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

NCT ID: NCT02046460

Last Updated: 2024-05-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 194 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-09-30
• Study Completion Date: 2019-06-30

Brief 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.

Detailed 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.

Conditions

Cervical Artery Dissection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Oral Anticoagulation

Vitamin K-Antagonists, target INR 2.0-3.0

Group Type: ACTIVE_COMPARATOR

Vitamin K antagonist

Intervention Type: DRUG

Vitamin K-antagonists, target INR 2.0-3.0

Antiplatelets

Acetylsalicylic acid, 300mg o.p.d.

Group Type: EXPERIMENTAL

Acetylsalicylic acid

Intervention Type: DRUG

Acetylsalicylic acid, 300mg o.p.d.

Interventions

Acetylsalicylic acid

Acetylsalicylic acid, 300mg o.p.d.

Intervention Type: DRUG

Vitamin K antagonist

Vitamin K-antagonists, target INR 2.0-3.0

Intervention Type: DRUG

Other Intervention Names

ASA; Phenprocoumon, Warfarin, Acenocoumarol

Eligibility Criteria

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Stefan Engelter

OTHER

Sponsor Role: lead

Responsible Party

Stefan Engelter

Prof. Dr. med., MD

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Stefan T. Engelter, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Neurorehab. Felix Platter, University of Basel, Switzerland

Locations

University Hospital, Stroke Center Bispebjerg Hospital Copenhagen, Denmark

Copenhagen, , Denmark

University Hospital, Stroke Center Charite Berlin, Germany

Berlin, , Germany

University Hospital, Stroke Center LMU Munich, Germany

Munich, , Germany

Kantonsspital, Stroke Center Aarau, Switzerland

Aarau, , Switzerland

University Hospital, Stroke Center Basel, Switzerland

Basel, , Switzerland

University Hospital, Stroke Center Inselspital Berne, Switzerland

Bern, , Switzerland

University Hospital, Stroke Center Geneva, Switzerland

Geneva, , Switzerland

University Hospital, Stroke Center CHUV Lausanne, Switzerland

Lausanne, , Switzerland

Kantonsspital, Stroke Center St. Gallen, Switzerland

Sankt Gallen, , Switzerland

University Hospital, Stroke Center Zurich, Switzerland

Zurich, , Switzerland

Countries

Denmark; Germany; Switzerland

References

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.

Reference Type: BACKGROUND

PMID: 33072885 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 33765420 (View on PubMed)

Engelter ST, Enz LS, Ravanelli F, Kaufmann JE, Gensicke H, Schaedelin S, Luft AR, Globas C, Goeggel-Simonetti B, Fischer U, Strambo D, Kagi G, Nedeltchev K, Kahles T, Kellert L, Rosenbaum S, von Rennenberg R, Brehm A, Seiffge D, Renaud S, Brandt T, Sarikaya H, Zietz A, Wischmann J, Polymeris AA, Fischer S, Bonati LH, De Marchis GM, Peters N, Nolte CH, Christensen H, Wegener S, Psychogios MN, Arnold M, Lyrer P, Traenka C. The 6-months follow-up of the TREAT-CAD trial: Aspirin versus anticoagulation for stroke prevention in patients with cervical artery dissection. Eur Stroke J. 2025 Sep;10(3):871-881. doi: 10.1177/23969873251315362. Epub 2025 Feb 5.

Reference Type: DERIVED

PMID: 39910883 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

340/12

Identifier Type: -

Identifier Source: org_study_id