Clinical trial NCT01204333: Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis
Official title: Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TOACT)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Sinus Thrombosis, Intracranial
Keywords: Cerebral venous and sinus thrombosis
Cerebral venous thrombosis
Sinus Thrombosis, Intracranial
Endovascular thrombolysis
Thrombolysis
Thrombectomy
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: Dutch Heart Foundation
First posted: 2010-09-17
Enrollment: 67
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: Background: Endovascular thrombolysis, with or without mechanical clot removal (ET), may be beneficial for a subgroup of patients with cerebral venous sinus thrombosis (CVT), who have a poor prognosis despite treatment with heparin. Published experience with ET is promising, but only based on case series and not on controlled trials.

Objective: The main objective of the TO-ACT trial is to determine if ET improves the functional outcome of patients with a severe form of CVT

Study design: The TO-ACT trial will be designed as a multi-centre, prospective, randomized, open-label, blinded endpoint (PROBE) trial.

Study population: Patients are eligible if they have a radiologically proven CVT, a high probability of poor outcome (defined by presence of one or more of the following risk factors: mental status disorder, coma, intracranial hemorrhagic lesion or thrombosis of the deep cerebral venous system) and the responsible physician is uncertain if ET or standard anti-coagulant treatment is better.

Intervention: Patients will be randomized to receive either ET or standard therapy (therapeutic doses of heparin). ET consists of local application of alteplase or urokinase within the thrombosed sinuses, and/or mechanical thrombectomy. Glasgow coma score, NIH stroke scale and relevant laboratory parameters will be assessed at baseline.

Endpoints: The primary endpoint is the modified Rankin scale (mRS) at 12 months. The most important secondary outcomes are the mRS, mortality and recanalization rate at 6 months. Major intra- and extracranial hemorrhagic complications within one week following the intervention are the principal safety outcome. Results will be analyzed according to the "intention-to-treat" principle. Assessment of study endpoints will be carried out according to standardized questionnaires by a blinded neurologist or research nurse who is not involved in the treatment of the patient.

Study size: To detect a 50% relative reduction in mRS≥2 (from 40 to 20%), 164 patients (82 in each treatment arm) have to be included (two-sided alpha, 80% power).

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Included patients may benefit directly from ET. Complications of ET, most notably intracranial hemorrhages, constitute the most important risk of the study.


Eligibility criteria: Inclusion Criteria:

1. Cerebral venous thrombosis, confirmed by cerebral angiography (with intra-arterial contrast injection), magnetic resonance venography or computed tomographic venography.
2. Severe form of CVT with a high chance of incomplete recovery, as defined by the presence of one or more of the following risk factors

   1. Intracerebral hemorrhagic lesion due to CVT
   2. Mental status disorder
   3. Coma (Glasgow coma scale \< 9)
   4. Thrombosis of the deep cerebral venous system
3. Uncertainty by the treating physician if ET or standard heparin therapy is the optimal therapy for the patient.

Exclusion Criteria:

* Age less than 18 years
* Duration from diagnosis to randomization of more than 10 days
* Recurrent CVT
* Any thrombolytic therapy within last 7 days
* Pregnancy (women in the puerperium may be included)
* Isolated cavernous sinus thrombosis
* Isolated intracranial hypertension (without focal neurological signs, with the exception of papilloedema and 6th cranial nerve palsy)
* Cerebellar venous thrombosis with 4th ventricle compression and hydrocephalus, which requires surgery
* Contraindication for anti-coagulant or thrombolytic treatment

  1. documented generalized bleeding disorder
  2. concurrent thrombocytopenia (\<100 x 10E9/L)
  3. documented severe hepatic or renal dysfunction, that interferes with normal coagulation
  4. uncontrolled severe hypertension (diastolic \> 120 mm Hg)
  5. known recent (\< 3 months) gastrointestinal tract hemorrhage (not including he¬morrhage from rectal hemorrhoids)
* Any known associated condition (such as terminal cancer) with a poor short term (1 year) prognosis independent of CVT
* Clinical and radiological signs of impending transtentorial herniation due to large space-occupying lesions (e.g. large cerebral venous infarcts or hemorrhages)
* Recent (\< 2 weeks) major surgical procedure (does not include lumbar puncture) or severe cranial trauma
* Known allergy against contrast fluid used during endovascular procedures or the thrombolytic drug used in that particular centre
* Previously legally incompetent prior to CVT
* No informed consent

Primary outcomes:
measure: Favorable clinical outcome (modified Rankin score 0-1)
timeFrame: 12 months after randomization
Secondary outcomes:
measure: Favorable clinical outcome (modified Rankin score 0-1)
timeFrame: 6 months after randomization
measure: Recanalization rate of cerebral venous system
timeFrame: 6 months
measure: All cause mortality
timeFrame: 6 months
measure: Required surgical intervention in relation to CVT
timeFrame: 6 months
measure: Major extracranial and symptomatic intracranial hemorrhagic complications
timeFrame: 1 week after randomization
measure: Dead or dependency (modified Rankin score 3-6)
timeFrame: 6 and 12 months
measure: Modified Rankin Scale at 1 month after randomization
timeFrame: 1 month after randomization
Other outcomes:
measure: Interim analyses: Favorable clinical outcome (modified Rankin score 0-1)
timeFrame: After inclusion of 1/3rd and 2/3rd of patients
Locations:
city: Montréal
country: Canada
facility: Centre hospitalier de l'université de Montréal (CHUM)
city: Beijing
country: China
facility: XuanWu Hospital
city: Paris
country: France
facility: Hôpital Lariboisière
city: Amsterdam
country: Netherlands
facility: Academic Medical Centre
city: Groningen
country: Netherlands
facility: University Medical Centre Groningen
city: Nieuwegein
country: Netherlands
facility: St. Antonius hospital
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Centre
city: The Hague
country: Netherlands
facility: Haga hospital
city: The Hague
country: Netherlands
facility: Medical Centre Haaglanden
city: Braga
country: Portugal
facility: Hospital de Braga
city: Coimbra
country: Portugal
facility: Hospital da Universidade de Coimbra
city: Lisbon
country: Portugal
facility: Hospital Santa Maria
city: Lisbon
country: Portugal
facility: Hospital Sao Jose hospital
city: Porto
country: Portugal
facility: Hospital de Santo António
city: Bern
country: Switzerland
facility: Inselspital, University Hospital
Study officials:
affiliation: University of Amsterdam
name: Jan Stam, MD, PhD
role: STUDY_CHAIR
affiliation: Hospital Santa Maria, Lisbon, Portugal
name: Jose M Ferro, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Lariboisière, Paris, France
name: Marie-Germaine Bousser, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Santa Maria, Lisbon, Portugal
name: Patricia Canhão, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Lariboisière, Paris, France
name: Isabelle Crassard, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Amsterdam
name: Charles BL Majoie, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Amsterdam
name: Jim A Reekers, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Lariboisière, Paris, France
name: E Houdart, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Amsterdam
name: Rob J de Haan, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Coutinho JM, Stam J. How to treat cerebral venous and sinus thrombosis. J Thromb Haemost. 2010 May;8(5):877-83. doi: 10.1111/j.1538-7836.2010.03799.x. Epub 2010 Feb 9.
citation: Canhao P, Falcao F, Ferro JM. Thrombolytics for cerebral sinus thrombosis: a systematic review. Cerebrovasc Dis. 2003;15(3):159-66. doi: 10.1159/000068833.
citation: Ciccone A, Canhao P, Falcao F, Ferro JM, Sterzi R. Thrombolysis for cerebral vein and dural sinus thrombosis. Cochrane Database Syst Rev. 2004;2004(1):CD003693. doi: 10.1002/14651858.CD003693.pub2.
citation: Stam J, Majoie CB, van Delden OM, van Lienden KP, Reekers JA. Endovascular thrombectomy and thrombolysis for severe cerebral sinus thrombosis: a prospective study. Stroke. 2008 May;39(5):1487-90. doi: 10.1161/STROKEAHA.107.502658. Epub 2008 Mar 13.
citation: Coutinho JM, Zuurbier SM, Bousser MG, Ji X, Canhao P, Roos YB, Crassard I, Nunes AP, Uyttenboogaart M, Chen J, Emmer BJ, Roosendaal SD, Houdart E, Reekers JA, van den Berg R, de Haan RJ, Majoie CB, Ferro JM, Stam J; TO-ACT investigators. Effect of Endovascular Treatment With Medical Management vs Standard Care on Severe Cerebral Venous Thrombosis: The TO-ACT Randomized Clinical Trial. JAMA Neurol. 2020 Aug 1;77(8):966-973. doi: 10.1001/jamaneurol.2020.1022.
citation: Coutinho JM, Ferro JM, Zuurbier SM, Mink MS, Canhao P, Crassard I, Majoie CB, Reekers JA, Houdart E, de Haan RJ, Bousser MG, Stam J. Thrombolysis or anticoagulation for cerebral venous thrombosis: rationale and design of the TO-ACT trial. Int J Stroke. 2013 Feb;8(2):135-40. doi: 10.1111/j.1747-4949.2011.00753.x. Epub 2012 Feb 20.