Clinical trial NCT02046460: Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection - TREAT-CAD
Official title: Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection - TREAT-CAD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cervical Artery Dissection
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
First posted: 2014-01-27
Enrollment: 194
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Primary composite outcome measure - labeled Cerebrovascular Ischemia, major Hemorrhagic events or Death (CIHD) -
timeFrame: 3 months
Secondary outcomes:
measure: new ischemic strokes (including retinal infarction)
timeFrame: 3 months
measure: new acute lesions on diffusion-weighted MRI
timeFrame: 3 months
measure: any major extracranial hemorrhage
timeFrame: 3 months
measure: any symptomatic intracranial hemorrhage
timeFrame: 3 months
measure: any asymptomatic micro- or macrobleeds
timeFrame: 3 months
measure: any death
timeFrame: 3 months
measure: any increase in volume of the vessel wall hematoma at the followup cervical MRI as compared to the baseline MR-scan
timeFrame: 3 months
measure: independence in activity of daily living (modified Rankin scale 0-2) at 3 months and at 6 months
timeFrame: 3 months
measure: excellent functional outcome (modified Rankin scale 0,1) at 3 month and at 6 months
timeFrame: 3 months
measure: any TIA (classical definition)
timeFrame: 3 months
measure: recurrent cervical artery dissection
timeFrame: 3 months
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: University Hospital, Stroke Center Bispebjerg Hospital Copenhagen, Denmark
city: Berlin
country: Germany
facility: University Hospital, Stroke Center Charite Berlin, Germany
city: Munich
country: Germany
facility: University Hospital, Stroke Center LMU Munich, Germany
city: Aarau
country: Switzerland
facility: Kantonsspital, Stroke Center Aarau, Switzerland
city: Basel
country: Switzerland
facility: University Hospital, Stroke Center Basel, Switzerland
city: Berne
country: Switzerland
facility: University Hospital, Stroke Center Inselspital Berne, Switzerland
city: Geneva
country: Switzerland
facility: University Hospital, Stroke Center Geneva, Switzerland
city: Lausanne
country: Switzerland
facility: University Hospital, Stroke Center CHUV Lausanne, Switzerland
city: St. Gallen
country: Switzerland
facility: Kantonsspital, Stroke Center St. Gallen, Switzerland
city: Zurich
country: Switzerland
facility: University Hospital, Stroke Center Zurich, Switzerland
Study officials:
affiliation: University Hospital, Neurorehab. Felix Platter, University of Basel, Switzerland
name: Stefan T. Engelter, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.