Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection - TREAT-CAD

Cervical Artery Dissection Clinical Trial

— TREAT-CAD  

Official title:

Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection - TREAT-CAD

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02046460
• Other study ID #: 340/12
• Status: Completed
• Phase: Phase 3
• Start date: September 2013
• Est. completion date: June 2019

Study information

• Verified date: May 2024
• Source: University Hospital, Basel, Switzerland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Primary objective: To demonstrate the non-inferiority of acetylsalicylic acid (ASA) to anticoagulant treatment (vitamin K antagonists) in CAD-patients with regard to outcome and complication measures.

Methods: Randomized controlled, open labeled multicenter, non-inferiority trial with blinded assessment of outcome events.

Primary endpoint: Primary composite outcome measure - labeled Cerebrovascular Ischemia, major Hemorrhagic events or Death (CIHD) - includes the following efficacy and safety outcome measures during the treatment period: (i) occurrence of any stroke*, new acute lesions on diffusion weighted MRI (ii) any major extracranial hemorrhage, any symptomatic intracranial hemorrhage and any asymptomatic micro- or macrobleeds, (iii) death.

Description:

Substudies:

1. In-depth analysis of the TREAT-CAD randomized trial:

The investigators will perform a subgroup analysis on the per-protocol population investigating if the antithrombotic treatment effect (anticoagulation versus aspirin) depends on specific patient baseline characteristics. The investigators will look at the following subgroups: Presenting with cerebral ischemia - either clinical ischemic events, MRI lesions, or both - versus presenting with local symptoms only, occlusion of the dissected artery at baseline (no/yes), early versus delayed treatment start (divided by the median of the study population), acute recanalization therapy including intravenous thrombolysis and/or endovascular therapy (no/yes), intracranial extension of the dissected artery (no/yes), site of dissection defined as internal carotid artery dissection versus vertebral artery dissection, single versus multivessel dissection, younger versus older age (divided by the median of the study population), and male versus female.

2. TCD Monitoring Substudy:

The objective of the TREAT-CAD transcranial Doppler (TCD) substudy is to (i) detect the frequency of microembolic signals (MES) in CAD patients, stratified to the type of treatment (aspirin vs. anticoagulation) - in the setting of an RCT (randomized controlled trial)- and (ii) to evaluate the meaning of MES by addressing the following questions: (a) Is there an association of MES (presence or number) with the occurrence of clinical and/or surrogate MR (magnetic resonance) outcome measures; (b) Is there an interaction between MES, type of treatment and outcome events. Participants are asked to allow a 6-h TCD monitoring in between day 1 and day 4 since start of the allocated study treatment. Recordings were allowed to be split in up to three episodes (2 h each). In patients with ICAD (internal carotid artery dissection), the ipsilateral middle cerebral artery is investigated. In patients with VAD (vertebral artery dissection), the ipsilateral posterior cerebral artery is investigated.

3. Biomarker substudy:

The objective of the biomarker study is to investigate whether the plasma level of MMP9 (matrix-metalloproteinase 9) and the ratio of the plasma MMP9 to TIMP2 (tissue inhibitor of metalloproteinases 2) is associated with efficacy and safety measures in CAD patients, when stratified to the allocated treatment regime. Plasma samples are collected from participants at baseline (i.e., prior to start of the allocated treatment within the TREAT-CAD main study) and at Follow-up visit 1. The specific focus on MMP9 and TIMP2 is based on preliminary observational data pointing to higher MMP9 and MMP9/TIMP2 ratios in CAD versus control patients.

4. 6 Month-follow-up for TREAT-CAD To compare (i) the frequency of clinical and MRI outcomes 6 months after cervical artery dissection among the per-protocol participants of the TREAT-CAD trial and (ii) to focus on events occurring between 3 and 6 months, stratified to the type of antithrombotic medication taken (as-treated analysis).

5. Detailed imaging analysis in the TREAT-CAD study To identify possible imaging risk factors for recurrent stroke and to evaluate the dependence of antithromobotic therapy on imaging factors.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 194
• Est. completion date: June 2019
• Est. primary completion date: June 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Acute ischemic or non-ischemic symptoms within 2 weeks

2. Verification of CAD-diagnosis (carotid and/or vertebral) by MR-techniques (at least one):

• mural hematoma or

• pseudo-aneurysm or

• long filiform stenosis or

• intimal flap or

• double lumen or

• occlusion situated more than 2 cm above the bifurcation of the carotid artery, revealing a pseudo aneurysm or a long filiform stenosis after recanalisation.

3. Written informed consent by patient or next-to-kin

4. 24h latency period in case of thrombolysis

5. Age > 18 years by time of inclusion

Exclusion Criteria:

1. MR-contraindications (claustrophobia precluding MRI: patients agreeing to undergo MRI scanning with mild sedation may be entered into the study)

2. Contraindications to the use of anticoagulation (vitamin k antagonists, heparin) or ASA (according to the Swiss "Arzneimittelkompendium" http://www.compendium.ch/search/de or the "Rote Liste" (German centers) or "Lægemiddelstyrelsen - produktresume" for the Danish center (https://laegemiddelstyrelsen.dk/da/bivirkninger/find-medicin/produktresumeer/) and the judgment of the treating physician)

3. Pregnancy (Note: for women in child bearing age a pregnancy test has to be done prior to study entry)

Related Conditions & MeSH terms

• Aortic Dissection
• Cervical Artery Dissection

Intervention

Drug:
• Acetylsalicylic acid
Acetylsalicylic acid, 300mg o.p.d.
• Vitamin K antagonist
Vitamin K-antagonists, target INR 2.0-3.0

Locations

Country	Name	City	State
Denmark	University Hospital, Stroke Center Bispebjerg Hospital Copenhagen, Denmark	Copenhagen
Germany	University Hospital, Stroke Center Charite Berlin, Germany	Berlin
Germany	University Hospital, Stroke Center LMU Munich, Germany	Munich
Switzerland	Kantonsspital, Stroke Center Aarau, Switzerland	Aarau
Switzerland	University Hospital, Stroke Center Basel, Switzerland	Basel
Switzerland	University Hospital, Stroke Center Inselspital Berne, Switzerland	Berne
Switzerland	University Hospital, Stroke Center Geneva, Switzerland	Geneva
Switzerland	University Hospital, Stroke Center CHUV Lausanne, Switzerland	Lausanne
Switzerland	Kantonsspital, Stroke Center St. Gallen, Switzerland	St. Gallen
Switzerland	University Hospital, Stroke Center Zurich, Switzerland	Zurich

Sponsors (1)

Lead Sponsor	Collaborator
Stefan Engelter

Countries where clinical trial is conducted

Denmark,  Germany,  Switzerland, 

References & Publications (2)

Engelter ST, Traenka C, Gensicke H, Schaedelin SA, Luft AR, Simonetti BG, Fischer U, Michel P, Sirimarco G, Kagi G, Vehoff J, Nedeltchev K, Kahles T, Kellert L, Rosenbaum S, von Rennenberg R, Sztajzel R, Leib SL, Jung S, Gralla J, Bruni N, Seiffge D, Feil K, Polymeris AA, Steiner L, Hamann J, Bonati LH, Brehm A, De Marchis GM, Peters N, Stippich C, Nolte CH, Christensen H, Wegener S, Psychogios MN, Arnold M, Lyrer P; TREAT-CAD investigators. Aspirin versus anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial. Lancet Neurol. 2021 May;20(5):341-350. doi: 10.1016/S1474-4422(21)00044-2. Epub 2021 Mar 23. — View Citation

Traenka C, Gensicke H, Schaedelin S, Luft A, Arnold M, Michel P, Kagi G, Kahles T, Nolte CH, Kellert L, Rosenbaum S, Sztaizel R, Brehm A, Stippich C, Psychogios M, Lyrer P, Engelter ST; TREAT-CAD investigators. Biomarkers and antithrombotic treatment in cervical artery dissection - Design of the TREAT-CAD randomised trial. Eur Stroke J. 2020 Sep;5(3):309-319. doi: 10.1177/2396987320921151. Epub 2020 Jun 29. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Primary composite outcome measure - labeled Cerebrovascular Ischemia, major Hemorrhagic events or Death (CIHD) -	CIHD - includes the following efficacy and safety outcome measures during the treatment period: includes the following efficacy and safety outcome measures during the treatment period: (i) occurrence of any stroke (including retinal infarction), new acute lesions on diffusion weighted MRI (ii) any major extracranial hemorrhage, any symptomatic intracranial hemorrhage and any asymptomatic micro- or macrobleeds, (iii) death.	3 months
Secondary	new ischemic strokes (including retinal infarction)		3 months
Secondary	new acute lesions on diffusion-weighted MRI		3 months
Secondary	any major extracranial hemorrhage		3 months
Secondary	any symptomatic intracranial hemorrhage		3 months
Secondary	any asymptomatic micro- or macrobleeds		3 months
Secondary	any death		3 months
Secondary	any increase in volume of the vessel wall hematoma at the followup cervical MRI as compared to the baseline MR-scan		3 months
Secondary	independence in activity of daily living (modified Rankin scale 0-2) at 3 months and at 6 months		3 months
Secondary	excellent functional outcome (modified Rankin scale 0,1) at 3 month and at 6 months		3 months
Secondary	any TIA (classical definition)		3 months
Secondary	recurrent cervical artery dissection		3 months