A Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate With Warfarin in Patients With Cerebral Venous and Dural Sinus Thrombosis (RE-SPECT CVT)

Study Overview
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Brief Summary
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This is a multi-center, prospective, international, randomized (1:1), open-label study with two parallel groups. This phase III study is planned to investigate the efficacy and safety of dabigatran etexilate versus dose-adjusted warfarin on a net clinical benefit endpoint of major bleeding (ISTH criteria) and new venous thrombotic event (VTE) (primary endpoint) with blinded endpoint adjudication.

Official Title
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RE-SPECT CVT: a Randomised, Open-label, Exploratory Trial With Blinded Endpoint Adjudication (PROBE), Comparing Efficacy and Safety of Oral Dabigatran Etexilate Versus Oral Warfarin in Patients With Cerebral Venous and Dural Sinus Thrombosis Over a 24-week Period

Conditions
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Thromboembolism

Intervention / Treatment
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* Drug: Dabigatran etexilate
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Written informed consent in accordance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines and local legislation and/or regulations Confirmed diagnosis of Cerebral Venous or dural sinus thrombosis (CVT), with or without intracranial haemorrhage Completion of anticoagulation therapy for 5-15 days which has been administered until randomisation; anticoagulation must include full-dose low molecular weight heparin or unfractionated heparin Eligibility for treatment with an oral anticoagulant Further inclusion criteria apply Exclusion criteria: Cerebral Venous or dural sinus thrombosis (CVT) associated with central nervous system infection or due to head trauma Planned surgical treatment for CVT Conditions associated with increased risk of bleeding History of symptomatic non-traumatic intracranial haemorrhage with risk of recurrence according to Investigator judgment Treatment with an antithrombotic regimen for an indication other than CVT and requiring continuation of that treatment for the original diagnosis without change in the regimen Severe renal impairment Active liver disease Pregnancy, nursing or planning to become pregnant while in the trial Further exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 78 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dabigatran etexilate<br> | Drug: Dabigatran etexilate<br> <br> |
| Active Comparator: Warfarin<br> | Drug: Warfarin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Composite of Venous Thrombotic Event (VTE) or Major Bleeding Event (MBE) According to International Society on Thrombosis and Haemostasis (ISTH) Criteria in Full Observation Period. | Composite of the percentage of participants with MBE according to ISTH criteria and VTE (recurring cerebral venous thrombosis (CVT); deep venous thrombosis (DVT) of any limb, pulmonary embolism (PE), splanchnic vein thrombosis) in full observation period. All components were adjudicated in a blinded manner. Major bleeds were defined according to the ISTH definition of a major bleed, as follows: Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome and/or Bleeding associated with a reduction in haemoglobin of at least 2 grams/deciLitre (1.24 millimole/Litre) within 24 h, or leading to transfusion of 2 or more units of blood or packed cells and/or Fatal bleed | From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Recurring Cerebral Venous and Dural Sinus Thrombosis; DVT of Any Limb, PE or Splanchnic Vein Thrombosis in Full Observation Period | VTE criterions: New neurological signs/symptoms or worsening of previous signs/symptoms with new CVT on neuroimaging. DVT of any limb was documented by: Abnormal compression ultrasonography; An intraluminal filling defect on venography; At autopsy Splanchnic vein thrombosis: The presence of endoluminal material/absence of flow in the extrahepatic portal veins/mesenteric veins as shown by duplex-Doppler ultrasound/contrast-enhanced CT scan/MRI. PE was documented by: An intraluminal filling defect in segmental/more proximal branches on spiral CT scan; An intraluminal filling defect/an extension of an existing defect/a sudden cut-off of vessels>2.5 mm in diameter on the pulmonary angiogram; Perfusion defect of at least 75% of a segment with a local normal ventilation result on ventilation/perfusion lung scan; Inconclusive spiral CT, pulmonary angiography/lung scintigraphy with demonstration of DVT in the lower extremities by compression ultrasonography/venography; At autopsy. | From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. | 
| Cerebral Venous Recanalisation as Measured by the Change in Number of Occluded Cerebral Veins and Sinuses at Week 24 | Cerebral venous recanalisation was assessed by imaging and was adjudicated. Occlusion of cerebral veins and sinuses was scored as: 1 = full occlusion; 0 = no occlusion/partial occlusion. This score was applied using the below conventions: Superior sagittal, straight, cavernous sinuses, left and right jugular veins each scored individually as either 0 or 1; Right lateral transverse and sigmoid sinus were scored together, Left lateral transverse and sigmoid sinus were scored together, Superior petrous sinus and inferior petrous sinus were scored together; Deep venous system, Superficial cortical veins, Cerebellar veins were scored as systems. For each patient a total score was calculated at baseline and at EOT and the recanalisation score was calculated as EOT - baseline total scores with conventions as 0 = no cerebral veins or sinuses fully occluded and 11 = all cerebral veins and sinuses fully occluded; the lower the score, the better. | Baseline and week 24 | 
| Percentage of Participants With Major Bleeding According to ISTH Criteria in Full Observation Period | Major bleeds were defined according to the ISTH definition of a major bleed, as follows: Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome and/or Bleeding associated with a reduction in haemoglobin of at least 2 grams/deciLitre (1.24 millimole/Litre) within 24 h, or leading to transfusion of 2 or more units of blood or packed cells and/or Fatal bleed | From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. | 
| Composite Endpoint of Percentage of Participants With New Intracranial Haemorrhage or Worsening of the Haemorrhagic Component of a Previous Lesion After up to 24 Weeks | Intracranial haemorrhage (ICH) comprised the subtypes of intracerebral bleeds, subdural bleeds, epidural bleeds and subarachnoid bleeds that were recorded. | From first administration of trial medication until end of treatment visit, up to 24 weeks. | 
| Percentage of Participants With Clinically Relevant Non-major Bleeding Events in Full Observation Period. | A clinically relevant non-major bleeding event (CRNMBE) was a clinically overt bleed that did not meet the criteria for a major bleed but prompted a clinical response, in that it led to at least 1 of the following: A hospital admission (i.e. overnight stay in the hospital) for bleeding / A physician guided medical or surgical treatment for bleeding / A physician guided change, interruption or discontinuation of trial medication. | From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks. | 
| Percentage of Participants With Major Bleeding According to ISTH Criteria or CRNMBEs After up to 24 Weeks | Percentage of participants with major bleeding according to ISTH criteria or CRNMBEs after up to 24 weeks. | From first administration of trial medication until end of treatment visit, up to 24 weeks. | 
| Percentage of Participants With Any Bleeding Event After up to 24 Weeks | Percentage of participants with any bleeding event after up to 24 weeks where any bleeding event is the sum of all major and non-major bleeding events. | From first administration of trial medication until end of treatment visit, up to 24 weeks. |