Sinus Thrombosis, IntracranialPhase 2/3TOACTNCT01204333
Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis
A Phase 2/3 study testing Endovascular thrombolysis and Heparin in people with Sinus Thrombosis, Intracranial, run by Jan Stam, MD, PhD at 15 sites in 6 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sinus Thrombosis, Intracranial
- What is being tested?
- Endovascular thrombolysis and Heparin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 67 participants
- Where
- 15 sitesin 6 countries
- Study dates
- Sep 2011to Oct 2017
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 20Show fewer
- 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
- 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
Trial locations and contacts
15 sites in 6 countries.
15 sites in 6 countries
Netherlands6 sites
Academic Medical Centre
Amsterdam
University Medical Centre Groningen
Groningen
St. Antonius hospital
Nieuwegein
Erasmus Medical Centre
Rotterdam
Haga hospital
The Hague
Medical Centre Haaglanden
The Hague
Portugal5 sites
Hospital de Braga
Braga
Hospital da Universidade de Coimbra
Coimbra
Hospital Santa Maria
Lisbon
Hospital Sao Jose hospital
Lisbon
Hospital de Santo António
Porto
About this study
Official title: Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TOACT)
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
Read more
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
- Being tested
- Endovascular thrombolysis, Heparin
- Keywords
- Cerebral venous and sinus thrombosis, Cerebral venous thrombosis, Sinus Thrombosis, Intracranial, Endovascular thrombolysis, Thrombolysis, Thrombectomy
- Medical subject headings
- Sinus Thrombosis, Intracranial, Intracranial Thrombosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Endovascular thrombolysisDrug
Also called Alteplase, Urokinase
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.
HeparinDrug
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 group | Role | What they receive |
|---|---|---|
| Endovascular thrombolysis | Experimental | Not described Receives: Drug: Endovascular thrombolysis |
| Standard treatment | Active comparator | Not described Receives: Drug: Heparin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 12 months after randomization
Secondary outcomes (7)
Favorable clinical outcome (modified Rankin score 0-1)
Measured: 6 months after randomization
Recanalization rate of cerebral venous system
Measured: 6 months
All cause mortality
Measured: 6 months
Required surgical intervention in relation to CVT
The proportion of surgical intervention that are required in relation to cerebral venous thrombosis (e.g. ventricular shunting procedures or craniotomy)
Measured: 6 months
Major extracranial and symptomatic intracranial hemorrhagic complications
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.
Measured: 1 week after randomization
Dead or dependency (modified Rankin score 3-6)
Measured: 6 and 12 months
Modified Rankin Scale at 1 month after randomization
Measured: 1 month after randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Sep 2010 (estimated)
- Study startSep 2011
- Primary completionDec 2016
- Study completionOct 2017 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Sinus Thrombosis, IntracranialStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 67 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jan Stam, MD, PhD
- Sponsor type
- University, hospital or other
- Collaborators
- Dutch Heart Foundation
- Responsible party
- Sponsor-investigator, Jan Stam, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
- Investigators
- Jan Stam, MD, PhD, Study chair, University of AmsterdamJose M Ferro, MD, PhD, Principal investigator, Hospital Santa Maria, Lisbon, PortugalMarie-Germaine Bousser, MD, PhD, Principal investigator, Hôpital Lariboisière, Paris, FrancePatricia Canhão, MD, PhD, Principal investigator, Hospital Santa Maria, Lisbon, PortugalIsabelle Crassard, MD, PhD, Principal investigator, Hôpital Lariboisière, Paris, FranceCharles BL Majoie, MD, PhD, Principal investigator, University of AmsterdamJim A Reekers, MD, PhD, Principal investigator, University of AmsterdamE Houdart, MD, PhD, Principal investigator, Hôpital Lariboisière, Paris, France
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01204333
- Sponsor's protocol ID
- TOACT
- Acronym
- TOACT
- Status last verified
- Nov 2016
- First submitted
- 15 Sep 2010
- Last updated
- 14 Feb 2017
- Results posted
- No
- Data monitoring committee
- Yes
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.
PubMed 20149074Canhao P, Falcao F, Ferro JM. Thrombolytics for cerebral sinus thrombosis: a systematic review. Cerebrovasc Dis. 2003;15(3):159-66. doi: 10.1159/000068833.
PubMed 12646773Ciccone 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.
PubMed 14974030Stam 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.
PubMed 18340091Coutinho 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.
PubMed 32421159Coutinho 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.
PubMed 22340437
Study at a glance
From the registry record, last updated by the sponsor on 14 Feb 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TOACT)
- ClinicalTrials.gov ID
- NCT01204333
- Acronym / sponsor ID
- TOACT / TOACT
- Conditions
- Sinus Thrombosis, Intracranial
- Keywords
- Cerebral venous and sinus thrombosis, Cerebral venous thrombosis, Sinus Thrombosis, Intracranial, Endovascular thrombolysis, Thrombolysis, Thrombectomy
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Terminated
- Enrolment
- 67 participants (actual)
- Lead sponsor
- Jan Stam, MD, PhDUniversity, hospital or other
- Collaborators
- Dutch Heart Foundation
- Study start
- Sep 2011
- Primary completion
- Dec 2016 (actual)
- Study completion
- Oct 2017 (estimated)
- First posted
- 17 Sep 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Endovascular thrombolysis | Experimental | Drug: Endovascular thrombolysis |
| Standard treatment | Active comparator | Drug: Heparin |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
- Uncertainty by the treating physician if ET or standard heparin therapy is the optimal therapy for the patient.
Key exclusion criteria (20 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Endovascular thrombolysisAlso: Alteplase, UrokinaseEndovascular 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. | Drug | Endovascular thrombolysis |
| HeparinThe 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 | Drug | Standard treatment |
Primary outcome
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).
7 secondary outcomes
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
Major extracranial and symptomatic intracranial hemorrhagic complications
Time frame: 1 week after randomization
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
Results and safety
The study was stopped early. Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Feb 2017.
- Background: PubMed 20149074Coutinho 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.
- Background: PubMed 12646773Canhao P, Falcao F, Ferro JM. Thrombolytics for cerebral sinus thrombosis: a systematic review. Cerebrovasc Dis. 2003;15(3):159-66. doi: 10.1159/000068833.
- Background: PubMed 14974030Ciccone 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.
- Background: PubMed 18340091Stam 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.
- Derived from this study: PubMed 32421159Coutinho 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.
- Derived from this study: PubMed 22340437Coutinho 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jan Stam, MD, PhD study chair
University of Amsterdam
Jose M Ferro, MD, PhD principal investigator
Hospital Santa Maria, Lisbon, Portugal
Marie-Germaine Bousser, MD, PhD principal investigator
Hôpital Lariboisière, Paris, France
15 sites in 6 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Endovascular thrombolysis and Heparin in people with Sinus Thrombosis, Intracranial, run by Jan Stam, MD, PhD at 15 sites in 6 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 14 Feb 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 15 sites in Netherlands, Portugal, Canada, China, France and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early. Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Favorable clinical outcome (modified Rankin score 0-1) (time frame: 12 months after randomization). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01204333, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Feb 2017.