Sinus Thrombosis, Intracranial Clinical Trial
— TOACTOfficial title:
Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TOACT)
| Verified date | November 2016 |
| Source | Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Terminated |
| Enrollment | 67 |
| Est. completion date | October 2017 |
| Est. primary completion date | December 2016 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility |
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 |
| Country | Name | City | State |
|---|---|---|---|
| Canada | Centre hospitalier de l'université de Montréal (CHUM) | Montréal | |
| China | XuanWu Hospital | Beijing | |
| France | Hôpital Lariboisière | Paris | |
| Netherlands | Academic Medical Centre | Amsterdam | |
| Netherlands | University Medical Centre Groningen | Groningen | |
| Netherlands | St. Antonius hospital | Nieuwegein | |
| Netherlands | Erasmus Medical Centre | Rotterdam | |
| Netherlands | Haga hospital | The Hague | |
| Netherlands | Medical Centre Haaglanden | The Hague | |
| Portugal | Hospital de Braga | Braga | |
| Portugal | Hospital da Universidade de Coimbra | Coimbra | |
| Portugal | Hospital Santa Maria | Lisbon | |
| Portugal | Hospital Sao Jose hospital | Lisbon | |
| Portugal | Hospital de Santo António | Porto | |
| Switzerland | Inselspital, University Hospital | Bern |
| Lead Sponsor | Collaborator |
|---|---|
| Jan Stam, MD, PhD | Dutch Heart Foundation |
Canada, China, France, Netherlands, Portugal, Switzerland,
Canhão P, Falcão F, Ferro JM. Thrombolytics for cerebral sinus thrombosis: a systematic review. Cerebrovasc Dis. 2003;15(3):159-66. Review. — View Citation
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. — View Citation
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. Review. — View Citation
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. — View Citation
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | Interim analyses: Favorable clinical outcome (modified Rankin score 0-1) | 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. |
After inclusion of 1/3rd and 2/3rd of patients | |
| Primary | 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 | Favorable clinical outcome (modified Rankin score 0-1) | 6 months after randomization | ||
| Secondary | Recanalization rate of cerebral venous system | 6 months | ||
| Secondary | All cause mortality | 6 months | ||
| Secondary | 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) | 6 months | |
| Secondary | 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. | 1 week after randomization | |
| Secondary | Dead or dependency (modified Rankin score 3-6) | 6 and 12 months | ||
| Secondary | Modified Rankin Scale at 1 month after randomization | 1 month after randomization |
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
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N/A |