Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TOACT)

• ClinicalTrials.gov Identifier: NCT01204333
• Recruitment Status: Terminated
• First Posted: September 17, 2010
• Last Update Posted: February 14, 2017
• Sponsor: Jan Stam, MD, PhD
• 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: September 15, 2010
• First Posted Date: September 17, 2010
• Last Update Posted Date: February 14, 2017
• Study Start Date: September 2011
• Actual Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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 (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: Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis
• Official Title: 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: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Sinus Thrombosis, Intracranial

Intervention

• 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

• Experimental: Endovascular thrombolysis
  Intervention: Drug: Endovascular thrombolysis
• Active Comparator: Standard treatment
  Intervention: Drug: Heparin

Publications *

• 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. Review.
• Canhão P, Falcão F, Ferro JM. Thrombolytics for cerebral sinus thrombosis: a systematic review. Cerebrovasc Dis. 2003;15(3):159-66. Review.
• Ciccone A, Canhão P, Falcão F, Ferro JM, Sterzi R. Thrombolysis for cerebral vein and dural sinus thrombosis. Cochrane Database Syst Rev. 2004;(1):CD003693. Review.
• 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.
• Coutinho JM, Zuurbier SM, Bousser MG, Ji X, Canhão 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.
• Coutinho JM, Ferro JM, Zuurbier SM, Mink MS, Canhão 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: February 11, 2017): 67
• Original Estimated Enrollment (submitted: September 16, 2010): 164
• Estimated Study Completion Date: October 2017
• Actual Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, China, France, Netherlands, Portugal, Switzerland

Administrative Information

• NCT Number: NCT01204333
• Other Study ID Numbers: TOACT
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Jan Stam, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Study Sponsor: Jan Stam, MD, PhD
• Collaborators: Dutch Heart Foundation

Investigators

• 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