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
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.
|Sinus Thrombosis, Intracranial||Drug: Endovascular thrombolysis Drug: Heparin||Phase 2 Phase 3|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
|Official Title:||Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TOACT)|
- 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).
- 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 ]
- 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.
|Study Start Date:||September 2011|
|Estimated Study Completion Date:||October 2017|
|Primary Completion Date:||December 2016 (Final data collection date for primary outcome measure)|
|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.
|Active Comparator: Standard treatment||
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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01204333
|Centre hospitalier de l'université de Montréal (CHUM)|
|Academic Medical Centre|
|University Medical Centre Groningen|
|St. Antonius hospital|
|Erasmus Medical Centre|
|The Hague, Netherlands|
|Medical Centre Haaglanden|
|The Hague, Netherlands|
|Hospital de Braga|
|Hospital da Universidade de Coimbra|
|Hospital Santa Maria|
|Hospital Sao Jose hospital|
|Hospital de Santo António|
|Inselspital, University Hospital|
|Study Chair:||Jan Stam, MD, PhD||Academic Medical Centre, Amsterdam, The Netherlands|
|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||Academic Medical Centre, Amsterdam, The Netherlands|
|Principal Investigator:||Jim A Reekers, MD, PhD||Academic Medical Centre, Amsterdam, The Netherlands|
|Principal Investigator:||E Houdart, MD, PhD||Hôpital Lariboisière, Paris, France|
|Principal Investigator:||Rob J de Haan, PhD||Academic Medical Centre, Amsterdam, The Netherlands|