posted (Actual): January 25, 2019
• Last Update Submitted That Met QC Criteria: January 23, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• 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; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin
• Other Study ID Numbers: PROTECT-U_V2.2_20_Feb_2017; 2017-000514-35 (EudraCT Number)

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