Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis

NCT01204333 | Terminated Phase 2 DMC

• 1 other identifier: TOACT
• Study Type: interventional
• Target: 67
• Locations: 6 countries
• Sites: 15

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.

Conditions

Sinus Thrombosis, Intracranial

Keywords

Cerebral venous and sinus thrombosis; Cerebral venous thrombosis; Sinus Thrombosis, Intracranial; Endovascular thrombolysis; Thrombolysis; Thrombectomy

Outcome Measures

Primary Outcomes (1)

• Favorable clinical outcome (modified Rankin score 0-1)

  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).

  12 months after randomization

Secondary Outcomes (7)

• Favorable clinical outcome (modified Rankin score 0-1)

  6 months after randomization

• Recanalization rate of cerebral venous system

  6 months

• All cause mortality

  6 months

• Required surgical intervention in relation to CVT

  6 months

• Major extracranial and symptomatic intracranial hemorrhagic complications

  1 week after randomization

Other Outcomes (1)

• Interim analyses: Favorable clinical outcome (modified Rankin score 0-1)

  After inclusion of 1/3rd and 2/3rd of patients

Study Arms (2)

Endovascular thrombolysis

EXPERIMENTAL

Drug: Endovascular thrombolysis

Standard treatment

ACTIVE COMPARATOR

Drug: Heparin

Interventions

Endovascular thrombolysis DRUG

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.

Also known as: Alteplase, Urokinase

Endovascular thrombolysis

Heparin DRUG

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

Standard treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Cerebral venous thrombosis, confirmed by cerebral angiography (with intra-arterial contrast injection), magnetic resonance venography or computed tomographic venography.
• 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
• Intracerebral hemorrhagic lesion due to CVT
• Mental status disorder
• Coma (Glasgow coma scale \< 9)
• Thrombosis of the deep cerebral venous system
• Uncertainty by the treating physician if ET or standard heparin therapy is the optimal therapy for the patient.

You may not qualify if:

• 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
• documented generalized bleeding disorder
• concurrent thrombocytopenia (\<100 x 10E9/L)
• documented severe hepatic or renal dysfunction, that interferes with normal coagulation
• uncontrolled severe hypertension (diastolic \> 120 mm Hg)
• 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

Sponsors & Collaborators

• Jan Stam, MD, PhD: lead
• Dutch Heart Foundation: collaborator

Study Sites (15)

Centre hospitalier de l'université de Montréal (CHUM)

Montreal, Canada

Location

XuanWu Hospital

Beijing, China

Location

Hôpital Lariboisière

Paris, France

Location

Academic Medical Centre

Amsterdam, Netherlands

Location

University Medical Centre Groningen

Groningen, Netherlands

Location

St. Antonius hospital

Nieuwegein, Netherlands

Location

Erasmus Medical Centre

Rotterdam, Netherlands

Location

Haga hospital

The Hague, Netherlands

Location

Medical Centre Haaglanden

The Hague, Netherlands

Location

Hospital de Braga

Braga, Portugal

Location

Hospital da Universidade de Coimbra

Coimbra, Portugal

Location

Hospital Santa Maria

Lisbon, Portugal

Location

Hospital Sao Jose hospital

Lisbon, Portugal

Location

Hospital de Santo António

Porto, Portugal

Location

Inselspital, University Hospital

Bern, Switzerland

Location

Related Publications (6)

• 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.

  PMID: 20149074 BACKGROUND

• 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.

  PMID: 12646773 BACKGROUND

• 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.

  PMID: 14974030 BACKGROUND

• 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.

  PMID: 18340091 BACKGROUND

• 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.

  PMID: 32421159 DERIVED

• 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.

  PMID: 22340437 DERIVED

MeSH Terms

Conditions

Sinus Thrombosis, Intracranial; Intracranial Thrombosis

Interventions

Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; Heparin

Condition Hierarchy (Ancestors)

Intracranial Embolism and Thrombosis; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Thromboembolism; Embolism and Thrombosis

Intervention Hierarchy (Ancestors)

Serine Endopeptidases; Endopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Serine Proteases; Plasminogen Activators; Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Biological Factors; Glycosaminoglycans; Polysaccharides; Carbohydrates

Study Officials

• Jan Stam, MD, PhD

  University of Amsterdam

  STUDY CHAIR

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr. J. Stam

Study Record Dates

• First Submitted: September 15, 2010
• First Posted: September 17, 2010
• Study Start: September 1, 2011
• Primary Completion: December 1, 2016
• Study Completion: October 1, 2017
• Last Updated: February 14, 2017

Record last verified: 2016-11

Locations

FR (1); CN (1); PT (5); CH (1); CA (1); NL (6)