Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis

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

Interventions

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.

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

Sponsors & Collaborators

• Dutch Heart Foundation

  collaborator OTHER

• Jan Stam, MD, PhD

  lead OTHER

Principal Investigators

• Jan Stam, MD, PhD · University of Amsterdam

• Jose M Ferro, MD, PhD · Hospital Santa Maria, Lisbon, Portugal

• Marie-Germaine Bousser, MD, PhD · Hôpital Lariboisière, Paris, France

• Patricia Canhão, MD, PhD · Hospital Santa Maria, Lisbon, Portugal

• Isabelle Crassard, MD, PhD · Hôpital Lariboisière, Paris, France

• Charles BL Majoie, MD, PhD · University of Amsterdam

• Jim A Reekers, MD, PhD · University of Amsterdam

• E Houdart, MD, PhD · Hôpital Lariboisière, Paris, France

• Rob J de Haan, PhD · University of Amsterdam

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2011-09-30

Primary Completion

2016-12-31

Completion

2017-10-31

Countries

• Canada
• China
• France
• Netherlands
• Portugal
• Switzerland

Study Locations