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Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TOACT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01204333
Recruitment Status : Terminated
First Posted : September 17, 2010
Last Update Posted : February 14, 2017
Sponsor:
Collaborator:
Dutch Heart Foundation
Information provided by (Responsible Party):
Jan Stam, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Tracking Information
First Submitted Date  ICMJE September 15, 2010
First Posted Date  ICMJE September 17, 2010
Last Update Posted Date February 14, 2017
Study Start Date  ICMJE September 2011
Actual Primary Completion Date December 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 16, 2010)
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 6, 2014)
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 16, 2010)
  • 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 ]
Current Other Pre-specified Outcome Measures
 (submitted: November 27, 2016)
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.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis
Official Title  ICMJE Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TOACT)
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Sinus Thrombosis, Intracranial
Intervention  ICMJE
  • 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
  • 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
Study Arms  ICMJE
  • Experimental: Endovascular thrombolysis
    Intervention: Drug: Endovascular thrombolysis
  • Active Comparator: Standard treatment
    Intervention: Drug: Heparin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: February 11, 2017)
67
Original Estimated Enrollment  ICMJE
 (submitted: September 16, 2010)
164
Estimated Study Completion Date  ICMJE October 2017
Actual Primary Completion Date December 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   China,   France,   Netherlands,   Portugal,   Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01204333
Other Study ID Numbers  ICMJE TOACT
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jan Stam, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Study Sponsor  ICMJE Jan Stam, MD, PhD
Collaborators  ICMJE Dutch Heart Foundation
Investigators  ICMJE
Study Chair: Jan Stam, MD, PhD University of Amsterdam
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 University of Amsterdam
Principal Investigator: Jim A Reekers, MD, PhD University of Amsterdam
Principal Investigator: E Houdart, MD, PhD Hôpital Lariboisière, Paris, France
Principal Investigator: Rob J de Haan, PhD University of Amsterdam
PRS Account Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Verification Date November 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP