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Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TOACT)

This study has been terminated.
Sponsor:
Collaborator:
Dutch Heart Foundation
Information provided by (Responsible Party):
Jan Stam, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier:
NCT01204333
First received: September 15, 2010
Last updated: February 11, 2017
Last verified: November 2016
  Purpose

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.


Condition Intervention Phase
Sinus Thrombosis, Intracranial Drug: Endovascular thrombolysis Drug: Heparin Phase 2 Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TOACT)

Resource links provided by NLM:


Further study details as provided by Jan Stam, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Primary Outcome Measures:
  • Favorable clinical outcome (modified Rankin score 0-1) [ Time Frame: 12 months after randomization ]
    Outcome on the modified Rankin Scale (mortality included) at 12 months after randomization is considered the primary study outcome to determine the efficacy of thrombolytic treatment. For the primary endpoint the mRS will be dichotomized between 1 and 2 (i.e. incomplete recovery is defined as a score of 2 or higher, including death).


Secondary Outcome Measures:
  • Favorable clinical outcome (modified Rankin score 0-1) [ Time Frame: 6 months after randomization ]
  • Recanalization rate of cerebral venous system [ Time Frame: 6 months ]
  • All cause mortality [ Time Frame: 6 months ]
  • Required surgical intervention in relation to CVT [ Time Frame: 6 months ]
    The proportion of surgical intervention that are required in relation to cerebral venous thrombosis (e.g. ventricular shunting procedures or craniotomy)

  • Major extracranial and symptomatic intracranial hemorrhagic complications [ Time Frame: 1 week after randomization ]
    Extracranial hemorrhage is classified as major if clinically overt and associated with fall in hemoglobin of 1.2 mmol/l (2 gram/dl) or more within 48 hours, if it is retroperitoneal, intracranial or intraocular, or requires a transfusion of two or more units of packed cells. Any bleeding requiring operation or leading to death is regarded as major. Symptomatic intracranial hemorrhage is defined as any apparently extravascular blood in the brain associated with an increase of 4 points or more on the NIHSS score, or leading to death.

  • Dead or dependency (modified Rankin score 3-6) [ Time Frame: 6 and 12 months ]
  • Modified Rankin Scale at 1 month after randomization [ Time Frame: 1 month after randomization ]

Other Outcome Measures:
  • Interim analyses: Favorable clinical outcome (modified Rankin score 0-1) [ Time Frame: After inclusion of 1/3rd and 2/3rd of patients ]

    The DSMB will perform two interim analyses after 55 and 110 patients (1/3rd and 2/3rd of all patients) have been randomized and completed the 12-month follow-up evaluation. As a stopping rule for efficacy, the Haybittle-Peto method will be used:

    • Interim analysis 1: p = 0,001
    • Interim analysis 2: p = 0,001

    In addition, the DSMB will assess futility during the interim analyses. The trial will be discontinued for futility if the conditional power (or probability of observing a statistically significant result in favor of the intervention group given the data obtained so far) is below 20%. This conditional power will be calculated under the assumption that in the remaining two-thirds/one-thirds of the study population the distributions of the primary endpoint will be the same as observed at the interim analysis.

    For the interim analyses the DSMB will use the primary outcome measure (modified Rankin score 0-1 at 12 months) for the determination of efficacy and futility.



Enrollment: 67
Study Start Date: September 2011
Estimated Study Completion Date: October 2017
Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Endovascular thrombolysis Drug: Endovascular thrombolysis
Endovascular thrombolysis consists of local application of alteplase or urokinase within the thrombosed sinuses. Standard endovascular techniques to mechanically remove clot material, such as thrombosuction, are allowed, but not mandatory.
Other Names:
  • Alteplase
  • Urokinase
Active Comparator: Standard treatment Drug: Heparin
The patients randomized to standard care will receive (or continue) either intravenous adjusted dose unfractionated heparin (aPTT value kept within 1.5 to 2.5 times the normal value), or any type of body-weight adjusted low molecular weight heparin in therapeutic dose, according to local custom and international guidelines

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01204333

Locations
Canada
Centre hospitalier de l'université de Montréal (CHUM)
Montréal, Canada
China
XuanWu Hospital
Beijing, China
France
Hôpital Lariboisière
Paris, France
Netherlands
Academic Medical Centre
Amsterdam, Netherlands
University Medical Centre Groningen
Groningen, Netherlands
St. Antonius hospital
Nieuwegein, Netherlands
Erasmus Medical Centre
Rotterdam, Netherlands
Haga hospital
The Hague, Netherlands
Medical Centre Haaglanden
The Hague, Netherlands
Portugal
Hospital de Braga
Braga, Portugal
Hospital da Universidade de Coimbra
Coimbra, Portugal
Hospital Santa Maria
Lisbon, Portugal
Hospital Sao Jose hospital
Lisbon, Portugal
Hospital de Santo António
Porto, Portugal
Switzerland
Inselspital, University Hospital
Bern, Switzerland
Sponsors and Collaborators
Jan Stam, MD, PhD
Dutch Heart Foundation
Investigators
Study Chair: Jan Stam, MD, PhD Academic Medical Centre, Amsterdam, The Netherlands
Principal Investigator: Jose M Ferro, MD, PhD Hospital Santa Maria, Lisbon, Portugal
Principal Investigator: Marie-Germaine Bousser, MD, PhD Hôpital Lariboisière, Paris, France
Principal Investigator: Patricia Canhão, MD, PhD Hospital Santa Maria, Lisbon, Portugal
Principal Investigator: Isabelle Crassard, MD, PhD Hôpital Lariboisière, Paris, France
Principal Investigator: Charles BL Majoie, MD, PhD Academic Medical Centre, Amsterdam, The Netherlands
Principal Investigator: Jim A Reekers, MD, PhD Academic Medical Centre, Amsterdam, The Netherlands
Principal Investigator: E Houdart, MD, PhD Hôpital Lariboisière, Paris, France
Principal Investigator: Rob J de Haan, PhD Academic Medical Centre, Amsterdam, The Netherlands
  More Information

Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Jan Stam, MD, PhD, Prof. Dr. J. Stam, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT01204333     History of Changes
Other Study ID Numbers: TOACT
Study First Received: September 15, 2010
Last Updated: February 11, 2017

Keywords provided by Jan Stam, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
Cerebral venous and sinus thrombosis
Cerebral venous thrombosis
Sinus Thrombosis, Intracranial
Endovascular thrombolysis
Thrombolysis
Thrombectomy

Additional relevant MeSH terms:
Thrombosis
Venous Thrombosis
Sinus Thrombosis, Intracranial
Intracranial Thrombosis
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Intracranial Embolism and Thrombosis
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Thromboembolism
Calcium heparin
Heparin
Tissue Plasminogen Activator
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 21, 2017