TOACT: Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis

Sponsor

Jan Stam, MD, PhD (Other)

Overall Status

Terminated

CT.gov ID

NCT01204333

Collaborator

Dutch Heart Foundation (Other)

Enrollment

Locations

Arms

Duration (Months)

4.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Sinus Thrombosis, Intracranial	Drug: Endovascular thrombolysis Drug: Heparin	Phase 2/Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

67 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TOACT)

Study Start Date :

Sep 1, 2011

Actual Primary Completion Date :

Dec 1, 2016

Anticipated Study Completion Date :

Oct 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
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

Arm

Intervention/Treatment

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

Outcome Measures

Primary Outcome Measures

Favorable clinical outcome (modified Rankin score 0-1) [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) [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]
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 [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) [6 and 12 months]
Modified Rankin Scale at 1 month after randomization [1 month after randomization]

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.

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

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

Contacts and Locations

Locations

	Site	City	Country
1	Centre hospitalier de l'université de Montréal (CHUM)	Montréal	Canada
2	XuanWu Hospital	Beijing	China
3	Hôpital Lariboisière	Paris	France
4	Academic Medical Centre	Amsterdam	Netherlands
5	University Medical Centre Groningen	Groningen	Netherlands
6	St. Antonius hospital	Nieuwegein	Netherlands
7	Erasmus Medical Centre	Rotterdam	Netherlands
8	Haga hospital	The Hague	Netherlands
9	Medical Centre Haaglanden	The Hague	Netherlands
10	Hospital de Braga	Braga	Portugal
11	Hospital da Universidade de Coimbra	Coimbra	Portugal
12	Hospital Santa Maria	Lisbon	Portugal
13	Hospital Sao Jose hospital	Lisbon	Portugal
14	Hospital de Santo António	Porto	Portugal
15	Inselspital, University Hospital	Bern	Switzerland

Sponsors and Collaborators

Jan Stam, MD, PhD
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